bims-fibdiv Biomed News
on Fibroblast diversity
Issue of 2026–01–18
fifty papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary
  1. Integrin-mediated adhesion drives microglial entry into the developing CNS.
  2. Targeting Activated Kidney Fibroblasts via Ferroptosis: A Potential Anti-Fibrotic Strategy.
  3. Extracellular Matrix Stiffness Regulates Cancer Stemness in Uveal Melanoma via the PIEZO1-DOT1L Axis.
  4. Research on rhubarb's natural components and their potential for treating chronic kidney disease.
  5. CXCL12 promotes EMT-mediated malignant transformation of endometriosis-associated ovarian cancer via PI3K/Akt signaling: An integrated transcriptomic and clinical study.
  6. Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.
  7. TGFβ/Smad2/3-Mediated Crosstalk Between Vocal Fold Fibroblasts and Myoblasts In Vitro.
  8. 3D mechanical stimulation modulates endothelial exosomes to promote fibroblast activation.
  9. Wnt Signaling Pathway: Biological Function, Diseases, and Therapeutic Interventions.
  10. Protective Effects of Estradiol on Disease Progression in a Murine Model of Fuchs Endothelial Corneal Dystrophy.
  11. A mechanomimetic model of skin fibrosis.
  12. [Extracellular matrix materials and tissue regeneration and repair].
  13. Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L-Mediated p-Smad2/3 Ubiquitination.
  14. Single-nucleus analysis reveals Dengzhan Shengmai capsule prevents cardiac fibrosis after myocardial infarction in rat by targeting Ltbp2+ fibroblast subset.
  15. Regulatory T cells clonally expand and contribute to stromal cell function in fibrotic response to synthetic implants.
  16. Aberrant VEGFR2 supports tumor growth by extracellular matrix remodeling.
  17. Fibroblast circSamd4 promotes cardiac fibrosis via activating plasminogen activator inhibitor-1.
  18. Therapeutic potential of dehydroepiandrosterone in early osteoarthritis: Modulating cartilage ECM stiffness through LOX-RhoA/ROCK/MLC signalling - An in vivo study.
  19. The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells.
  20. Cadmium-induced activation of inflammatory cancer-associated fibroblasts-like cells enhances malignant phenotypes of lung cancer cells.
  21. Matrix Metalloproteinase Inhibition in Melanoma.
  22. Menopause and Dermal White Adipose Tissue Depletion: Mechanistic Links, Adipogenesis, and Regenerative Therapeutic Replacement.
  23. Fibroblast growth factor 9 activates fibroblast activation and drives the progress of shoulder stiffness.
  24. Multifunctional Collagen-Like Protein as a Gene Therapy Vehicle for Biomedical Applications.
  25. Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.
  26. iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ-STAT1 signaling.
  27. A multiscale sarcomere-to-fiber modeling approach for time-dependent uniaxial skeletal muscle mechanics.
  28. Functional inhibition of miR-204-5p elevated during lactation restores Runx2 and enhances osteogenesis in estrogen-deficient bone loss.
  29. The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis.
  30. Grhl3 Downregulation Facilitates ECM Adaptation for Fibroblast to iCM Commitment.
  31. Investigational insights into the potential of angiotensin type II receptor agonists as therapeutics for idiopathic pulmonary fibrosis.
  32. A chalcone-rich extract from licorice root inhibits liver steatosis and fibrosis via regulating PPARα and TGFβ signaling.
  33. Hyperactive BMP and Mechanosignaling Remodel Chromatin to Drive Aberrant Osteogenesis in FOP.
  34. Chondrocyte-Targeted Nanoparticles Loaded with N-Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance.
  35. Shen-Shuai-II-Recipe inhibits aerobic glycolysis through SIRT1 in 5/6 ablation/infarction renal failure model.
  36. Acupuncture Mechanics, Stimulation, and Cellular Serotonin Detection by a Magneto-Responsive Nanomesh Sensor.
  37. Fueling fibrosis: The PBX1-IL7R axis and its role in hepatic stellate cell activation.
  38. Exploring the Role of Cartilage Hypertrophy in Osteoarthritis Progression: A Structural and Biochemical Analysis of Glycosaminoglycan Loss and ECM Integrity.
  39. Mechanism of RNA Oxidation and Its Inhibitor Involved in Ang II-Induced Cardiomyocyte Hypertrophy.
  40. <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>.
  41. Thermosensitive Hydrogel Derived from a Human Amniotic Membrane Promotes Diabetic Wound Healing.
  42. Selectivity screening of cytotoxicity evoked by viper venoms and their toxins after nanofractionation.
  43. The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.
  44. Krüppel-Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment.
  45. Development of a Physiologically Based Model of Bilirubin Metabolism in Health and Disease and Its Comparison With Real-World Data.
  46. Degradation of Elastic Fiber Triggers Lacrimal Gland Dysfunction in Marfan Syndrome Mice.
  47. An In Vitro Ubiquitination Assay to Study Phytoplasmal Effector Function.
  48. Genetic deletion of cytoglobin exacerbates cardiac hypertrophy and inhibits cardiac fibroblast activation independent of changes in blood pressure.
  49. Dietary Quercetin-3-Glucuronide Mitigates Oxidative Stress, Inflammation, and Fibroblast Transition by Regulating Nrf2 and Autophagy in Pulmonary Fibrosis.
  50. Danshen/Huanglian-loaded gelatin/Bletilla striata gum dressings accelerate wound healing in anal fistula by promoting angiogenesis through TGF-β/Smad pathway activation.
  1. Dev Cell. 2026 Jan 14. pii: S1534-5807(25)00767-1. [Epub ahead of print]61(1): 7-8
    Integrin-mediated adhesion drives microglial entry into the developing CNS.
    Fanny Jaudon, Lorenzo A Cingolani.
      In this issue of Developmental Cell, Petry et al. show that early microglial progenitors infiltrate the embryonic CNS via an extracellular matrix (ECM)-rich pial route requiring talin-1-dependent integrin activation. This work revises long-standing vascular entry models and highlights mechanosensitive adhesion as a regulator of early neuroimmune assembly.
    DOI:  https://doi.org/10.1016/j.devcel.2025.12.006
  2. Am J Physiol Cell Physiol. 2026 Jan 14.
    Targeting Activated Kidney Fibroblasts via Ferroptosis: A Potential Anti-Fibrotic Strategy.
    Inga Söerensen-Zender, Rong Song, Julius Sinning, Tamar Kapanadze, Kai M Schmidt-Ott, Anette Melk, Roland Schmitt.
      Kidney fibrosis is characterized by excessive deposition of extracellular matrix, which is ultimately disrupting normal renal architecture. Despite its clinical relevance, no targeted anti-fibrotic therapies are currently available. Myofibroblasts, primarily derived from pericytes and resident fibroblasts, are key effectors of fibrosis due to their high extracellular matrix production. Here, we tested the hypothesis that ferroptosis induction would enable the targeted elimination of activated kidney fibroblasts. We found that kidney fibroblasts exhibit marked sensitivity to ferroptotic cell death upon exposure to the ferroptosis inducer RAS-selective lethal 3 (RSL3), an effect further amplified by TGF-β stimulation. In tissue slice cultures of murine fibrotic kidneys, RSL3 eliminated myofibroblasts without causing overt damage to other cell types. Extending these findings in vivo, we applied a post-ischemia/reperfusion model of kidney fibrosis and demonstrated that repeated low-dose systemic administration of RSL3 significantly reduced the activated fibroblast population without inducing appreciable injury to parenchymal cells. These results provide proof-of-principle that the ferroptosis susceptibility of activated fibroblasts may offer a potential strategy for the selective depletion of profibrotic effector cells in kidney fibrosis.
    Keywords:  ferroptosis; fibroblasts; fibrosis; kidney; tgf-beta
    DOI:  https://doi.org/10.1152/ajpcell.00660.2025
  3. Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 57
    Extracellular Matrix Stiffness Regulates Cancer Stemness in Uveal Melanoma via the PIEZO1-DOT1L Axis.
    Yu Zhang, Jinfeng Cao, Shuyang Zhang, Songtao Wang, Jinrong Cui, Jinsong Zhao.
       Purpose: Cancer stemness drives aggressive behavior and treatment resistance in uveal melanoma (UM). This study aimed to investigate how mechanical signals from the extracellular matrix (ECM) regulated UM stemness through the piezo-type mechanosensitive ion channel component 1 (PIEZO1)-disruptor of telomeric silencing 1-like (DOT1L) signaling axis.
    Methods: PIEZO1 expression was assessed using immunofluorescence in human UM and adjacent normal tissues. Polyacrylamide hydrogel models with tunable stiffness were used to simulate the biomechanical microenvironment in vitro. Stemness was assessed by analyzing colony formation, tumorsphere assays, apoptosis resistance, and expression of the stemness markers NANOG and SOX2. In vivo, ECM stiffness was reduced to examine its effects on UM progression and stemness. The roles of PIEZO1 and DOT1L in ECM stiffness-mediated regulation of stemness were examined both via short-hairpin RNA (shRNA), lentiviral overexpression, and a PIEZO1 agonist.
    Results: PIEZO1 was upregulated in UM tissues. In vitro, increased ECM stiffness enhanced UM stemness through PIEZO1. Functioning as a mechanosensor, PIEZO1 promoted DOT1L expression, which consequently upregulated the stemness markers. In vivo, reduced ECM stiffness suppressed tumor growth and downregulated the PIEZO1-DOT1L axis and stemness markers. Inhibition of PIEZO1 or DOT1L diminished stemness properties and tumor growth both in vitro and in vivo.
    Conclusions: The PIEZO1-DOT1L axis mediated ECM stiffness-driven stemness and tumor progression in UM. Targeting this mechanotransduction pathway by modulating ECM stiffness or its downstream effectors may provide a novel therapeutic strategy for UM.
    DOI:  https://doi.org/10.1167/iovs.66.15.57
  4. Tissue Cell. 2026 Jan 09. pii: S0040-8166(26)00013-3. [Epub ahead of print]99 103321
    Research on rhubarb's natural components and their potential for treating chronic kidney disease.
    Min Chen, Jialin Yao, Zuoli Liu.
      Renal fibrosis, a major pathological alteration in chronic kidney disease, is characterized by several changes, such as excessive extracellular matrix deposition, renal tubular cells' epithelial-mesenchymal transition, and fibroblast proliferation and activation. It has been demonstrated that rhubarb, a possible natural substance, may be used as a regular or supplemental treatment for chronic renal disease. Through a variety of pharmacological actions, including the anti-inflammatory and antioxidant qualities of natural ingredients, it may target renal fibrosis and produce its effects. This article offers fresh concepts for the creation of novel anti-renal fibrosis medications by succinctly introducing the pathological process of renal fibrosis and methodically summarizing the most recent studies on the use of rhubarb's natural constituents to treat renal fibrosis.
    Keywords:  Chronic kidney disease; ECM; EMT; Renal fibrosis; Rhubarb
    DOI:  https://doi.org/10.1016/j.tice.2026.103321
  5. Biol Reprod. 2026 Jan 16. pii: ioag016. [Epub ahead of print]
    CXCL12 promotes EMT-mediated malignant transformation of endometriosis-associated ovarian cancer via PI3K/Akt signaling: An integrated transcriptomic and clinical study.
    Xiaochuan Yu, Lijuan Shi, Zhibo Qi, Qi Chen, Yating Zhang, Huali Wang.
       BACKGROUND: Endometriosis-associated ovarian cancer (EAOC) is a distinct form of epithelial ovarian cancer that arises from the malignant transformation of benign endometriotic lesions. While epithelial-mesenchymal transition (EMT) is acknowledged as a crucial process in the progression of EAOC, the upstream regulatory mechanisms and key molecular drivers are not fully understood. This study focuses on the chemokine CXCL12, its biological function, molecular mechanisms, and clinical prognostic significance in the transition from endometriosis to EAOC.
    METHODS: Differentially expressed genes (DEGs) between benign endometriosis and EAOC tissues were identified using Gene Expression Omnibus (GEO) datasets. CXCL12 emerged as a candidate regulator. To further elucidate the functional role of CXCL12, we conducted in vitro studies by establishing cell models with either CXCL12 overexpression or knockdown. Additionally, we investigated the underlying mechanism of CXCL12's function, focusing on its interaction with the PI3K/Akt signaling pathway and its regulation of downstream EMT-associated proteins. A retrospective analysis of clinical data from 38 EAOC patients was performed to evaluate the association between CXCL12 expression levels and patient prognosis.
    RESULTS: CXCL12 expression was significantly elevated in EAOC tissues compared to benign endometriosis samples and was closely associated with EMT-related phenotypes. In vitro functional assays demonstrated that CXCL12 enhanced cellular migratory and invasive capacities. Mechanistically, CXCL12 was found to induce EMT by activating the PI3K/Akt signaling pathway. Clinical analysis further revealed that high CXCL12 expression was associated with reduced overall survival and increased recurrence risk in EAOC patients. Multivariate Cox regression analysis identified CXCL12 as an independent adverse prognostic factor in EAOC.
    CONCLUSION: This study is the first to systematically define the critical role of CXCL12 in the malignant transformation of endometriosis to EAOC.Our findings demonstrate that CXCL12 promotes tumor cell invasion and metastasis through PI3K/Akt-mediated induction of EMT. These results provide novel insights into the pathogenesis of EAOC and highlight CXCL12 as a promising biomarker for early diagnosis and a potential therapeutic target, offering new avenues for precision management of EAOC.
    Keywords:  CXCL12; EAOC; EMT; Endometriosis
    DOI:  https://doi.org/10.1093/biolre/ioag016
  6. Mol Neurobiol. 2026 Jan 12. 63(1): 357
    Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.
    Yumeng Sun, Chao Huang, Yan Pan, Xudong He, Hao Zhang.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.
    Keywords:  Amyotrophic lateral sclerosis; Biomarker; Extracellular matrix; Fibrosis; Targeted therapies
    DOI:  https://doi.org/10.1007/s12035-025-05658-y
  7. Laryngoscope. 2026 Jan 14.
    TGFβ/Smad2/3-Mediated Crosstalk Between Vocal Fold Fibroblasts and Myoblasts In Vitro.
    Masayoshi Yoshimatsu, Ryosuke Nakamura, Renjie Bing, Gary J Gartling, Aaron M Johnson, Ryan C Branski.
       OBJECTIVES: Traditionally, disorders of the vocal fold (VF) mucosa and underlying musculature have been regarded as mutually exclusive entities. However, emerging evidence from other organ systems suggests mucosal and muscle compartments engage in reciprocal interactions with functional consequences. We hypothesized that similar crosstalk exists in the VF, whereby fibrotic mucosa influences adjacent muscle. To model this process, we stimulated human VF fibroblasts (HVOX) with TGF-β1, a central mediator of fibrosis, and examined the effects on rat VF myoblasts (rVF-Mbs), as well as reciprocal influences of rVF-Mbs on fibroblasts.
    METHODS: HVOX fibroblasts were stimulated with 10 ng/mL TGF-β1, and the effects on rVF-Mbs were assessed using conditioned media and co-culture. Myotube formation was evaluated by immunofluorescence, and nuclear localization of Smad2/3 was examined in conditioned media experiments. qRT-PCR quantified transcripts related to myogenic differentiation and Smad2/3 signaling. ALK4/5 inhibition was performed in co-culture to test TGF-β/Smad2/3-signaling pathway involvement. Reciprocal effects were examined by changes in fibrogenic gene expression in HVOX fibroblasts.
    RESULTS: Both conditioned media and co-culture suppressed myogenic differentiation in rVF-Mbs; increased inhibition was observed in co-culture, as indicated by reduced myotube formation, decreased Myh2 expression, and activation of Smad2/3 signaling. ALK4/5 inhibition abrogated these effects. Differentiating rVF-Mbs attenuated the fibrogenic phenotype of HVOX fibroblasts.
    CONCLUSIONS: Fibrotic VF mucosal cells can impair myogenic differentiation through TGF-β/Smad2/3-mediated fibroblast-myoblast crosstalk, and myogenic cells may exert reciprocal anti-fibrotic effects. These findings suggest mucosa-muscle interactions may contribute to VF pathology and highlight Smad2/3 as a potential therapeutic target.
    LEVEL OF EVIDENCE: NA STUDY DESIGN: In vitro.
    Keywords:  Smad; atrophy; crosstalk; fibroblast; fibrosis; myoblast; transforming growth factor; vocal fold; voice
    DOI:  https://doi.org/10.1002/lary.70366
  8. Tissue Cell. 2026 Jan 12. pii: S0040-8166(26)00008-X. [Epub ahead of print]99 103316
    3D mechanical stimulation modulates endothelial exosomes to promote fibroblast activation.
    Ye Qiu, Zhenkun Lv, Xingying Zhu, Xiaoqian Yang, Jiaming Wan.
       BACKGROUND: Mechanical forces play a crucial role in regulating cellular communication during tissue repair; however, it remains unclear how mechanical stimulation modulates endothelial exosome secretion and its effects on fibroblast activation.
    METHODS: In this study, endothelial cells were incorporated into 3D bioprinted tissue-engineered dermal constructs and cultured under static or mechanically stretched conditions. Exosomes were isolated from these cells, characterised, and applied to human dermal fibroblasts to assess their influence on proliferation, migration, and extracellular matrix formation. Data-independent acquisition proteomics was performed to analyse exosomal protein cargo and associated signalling pathways.
    RESULTS: Mechanical loading increased exosome secretion by approximately 2.5-fold without altering vesicle morphology. Functionally, mechanically stimulated exosomes enhanced fibroblast migration and type I collagen synthesis more significantly than controls. Proteomics profiling identified 4476 proteins in the exosomes, of which 677 were differentially expressed. Enrichment analysis revealed activation of the VEGF, HIF-1, Relaxin, and AGE-RAGE pathways, implicating roles in angiogenesis, metabolic regulation, and extracellular matrix remodelling.
    CONCLUSION: These findings demonstrate that 3D mechanical stimulation not only augments the quantity of endothelial exosomes but also reshapes their molecular cargo, thereby enhancing biomechanical communication between endothelial cells and fibroblasts. Building on prior evidence that fibroblast-derived exosomes promote endothelial angiogenesis, we propose a bidirectional 'mechanical stimulation-exosome-communication-tissue reconstruction' loop, providing a theoretical foundation for optimising exosome-based strategies in skin tissue engineering.
    Keywords:  Endothelial exosomes; Fibroblast activation; Mechanical stimulation; Mechanotransduction
    DOI:  https://doi.org/10.1016/j.tice.2026.103316
  9. MedComm (2020). 2026 Jan;7(1): e70580
    Wnt Signaling Pathway: Biological Function, Diseases, and Therapeutic Interventions.
    Xiaoyu Jin, Jiahui Wang, Runyi Cao, Dongsheng Jiang.
      The Wnt signaling pathway deeply participates in multiple physiological and pathological processes. Its activity is intricately regulated by a diverse network of modulators, reflecting the pathway's structural and functional complexity. Dysregulation of Wnt signaling leads to cellular dysfunction and is associated with a wide spectrum of diseases, among which tissue fibrosis represents a major pathological outcome, characterized by activation of myofibroblasts and subsequent excessive deposition of extracellular matrix in response to injury. Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce. In this review, we provide a comprehensive overview of Wnt pathway components, regulatory mechanisms, and therapeutic approaches. We systematically examine how Wnt signaling governs both developmental processes and pathological conditions, with particular emphasis on its role in fibrosis while also extending discussion to other diseases. Special attention is devoted to the secreted frizzled-related proteins (SFRPs) family, soluble regulators with biphasic, context-dependent effects that are especially relevant in fibrosis. Finally, we summarize insights from preclinical and clinical studies, review advances and challenges in the development of small-molecule compounds targeting Wnt components, highlighting the vital role of SFRPs as promising targets for antifibrotic intervention.
    Keywords:  Wnt signaling; fibrosis; myofibroblast activation; secreted frizzled‐related protein (SFRP); therapeutic targeting
    DOI:  https://doi.org/10.1002/mco2.70580
  10. Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 64
    Protective Effects of Estradiol on Disease Progression in a Murine Model of Fuchs Endothelial Corneal Dystrophy.
    Itsuki Oka, Sohya Fujimoto, Tomohiro Fukui, Kota Mayumi, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Albert S Jun, Noriko Koizumi, Naoki Okumura.
       Purpose: The purpose of this study was to investigate the protective effects of estradiol (E2) on disease progression in Fuchs endothelial corneal dystrophy (FECD) and to explore potential underlying mechanisms.
    Methods: E2-supplemented drinking water was administered to Col8a2Q455K/Q455K mice, a mouse model of FECD. The corneal endothelial phenotype was evaluated using contact specular microscopy. In vitro studies were performed using immortalized FECD (iFECD) cells derived from patients with and without TCF4 triplet repeat expansion to assess the effects of E2 on extracellular matrix (ECM) production and protein aggregation through immunofluorescence, whereas transforming growth factor-beta (TGF-β) signaling and epithelial-mesenchymal transition (EMT)-related factors were evaluated by Western blot analysis.
    Results: E2 treatment significantly reduced guttae formation (0.55 ± 0.23% vs. 0.97 ± 0.22%, P < 0.001) and maintained higher endothelial cell density (2263 ± 177 vs. 2058 ± 118 cells/mm², P = 0.004) in FECD mice compared with untreated controls at 20 weeks of age. In vitro studies demonstrated that E2 suppressed TGF-β2-induced upregulation of ECM proteins (fibronectin, biglycan, and collagen I) and reduced protein aggregation in both iFECD cell lines. Mechanistically, E2 inhibited TGF-β signaling by suppressing Smad2/3 phosphorylation and downregulating EMT-related factors (Snail and ZEB1).
    Conclusions: E2 ameliorates FECD progression by suppressing excessive ECM production. Our in vitro data suggest this protective effect is mediated through the inhibition of the TGF-β-Smad signaling pathway. These findings provide critical in vivo evidence for the therapeutic potential of E2, establishing a strong rationale for its clinical investigation as a novel treatment for FECD.
    DOI:  https://doi.org/10.1167/iovs.66.15.64
  11. Lab Chip. 2026 Jan 12.
    A mechanomimetic model of skin fibrosis.
    Alberto Pappalardo, Deniz Ornek, Laura Garriga Cerda, Charlotte Y Lee, Kristin Myers, Jeffrey W Kysar, Hasan Erbil Abaci.
      Skin fibrosis results from excessive extracellular matrix (ECM) deposition and tissue remodeling due to persistent inflammation and mechanotransduction dysregulation. Current in vivo animal models lack human relevance, while conventional 2D and 3D in vitro models misrepresent physiological mechanical forces. To address this gap, we developed a miniaturized edgeless-skin chip (ESC) platform with gravity-driven perfusion, enabling enhanced biomechanical mimicry for fibrosis modeling. ESCs present bioengineered skin grown around a 3D-printed scaffold, mimicking the continuous geometry of human skin and in vivo mechanical balance. Compared to conventional skin constructs (CSCs) that have open boundaries on all sides, ESCs exhibited higher sensitivity to TGF-β1, leading to increased ECM deposition, myofibroblast activation, YAP signaling upregulation, matrix stiffness and reduced hydraulic permeability. Inhibiting YAP signaling with verteporfin (VTP) reduced collagen deposition, prevented tissue stiffening, and attenuated several fibrosis markers, confirming the role of mechanotransduction in fibrosis progression using human cells. Transcriptome analysis revealed upregulation of fibrosis-associated genes, including COL10A1, COL11A1, and ACTA2, counterbalanced by elevation of anti-fibrotic regulators such as DKK2, which suggests the activation of negative feedback mechanisms. These findings establish the ESC platform as a robust human-relevant mechanomimetic model for studying fibrosis and evaluating anti-fibrotic therapies, addressing a critical need for translational drug discovery.
    DOI:  https://doi.org/10.1039/d5lc00560d
  12. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2026 Jan 15. 40(1): 132-145
    [Extracellular matrix materials and tissue regeneration and repair].
    Longmei Zhao, Huiqi Xie.
      The extracellular matrix (ECM) plays a pivotal role in regulating cellular behavior and driving tissue regeneration. Its unique structural characteristics and bioactivity not only provide physical support for cell growth, but also orchestrate tissue repair and functional reconstruction through multiple signaling pathways. This review systematically synthesizes preparation strategies for natural and engineered ECM materials from the perspective of ECM-mediated tissue regeneration mechanisms, with particular emphasis on recent advances in component preservation, structural biomimicry, and functional optimization. Furthermore, it delves into the application potential of cutting-edge technologies-including artificial intelligence, flexible electronics, and organoids-in ECM engineering, while critically analyzing the standardization and safety challenges hindering clinical translation. This article aims to provide a theoretical foundation and reference for constructing next-generation ECM-based regenerative medicine platforms.
    Keywords:  Extracellular matrix; application challenges; architectural optimization; biological functionality
    DOI:  https://doi.org/10.7507/1002-1892.202511037
  13. Acta Physiol (Oxf). 2026 Feb;242(2): e70163
    Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L-Mediated p-Smad2/3 Ubiquitination.
    Meng Li, Luosha Long, Xiaoduo Zhao, Xi Yuan, Minghui Wang, Jinyi Lin, Long Xu, Xinyan Wu, Ruiqi Bai, Suchun Li, Weidong Wang, Wei Chen, Lihe Lu, Chunling Li.
       AIM: Renal fibrosis is a major contributor to chronic kidney disease (CKD) progression and eventual organ failure. G protein-coupled bile acid receptor 1 (TGR5) was previously shown to have beneficial effects on kidney diseases. The current study aimed to investigate whether TGR5 activation prevents kidney fibrosis and to clarify the underlying mechanism.
    METHODS: TGR5 expression was examined in human fibrotic kidneys. Two animal models of renal fibrosis were used: unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury with contralateral nephrectomy (uIRIx) in wild-type and TGR5 knockout mice. Renal histology, extracellular matrix (ECM) deposition, and renal function were examined. In vitro studies were performed on human proximal tubular HK2 cells by treating them with transforming growth factor-β1 and TGR5 agonists/antagonists.
    RESULTS: TGR5 was significantly downregulated in fibrotic human kidneys. In both UUO and uIRIx models, TGR5 activation by lithocholic acid alleviated renal fibrosis, reduced ECM deposition, and improved kidney function. Conversely, Tgr5 knockout in mice exacerbated fibrotic injury. Mechanistically, TGR5 activation prevented fibrosis development, probably by enhancing NEDD4L-mediated ubiquitination and degradation of phosphorylated Smad2/3 by inhibiting the upstream PI3K-SGK1 pathway.
    CONCLUSION: TGR5 activation protects against renal fibrosis by inhibiting the PI3K-SGK1-NEDD4L axis and promoting p-Smad2/3 degradation.
    Keywords:  NEDD4L; PI3K‐SGK1 pathway; TGR5; chronic kidney disease; p‐Smad2/3; renal fibrosis; ubiquitination
    DOI:  https://doi.org/10.1111/apha.70163
  14. Phytomedicine. 2026 Jan 07. pii: S0944-7113(26)00048-6. [Epub ahead of print]151 157811
    Single-nucleus analysis reveals Dengzhan Shengmai capsule prevents cardiac fibrosis after myocardial infarction in rat by targeting Ltbp2+ fibroblast subset.
    Maolin Wang, Jie Zhao, Liangliang Tian, Guangzhao Cao, Yu Chen, Jinlong Tan, Jing Xu, Shuyu Liao, Hongbo Wu, Jingjing Zhang, Hongjun Yang.
       BACKGROUND: Cardiac fibrosis is a distinguishing hallmark of ischemic heart diseases with limited therapeutic options due to the incomplete comprehension of cellular heterogeneity. Our previous research demonstrated that Dengzhan Shengmai capsule (DZSMC) could significantly attenuate myocardial fibrosis, yet its cell-type-specific targets remain elusive.
    OBJECTIVES: This work aimed to investigate the mechanisms of DZSMC on cardiac fibrosis in post-myocardial infarction (MI) rats at single-cell resolution.
    METHODS: MI rats were produced by ligating the left anterior descending artery. DZSMC (97.2 mg/kg) and captopril (4.5 mg/kg) were administered orally for four weeks following MI. Cardiac function was assessed by echocardiography. Histopathological analysis was employed via hematoxylin-eosin and Masson's trichrome staining. The overall cell profiles in MI rat hearts were analyzed by single-nucleus RNA sequencing (snRNA-seq). In vitro, the role of latent transforming growth factor beta binding protein 2 (Ltbp2) was confirmed by small interfering RNA targeting Ltbp2 (siLtbp2) in primary cardiac fibroblasts (CFs).
    RESULTS: DZSMC substantially enhanced cardiac function and attenuated pathological myocardial fibrosis in post-MI rats. snRNA-seq analysis of 28,317 nuclei from Sham, Model and DZSMC group hearts revealed ten distinct cell types. Notably, CFs exhibited the most pronounced transcriptomic alterations after DZSMC intervention. Re-clustering of CFs identified eight subsets. Interestingly, cluster 5 CFs specifically exhibited high expression of Ltbp2, along with elevated levels of Tgfb1, col1a1, and col3a1. This sub-population was functionally enriched in extracellular matrix organization and TGF-β signaling. Ltbp2 knockdown attenuated angiotensin II (Ang II) induced CFs activation and down-regulated the expression of TGF-β and pSmad3. Furthermore, DZSMC treatment significantly inhibited Ltbp2 expression and TGF-β signaling both in vitro and in vivo.
    CONCLUSIONS: This study reveals Ltbp2 as a novel fibroblast-specific target for cardiac fibrosis and DZSMC exerts its anti-fibrotic effects by targeting Ltbp2+ CFs.
    Keywords:  Cardiac fibrosis; Cellular heterogeneity; Dengzhan shengmai capsule; latent transforming growth factor beta binding protein 2; snRNA-seq
    DOI:  https://doi.org/10.1016/j.phymed.2026.157811
  15. bioRxiv. 2026 Jan 06. pii: 2026.01.05.697727. [Epub ahead of print]
    Regulatory T cells clonally expand and contribute to stromal cell function in fibrotic response to synthetic implants.
    Joscelyn C Mejías, Kavita Krishnan, Anna Ruta, A Shri Ramanujam, Elise F Gray-Gaillard, Locke Davenport Huyer, David R Maestas, Sushma Nagaraj, Frank Haoning Yu, Alexandra N Rindone, Peter Abraham, Maria Browne, Elana J Fertig, Drew M Pardoll, Jennifer H Elisseeff.
      Fibrosis plays a key role in both chronic disease progression and failure of synthetic biomaterial implants. However, the contribution of adaptive immunity to fibrotic development remains incompletely understood, particularly for regulatory T cells (Tregs). Here, we used single-cell multiomic profiling, integrating transcriptomics with T cell receptor (TCR) sequencing, to map Treg heterogeneity and clonal dynamics in a synthetic material-induced model of fibrosis. We uncovered progressive Treg clonal expansion accompanied by TCR activation signatures and an increasingly immunosuppressive phenotype along a continuous transcriptional trajectory. These Tregs suppressed immune responses and influenced extracellular matrix and vascular gene expression. Cell-cell communication inference predicted Treg-driven activation of pro-fibrotic and vasculogenic transcriptional programs in fibroblasts and endothelial cells, including Sox-family transcription factors. Functional Treg depletion increased inflammation and significantly reduced neovascularization. Together, these findings identify Treg functions in the fibro-vascular niche through stromal cell modulation, highlighting immune-stromal interactions as an important axis in fibrosis.
    DOI:  https://doi.org/10.64898/2026.01.05.697727
  16. Cell Death Dis. 2026 Jan 15.
    Aberrant VEGFR2 supports tumor growth by extracellular matrix remodeling.
    Michela Corsini, Cosetta Ravelli, Mattia Domenichini, Anna Ventura, Camilla Maggi, Elisa Moreschi, Mirko Tamma, Chiara Romani, Claudia Piccoli, Elisabetta Grillo, Stefania Mitola.
      The extracellular matrix shapes tumor architecture, cell behavior and therapy response. Here, we identify aberrant activation of the receptor tyrosine kinase VEGFR2 as a driver of tumor-promoting ECM remodeling in melanoma and ovarian cancer. ECM alterations in terms of composition and organization were observed in Sk-Mel-31 melanoma xenografts expressing the oncogenic VEGFR2R1032Q and in ovarian tumors with VEGFR2 hyperactivation. Down-modulation of VEGFR2 normalized ECM architecture. Decellularized ECM from VEGFR2R1032Q melanoma cells directly modified the behavior of VEGFR2WT tumor cells, increasing monolayer fluidity and mitochondrial activation. Transcriptomic profiling revealed a dysregulation of genes involved in ECM structure and remodeling, mediated by the PI3K-AKT and ERK pathways. Pharmacological inhibition of VEGFR2 with tyrosine kinase inhibitors, such as lenvatinib, partially reverted ECM alterations in vitro and in vivo, reducing matrix deposition and modifying its organization. These data identify VEGFR2 as a regulator of tumor ECM dynamics and suggest that its inhibition may restore ECM organization, offering a therapeutic strategy to reprogram the tumor microenvironment and limit cancer progression.
    DOI:  https://doi.org/10.1038/s41419-025-08404-3
  17. Redox Biol. 2026 Jan 09. pii: S2213-2317(26)00016-9. [Epub ahead of print]90 104018
    Fibroblast circSamd4 promotes cardiac fibrosis via activating plasminogen activator inhibitor-1.
    Yan Chen, Zhewei Zhang, Yue Cheng, Xiaofeng Chen, Junteng Zhou, Zisong Wei, Han Yao, Shuwen Zhang, Qihang Kong, Hao Tang, Wenchao Wu, Zhichao Zhou, Xiaoqiang Tang, Xiaojing Liu.
      Cardiac fibrosis remains an unresolved clinical issue in patients with heart diseases. CircRNAs have emerged as potential targets for treatment of heart diseases. Exploring the functional circRNAs in fibroblast activation is one of the ways to develop innovative drugs for the treatment of cardiac fibrosis. This study aimed to screen for fibroblast-related circRNAs in cardiac fibrosis and elucidate their roles and underlying mechanisms. By screening for fibrosis-responsible circular RNAs (circRNAs), we identified a highly conserved circRNA, circular RNA Sterile alpha motif domain containing 4 (circSamd4), that drives cardiac fibrosis. circSamd4 is prominently expressed in cardiac fibroblasts (CFs) and is upregulated in the fibrotic hearts of humans and mice. Fibroblast-specific silencing of circSamd4 reduced cardiac fibroblast activation and alleviates cardiac fibrosis. Conversely, overexpression of circSamd4 in fibroblasts exacerbates cardiac fibrosis and rescues cardiac function. Bioinformatics and functional analyses revealed that circSamd4 regulates the plasminogen activation. Plasminogen activator inhibitor-1 (PAI-1, encoded by Serpine1) is a key effector of plasminogen activation and redox homeostasis and contributes to fibrotic diseases. Here, PAI-1 serves as a leading functional downstream factor of circSamd4 because PAI-1 is highly expressed in cardiac fibroblasts and contributes to circSamd4 functions in regulating fibroblast activation and cardiac fibrosis. Mechanistically, circSamd4 functions as a sponge for miR-1894-3p to trigger Serpine1 expression and subsequent fibroblast activation, and cardiac fibrosis. Therefore, we identified a fibroblast-specific circSamd4-miR-1894-3p-Serpine1 axis driving fibroblast activation and cardiac fibrosis. Adeno-associated virus (AAV)-mediated knockdown of circSamd4 or Serpine1 alleviated cardiac fibrosis and cardiac dysfunction. These findings suggest that circSamd4 and Serpine1 are promising therapeutic targets for inhibiting cardiac fibrosis.
    Keywords:  Cardiac fibrosis; CircSamd4; Fibroblast; Serpine1; miR-1894-3p
    DOI:  https://doi.org/10.1016/j.redox.2026.104018
  18. J Steroid Biochem Mol Biol. 2026 Jan 12. pii: S0960-0760(26)00002-6. [Epub ahead of print]258 106936
    Therapeutic potential of dehydroepiandrosterone in early osteoarthritis: Modulating cartilage ECM stiffness through LOX-RhoA/ROCK/MLC signalling - An in vivo study.
    Kai Huang, Haili Cai, Cheng Jiang, Chunwei Zheng.
      Osteoarthritis (OA) is characterized by progressive cartilage degeneration and extracellular matrix (ECM) stiffening, yet effective disease-modifying therapies remain limited. This study evaluated the chondroprotective effect of dehydroepiandrosterone (DHEA) in early OA and elucidated its underlying mechanisms. Using rabbit and mouse models, we demonstrated that intra-articular DHEA administration attenuated cartilage damage, reduced catabolic enzyme expression, and preserved ECM elasticity. Mechanistically, DHEA downregulated lysyl oxidase (LOX), suppressed activation of the RhoA/ROCK/MLC signaling cascade, and thereby mitigated ECM stiffening. The protective effects were partly dependent on LOX inhibition, suggesting a dual regulatory mechanism. These findings identify DHEA as a potential disease-modifying agent that targets LOX-RhoA/ROCK/MLC signaling to maintain cartilage homeostasis in early OA, warranting further clinical investigation.
    Keywords:  Dehydroepiandrosterone; Extracellular matrix stiffness; Lysyl oxidase; Osteoarthritis; RhoA/ROCK/MLC pathway
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.106936
  19. Cell Signal. 2026 Jan 09. pii: S0898-6568(26)00008-2. [Epub ahead of print] 112359
    The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells.
    Tao Shu, Ning Luo, Yuqi Shu, Jingyan Wei, Hongxin Niu, Qicai Liu.
      Renal fibrosis is a primary pathological feature of chronic kidney disease, with a current lack of effective treatments. In this study, we observed that Limb-bud and Heart (LBH) expression was upregulated in kidney specimens obtained from patients with chronic kidney disease. During UUO-induced renal fibrosis, both the protein level and mRNA level of LBH were significantly elevated. Furthermore, knockdown of the mouse LBH gene significantly ameliorated renal fibrosis. The application of inhibitors, agonists, and knockout mouse models uniformly verified the role of LBH in alleviating both endoplasmic reticulum stress (ERS) and pyroptosis. Although renal tubular epithelial cells (RTECs) are conventionally considered the initial responders to renal fibrosis, the role and mechanism of LBH in these cells during disease progression remain unclear. Therefore, this study focused on investigating LBH's effects in damaged RTECs. Mechanistic studies demonstrated that within renal tubular epithelial cells, LBH significantly attenuates renal fibrosis by forming a positive feedback loop with TGFβ1 and ERS. This activated ERS subsequently further induces pyroptosis and partial epithelial-mesenchymal transition (pEMT), thereby promoting renal fibrosis. Importantly, LBH deficiency was shown to significantly attenuate renal fibrosis. These collective findings strongly suggest that LBH may constitute a promising therapeutic target for the treatment of renal fibrosis.
    Keywords:  ERS; LBH; Pyroptosis; Renal fibrosis; pEMT
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112359
  20. Food Chem Toxicol. 2026 Jan 08. pii: S0278-6915(26)00001-3. [Epub ahead of print]210 115927
    Cadmium-induced activation of inflammatory cancer-associated fibroblasts-like cells enhances malignant phenotypes of lung cancer cells.
    Qi Jiang, Lujiao Wang, Biyun Chen, Tianyi Dong, Wanyou Shen, Xue Zhou.
      Cancer-associated fibroblasts (CAFs), as key stromal components of the tumor microenvironment (TME), exert profound influences on tumor progression by secreting cytokines, exosomes, and remodeling the extracellular matrix (ECM). Cadmium (Cd), a hazardous heavy metal, is strongly associated with lung carcinogenesis through environmental and occupational exposure. However, the molecular mechanisms underlying Cd-induced activation of fibroblasts and their functional contributions to lung cancer development remain poorly understood. Our study demonstrated that acute Cd exposure promoted the transformation of normal fibroblasts (MRC-5 cells) into an inflammatory CAFs-like (iCAFs) phenotype through upregulation of fibroblast activation protein (FAP). This Cd-driven FAP overexpression was accompanied by upregulated IL-6 and CCL2 release. Functionally, Cd-activated iCAFs-like cells significantly promoted the proliferation, migration, and invasion of lung cancer cell lines (H460 and A549) via paracrine signaling. Notably, FAP knockdown in MRC-5 cells using siRNA abrogated Cd-induced secretion of inflammatory factors and reversed the tumor-promoting effects of Cd-activated fibroblasts on cancer cells, establishing FAP as a central mediator of Cd-driven stromal reprogramming. These findings uncover a novel mechanism by which environmental Cd exposure exacerbates lung cancer progression through FAP-dependent fibroblast activation. Furthermore, they identify FAP as a potential therapeutic target for mitigating Cd-induced carcinogenesis, with implications for environmental toxin-associated cancer prevention and treatment.
    Keywords:  Cadmium; Cancer-associated fibroblasts; FAP; Lung cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.fct.2026.115927
  21. Exp Dermatol. 2026 Jan;35(1): e70203
    Matrix Metalloproteinase Inhibition in Melanoma.
    Ellie Zhang, Varsha Thakur, Barbara Bedogni.
      Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix (ECM) and are found to participate in all stages of tumour progression including modifying signalling pathways, regulating cytokines and promoting tumour growth, particularly by inducing angiogenesis and facilitating cancer spread. Extensive research has been concentrated on identifying and developing MMP inhibitors for cancer treatment, including melanoma, with particular focus on MMP-2, MMP-9 and MMP-14. MMP-2 and MMP-9 are gelatinases involved in collagen degradation, tumour invasion and angiogenesis, while MMP-14 activates other MMPs and promotes tumour cell migration. Early broad-spectrum MMP inhibitors showed limited success and significant side effects. However, selective MMP inhibitors offer a more targeted approach that may address these problems. By focusing on specific MMPs essential for melanoma invasion, metastasis and angiogenesis, these inhibitors have the potential to improve treatment efficacy and reduce the off-target effects seen with earlier broad-spectrum therapies. Recent years have seen a marked increase in studies on natural MMP inhibitors for melanoma, driven by their biocompatibility and reduced side effects. In addition to inhibiting MMPs, many of these inhibitors also provide antioxidant, anti-inflammatory and immune-modulatory benefits, thus enhancing their therapeutic potential and overall effectiveness in cancer treatment. These findings highlight the promising role of MMP inhibitors in melanoma therapy, suggesting a shift towards more targeted and combinatory treatment strategies. This review aims to provide an up-to-date overview of the advancements and therapeutic prospects of both synthetic and natural MMP inhibitors in melanoma treatment.
    Keywords:  extracellular matrix; matrix metalloproteinase inhibitors; matrix metalloproteinases; melanoma
    DOI:  https://doi.org/10.1111/exd.70203
  22. J Cosmet Dermatol. 2026 Jan;25(1): e70671
    Menopause and Dermal White Adipose Tissue Depletion: Mechanistic Links, Adipogenesis, and Regenerative Therapeutic Replacement.
    Alan D Widgerow, Mary E Ziegler, Faiza Shafiq.
       BACKGROUND: Menopause is linked to typical skin changes such as textural alterations, loss of skin hydration, elasticity, thinning, and increased fragility. Dermal white adipose tissue (dWAT), a distinct fat component located in the dermis and involved in hair cycle regulation, antimicrobial peptide production, and extracellular matrix (ECM) modulation, decreases with aging and photodamage. Emerging evidence suggests that estrogen contributes to an inhibitory effect on dWAT and promotes fibrotic remodeling of adipose tissue of the dermis.
    OBJECTIVE: To examine the mechanistic evidence linking menopause with the loss of dWAT and to suggest and highlight potential strategies for replacing dWAT with agents such as magnolol, which promote the conversion of pre-adipocytes to adipocytes and restore lost fractions of the dWAT compartment.
    METHODS: A review of the literature, a mechanistic examination, a histologic examination, and a clinical trial assessment were conducted.
    RESULTS: The loss of dWAT and fibrotic replacement are likely a factor causally linked to the decrease in estrogen observed during menopause. Reduced dWAT produces fewer adipokines such as adiponectin, which is directly involved in skin health by promoting collagen and hyaluronic acid (HA) production. Evidence suggests that select non-hormonal agents can offer a potential therapeutic benefit to menopausal skin promoting dWAT restoration through adipogenic pathways.
    CONCLUSION: dWAT depletion likely contributes to menopausal skin changes. Potential candidates for non-hormonal alternatives to address these menopausal concerns are discussed in this paper.
    Keywords:  adipogenesis; adiponectin; dermal white adipose tissue; estrogen deficiency; extracellular matrix; magnolol; menopause; perilipin‐1; skin aging
    DOI:  https://doi.org/10.1111/jocd.70671
  23. Front Cell Dev Biol. 2025 ;13 1731453
    Fibroblast growth factor 9 activates fibroblast activation and drives the progress of shoulder stiffness.
    Jian Xu, Weihan Yu, Yunkang Kang, Dongqiang Yang, Yanlong Liu, Wenzhi Bi, Haiyang Yu, Beijie Qi, Biao Guo.
       Background: Shoulder stiffness (SS) is a common disease that causes pain and restricted range of motion (ROM), involving synovial inflammation and joint capsule fibrosis. The specific pathogenesis of SS remains unclear. This study aimed to delineate the key molecular driving capsule fibrosis in SS.
    Methods: Joint capsule samples from SS and non-SS patients were collected, and high-throughput RNA sequencing along with bioinformatic analysis were performed. A mouse SS model was established via joint immobilization. Functional and immunofluorescence assay were conducted on NIH3T3s. LY294002 was used both in NIH3T3s and mouse SS models.
    Results: Transcriptomic analysis identified 100 differentially expressed genes (DEGs). Among the top hub genes, FGF9 was notably upregulated in the SS capsules. In vitro, FGF9 promoted NIH3T3s migration, proliferation, and α-SMA expression, effects that were reversed by LY294002. In vivo, intra-articular LY294002 injection reduced capsule thickening, fibrosis, and improved passive ROM in SS mice.
    Conclusion: Our findings revealed that FGF9 drove fibroblast activation and joint capsule fibrosis in SS via the PI3K/Akt signaling pathway. Targeted inhibition of the PI3K/Akt signaling might represent a promising therapeutic strategy for SS.
    Keywords:  FGF9; PI3K/AKT; fibrosis; shoulder stiffness; transcriptomics
    DOI:  https://doi.org/10.3389/fcell.2025.1731453
  24. Cell Biochem Funct. 2026 Jan;44(1): e70154
    Multifunctional Collagen-Like Protein as a Gene Therapy Vehicle for Biomedical Applications.
    Gopalan Akilandeswari, Niraikulam Ayyadurai.
      Gene therapy, utilizing a protein-based delivery system, offers a promising alternative to viral vectors owing to their stability, cell specificity, and adaptability. This study investigates the potential of collagen, a key extracellular matrix (ECM) component, as a gene delivery vehicle. While natural collagens play a crucial role in tissue regeneration, their high molecular weight limit efficient cellular uptake. To overcome this, we engineered a collagen-like protein (CLP) containing G-X-Y repeats mimicking type I collagen and retaining its functional properties. Furthermore, mussel adhesive protein (MAP) with histone-like characteristics is capable of delivering foreign genetic material into mammalian cells. We hypothesize that fusing CLP with MAP, would synergize the ECM-binding of collagen with the cationic property of MAP, enhancing gene delivery efficiency. The recombinant fusion protein was successfully expressed in E. coli and purified. The fusion protein exhibited strong DNA binding ability similar to MAP and the protein-DNA complex remained stable even in the presence of serum and DNase enzyme. The in vitro transfection studies substantiate the potential of CLP-MAP to deliver plasmid DNA in NIH-3T3 cells. Our findings indicate that the CLP-MAP fusion protein is effective in DNA binding and biocompatible, positioning it as a promising novel gene delivery system.
    Keywords:  Collagen‐like protein; DNA binding; fusion protein; mussle adhesive protein
    DOI:  https://doi.org/10.1002/cbf.70154
  25. Apoptosis. 2026 Jan 10. 31(1): 18
    Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.
    Yu-Mei Gan, Nai-Shen Qin, Jun Ouyang, Yu-Ming Tang, Jia-Hui Qin, Shu-Min Wei, Hui Wang, Jiang-Nan Huang.
      The pathogenesis of atherosclerosis (AS) is a chronic disease marked by inflammation, and there are intimate associations with various forms of programmed cell death (PCD). Recently, the mechanisms of pyroptosis and autophagy in AS have attracted much attention. Pyroptosis is a form of PCD mediated by inflammasomes, which worsens local inflammatory responses by releasing proinflammatory factors (e.g., IL-18 and IL-1β) and favors plaque instability and thrombosis. Autophagy is a process that helps to keep cells healthy by breaking down damaged cell structures and abnormal proteins. Mitophagy, a specialized form of autophagy, is of major importance to redox homeostasis and the regulation of inflammation. However, the dysregulation of autophagy may disturb the cellular homeostasis, which then accelerates the progression of AS. Studies have found a complex mutual regulation between pyroptosis and autophagy. Autophagy can block the occurrence of pyroptosis by degrading the components of such as NLRP3. The inflammatory mediators released during pyroptosis may cause the disorder of autophagy, which aggravates the cell death and inflammatory response. The disorder of autophagy will also promote pyroptosis' occurrence and progress. Both of them play a vital role in AS. This study is mainly focused on clarifying the relationship and molecular mechanism between pyroptosis and autophagy in the context of AS. These findings pave the way for new avenues for understanding its pathogenesis and potentially therapeutic decision-making.
    Keywords:  Atherosclerosis; Autophagy; Inflammation; Mitophagy; Pyroptosis
    DOI:  https://doi.org/10.1007/s10495-025-02221-x
  26. Life Sci. 2026 Jan 13. pii: S0024-3205(26)00020-2. [Epub ahead of print] 124212
    iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ-STAT1 signaling.
    Laiping Zhang, Jie Liu, Xiao Guan, Boshi Liu, Ying Liu, Weinian Shou, Xin Chen, Xiaohui Li, Dayan Cao.
       AIMS: With the extensive application of immunotherapy in treating cancer, the immunotherapy-related cardiovascular toxicity (ITR-CVT) has gotten a rapid recognition due to its high mortality. Previously, we have found that potential cancer immunotherapies based on promoting iNKT cell activation exacerbate ISO-induced cardiac injury, but the underlying mechanism is unknown. The current study is to determine which specific cell type/s and the corresponding molecular pathways are responsible for such a cardiotoxicity.
    MATERIALS AND METHODS: Transcriptome sequencing and bioinformatic analysis were performed on heart tissues from an enhanced cardiac injury model following iNKT cell activation via α-Galactosylceramide (αGC). The role of IFN-γ-STAT1 signaling was validated using IFN-γ antibody blocking and JAK-STAT1 chemical inhibition. The experiments of Macrophage isolation and depletion were conducted to assess cell-specific contributions. In vitro co-culture experiments with αGC-primed macrophages and fibroblasts were conducted under STAT1 inhibition or silencing. Tumor-bearing mice were also examined.
    KEY FINDINGS: Transcriptome analysis identified IFN-γ-STAT1 signaling as central to the enhanced cardiac injury, blocking IFN-γ or inhibiting STAT1 could attenuate the injury. Macrophages were identified as the main source of IFN-γ-STAT1 activation, and their depletion significantly reversed cardiac injury exacerbation. In vitro, STAT1 inhibition or silencing reduced fibroblast activation induced by αGC-primed macrophages. In tumor-bearing mice, αGC also further exacerbated cardiac injury.
    SIGNIFICANCE: These findings revealed that the activation of STAT1 in cardiac macrophages via IFNγ critically contributes to cardiotoxicity induced by iNKT-immunotherapy, which provides a potential method to manage ITR-CVT in patients.
    Keywords:  Cardiovascular toxicity; IFN-γ; STAT1; iNKT cells
    DOI:  https://doi.org/10.1016/j.lfs.2026.124212
  27. Acta Biomater. 2026 Jan 08. pii: S1742-7061(26)00019-X. [Epub ahead of print]
    A multiscale sarcomere-to-fiber modeling approach for time-dependent uniaxial skeletal muscle mechanics.
    Maxime Hoyaux, Abderrahman Tamoud, Tang Gu, Fahmi Zaïri, Fahed Zaïri.
      A comprehensive understanding of skeletal muscle mechanics requires models that reflect its hierarchical structure and biophysical complexity. This study presents a multiscale continuum model grounded in sarcomere-level mechanisms and extending to the whole-muscle fiber scale under uniaxial loading conditions. Key structural components - including aligned myofibrils, helically oriented collagen fibers, and isotropic matrices such as the proteoglycan-rich extracellular matrix and muscle fiber membrane - are embedded in a composite framework that separates and integrates anisotropic and isotropic mechanical contributions. Based on a network decomposition strategy, myofibrils are divided into actin-myosin weak bindings and titin filaments, each modeled as a distinct macromolecular network. A network alteration framework models both subsystems as dynamic internal variables, with stiffness evolving through stretch-dependent recruitment and rate-sensitive kinetics. A non-affine deformation concept captures the asynchronous engagement of sarcomeric elements, providing a microstructural basis for delayed stiffness development. Though primarily focused on the uniaxial passive response, the model includes a minimal active term to explore how activation modulates stiffness through shared structural pathways. The formulation reproduces key passive features - including nonlinear stiffening, rate sensitivity, and relaxation - using time-dependent internal variables and microstructural recruitment. The model reproduced experimental data from human and animal muscle fibers across various loading protocols, showing strong agreement at both fiber and tissue scales. By linking molecular processes to macroscopic mechanics without relying on phenomenological viscoelastic terms, the model offers a computationally efficient and physiologically grounded tool for exploring skeletal muscle behavior under normal and altered conditions. STATEMENT OF SIGNIFICANCE: Accurately modeling skeletal muscle mechanics remains a major challenge due to the tissue structural complexity, time-dependent behavior, and scale-bridging physiological processes. This study introduces a multiscale continuum model that integrates sarcomere-level macromolecular mechanisms - namely titin unfolding/refolding, passive actin-myosin interactions, and non-affine filament engagement - into a computationally tractable tissue-scale formulation. By combining statistical mechanics-based representations of filament networks with dynamic internal variables, the model captures key experimental phenomena such as stress relaxation, strain-rate sensitivity, and nonlinear stiffening without relying on phenomenological viscoelastic laws. The approach is broadly applicable to musculoskeletal modeling and provides a biophysically interpretable framework for simulating healthy and diseased muscle, with direct relevance for tissue engineering, rehabilitation, and the study of degenerative muscle pathologies.
    Keywords:  Actin-myosin weak binding; Multiscale muscle modeling; Non-affine deformation; Time-dependent passive mechanics; Titin unfolding
    DOI:  https://doi.org/10.1016/j.actbio.2026.01.010
  28. Biomed Pharmacother. 2026 Jan 15. pii: S0753-3322(26)00010-7. [Epub ahead of print]195 118978
    Functional inhibition of miR-204-5p elevated during lactation restores Runx2 and enhances osteogenesis in estrogen-deficient bone loss.
    Anirban Sardar, Divya Rai, Shikha Verma, Bhaskar Maji, Anuj Raj, Ritu Trivedi.
      MicroRNAs (miRNAs) have emerged as critical regulators of diverse physiological processes, including skeletal remodeling. In our previous study, we identified miR-204-5p as significantly elevated in bone tissue during peak lactation, a physiological state characterised by transient osteoporosis due to low circulating estrogen levels. Given the similarity in hormonal changes observed during menopause, we investigated the putative role of miR-204-5p in regulating postmenopausal bone loss in this study. Functional assays demonstrated that miR-204-5p directly targets the 3' untranslated region of Runx2, a key transcription factor for osteoblast differentiation, and thus it recruits the target mRNA to the RNA-Induced Silencing Complex (RISC), as demonstrated in luciferase reporter and RNA immunoprecipitation (RNA-IP) assays. The miR-204-5p suppresses its identified target, Runx2, in a synergy of a combination of post-transcriptional mechanisms. Experimental evidence suggests that by enhancing the decay rate of the Runx2 mRNA and by impairing the protein turnover rate, the miRNA impedes its proposed target. Additionally, CRISPR/Cas9-mediated genetic manipulation of the studied miRNA further validated its regulatory role on osteoblast differentiation in vitro. In an ovariectomy-induced preclinical model of menopause, elevated miR-204-5p expression was found to be positively correlated with the bone loss, indicating its role in contributing to the pathophysiology of osteoporosis. Further studies confirm that the targeted inhibition of this miRNA restores the Runx2 expression and partially ameliorates the bone loss. Collectively, our findings establish miR-204-5p as a key modulator of estrogen-deficient bone loss and suggest that its inhibition may open more exciting and innovative strategies for osteoporosis prevention.
    Keywords:  CRISPR/Cas9; Menopause; MicroRNA therapeutics; Osteoporosis; Pre-miRNA; SgRNA
    DOI:  https://doi.org/10.1016/j.biopha.2026.118978
  29. Cell Signal. 2026 Jan 09. pii: S0898-6568(26)00011-2. [Epub ahead of print]140 112362
    The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis.
    Xianglian Wang, Jia He, Simeng Shen, Manwei Li, Siyi Yuan, Wei Xu, Shu Zhu, Yan Ding, Xiuli Wang.
      Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.
    Keywords:  Endometriosis; Fibroblast-to-myofibroblast transition; Fibrosis; Insulin-like growth factor-binding protein (IGFBP); Transforming growth factor-β (TGF-β)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112362
  30. Circ Res. 2026 Jan 15.
    Grhl3 Downregulation Facilitates ECM Adaptation for Fibroblast to iCM Commitment.
    Xin Wu, Lanbing Liu, Yuanru Huang, Yi Ling, Fang Luo, Dongyu Gu, Mengxin Liu, Zhenhua Jia, Zhangyi Yu, Xiangjie Kong, Hong Ma, Yanggan Wang, Li Wang.
       BACKGROUND: Direct cardiac reprogramming offers a promising therapeutic strategy for heart regeneration by converting endogenous fibroblasts to functional induced cardiomyocytes (iCMs) that integrate into the myocardium to restore heart structure and function. While ECM (extracellular matrix) plays critical roles in cardiac disease and repair, the dynamic changes and transcriptional regulation underlying ECM remodeling during reprogramming remain poorly understood.
    METHODS: We investigated ECM dynamics during iCM reprogramming using integrated transcriptomic, proteomic, and epigenetic analyses, focusing on cell type-specific ECM components. A loss-of-function screen was used to identify critical ECM components and regulators, including Itga8 (integrin alpha-8) and Grhl3 (grainyhead-like protein 3 homolog), respectively, as reprogramming barriers. Mechanistic studies integrated RNA sequencing, mass spectrometry, and Cleavage Under Targets and Tagmentation to define Grhl3-dependent regulation. Functional outcomes were evaluated in vitro using decellularized ECM and in vivo using a myocardial infarction model with genetic lineage tracing.
    RESULTS: Cardiac reprogramming induced dynamic ECM remodeling, with significant changes in collagen, fibrillar proteins, and integrins. Itga8 was identified as a pivotal ECM component that restricts iCM conversion via the TGF-β (transforming growth factor-β)/SMAD pathway. Grhl3 emerged as a key transcriptional regulator for ECM components, including Itga8. ECM derived from Grhl3-deficient fibroblasts enhanced iCM induction, while Grhl3 depletion also reduced fibroblast activation and increased cellular plasticity. These effects synergized with TF (transcription factor)-mediated reprogramming to improve iCM efficiency, structural organization, and functional maturation. In vivo, removing Grhl3 enhanced fibroblast-to-cardiomyocyte conversion, reduced scar formation, and improved cardiac function after myocardial infarction.
    CONCLUSIONS: Our findings establish ECM adaptation as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.
    Keywords:  cell plasticity; extracellular matrix; myocardial infarction; myocytes cardiac; transforming growth factors
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327726
  31. Expert Opin Investig Drugs. 2026 Jan 14. 1-11
    Investigational insights into the potential of angiotensin type II receptor agonists as therapeutics for idiopathic pulmonary fibrosis.
    Olivia N Young, Robert E Widdop, Jane E Bourke.
       INTRODUCTION: Current standard-of-care for idiopathic pulmonary fibrosis is limited to nintedanib and pirfenidone, which only slow the progressive loss of lung function and have significant adverse effects that are intolerable to many patients. There is therefore a significant unmet need for alternative treatments for this incurable disease.
    AREAS COVERED: This review describes emerging evidence implicating dysregulation of the renin-angiotensin system in IPF pathogenesis, and both pre-clinical and recent clinical data supporting activation of the anti-fibrotic AT2R as a promising therapeutic strategy. The efficacy of AT2R agonists across pre-clinical models of both IPF and relevant lung diseases is discussed, with a particular focus on favorable findings with the AT2R agonist C21 (buloxibutid), leading to its current clinical trials for IPF.
    EXPERT OPINION: Rapid translation of C21 (now named buloxibutid), the first-in-class orally available AT2R agonist, to early phase clinical trials for IPF have established its safety and disease-modifying potential. Ongoing development of novel, more highly selective AT2R agonists may deliver the same clinical benefit as C21 with reduced off-target effects. The AT2R drug class offers great promise as novel therapeutics, potentially extending beyond IPF to other inflammatory and fibrotic lung diseases.
    Keywords:  C21; Idiopathic pulmonary fibrosis; buloxibutid; fibrosis; inflammation; lung
    DOI:  https://doi.org/10.1080/13543784.2026.2616755
  32. Phytomedicine. 2025 Dec 28. pii: S0944-7113(25)01383-2. [Epub ahead of print]151 157749
    A chalcone-rich extract from licorice root inhibits liver steatosis and fibrosis via regulating PPARα and TGFβ signaling.
    Ying Tang, Baibo Xie, Yuqing Zhang, Shi Li, Haifeng Liu, Bojun Wang, Xiaohong Ye, Hu Zhou, James Hua Zhou.
       BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major liver disorder, which seriously affects human health globally. However, there are currently no satisfactory treatments for MASLD. The extraction of licorice root (Glycyrrhiza inflata Bat.) has multiple therapeutic effects, but it has not yet been fully explored for its therapeutic potential to liver steatosis and fibrosis. In addition, the active component of licorice root extract responsible for the therapeutic efficacy for MASLD is waiting for identified.
    PURPOSE: This study aimed to clarify the therapeutic effects of Z018B, an active component rich in chalcones from licorice root extraction, on fatty liver and liver fibrosis and to unravel the underlying molecular mechanism as well.
    METHODS: Two etiology-driven animal models including high fat diet (HFD)- and CCl4-induced rat models were employed to assess the therapeutic efficacy of Z018B on liver steatosis and fibrosis. Liver histology was evaluated by using immunohistochemistry, artificial intelligence (AI)-based second harmonic generation (SHG) analysis and MASH clinical research network (CRN) scoring system. The pathologic serum indexes were determined by biochemistry assays. Concurrently, in vitro studies were conducted to investigate the inhibitory effects of Z018B on steatosis by using an oleic acid-stimulated cell-based steatosis model and on fibrosis by using a TGFβ-induced hepatic stellate cell (HSC) activation model. The specific mRNA levels regulated by Z018B were analyzed by RT-PCR assay, while the specific protein levels regulated by Z018B were analyzed by western blotting and immunofluorescence assays. The functional molecular dependency of Z018B was determined by siRNA-mediated knockdown as well as by specific inhibitors.
    RESULTS: Z018B component rich in chalones was separated from the total extract of licorice root. In an HFD-induced rat fatty liver model, Z018B effectively inhibited the development of hepatic steatosis. In an HFD and CCl4-induced rat liver steatosis and fibrosis model, Z018B potently attenuated both the hepatic steatosis and fibrosis. Mechanistically, Z018B component contains activators of PPARα and it activated PPARα to stimulate the SIRT1-AMPK-ACC axis to reduce lipid accumulation in hepatocytes. Z018B also inhibited TGFβ-induced activation of HSCs by inhibiting the expression of Smad3.
    CONCLUSION: Our study demonstrates that Z018B component from licorice root is a potent inhibitor of hepatic steatosis and fibrosis, potentially through the activation of PPARα and inhibiting TGFβ/Smad signaling pathways. Thus, our study clarifies the therapeutic efficacy of licorice root on MASLD by employing multiple mechanisms. Importantly, our study unravels the active component - Z018B and highlights the synergistic therapeutic effect of different active substances in Z018B. The potent therapeutic effect of Z018B on MASLD warrants its further development.
    Keywords:  PPARα; SIRT1; Smad3; TGFβ; Z018B; fatty liver; licorice root; liver fibrosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157749
  33. bioRxiv. 2026 Jan 05. pii: 2026.01.05.697733. [Epub ahead of print]
    Hyperactive BMP and Mechanosignaling Remodel Chromatin to Drive Aberrant Osteogenesis in FOP.
    Ellen Y Zhang, Douglas W Roberts, Sang Hyun Lee, Bat-Ider Tumenbayar, Jaeun Jung, Loreilys Mejías Rivera, Inkyung Jung, Robert L Mauck, Eileen M Shore, Su Chin Heo.
      Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a recurrent ACVR1 (R206H) mutation drives progressive heterotopic ossification (HO). While aberrant BMP hypersensitivity has been studied, how this mutation enforces a persistent pro-osteogenic state remains unclear. Here, we combined super-resolution stochastic optical reconstruction microscopy (STORM), transposase-accessible chromatin with sequencing (ATAC-Seq), and RNA sequencing (RNA-Seq) to investigate how Acvr1 R206H remodels chromatin to promote osteogenic transcriptional programs. Mutant mouse embryonic fibroblasts (MEFs) exhibited globally decondensed chromatin and increased accessibility at developmental and osteogenic loci enriched for HOX, TEAD, and RUNX motifs. Integration of ATAC-Seq and RNA-Seq data identified transcriptional networks primed for osteochondrogenic gene expression, including ossification, extracellular matrix organization, and cell adhesion pathways, consistent with enhanced BMP-SMAD and mechanotransduction activity. Time-course experiments revealed heightened responses to BMP ligands in Acvr1 R206H/+ MEFs compared to wild-type, highlighting ligand hypersensitivity. Importantly, pharmacological modulation showed that chromatin alterations were dynamic and reversible: activation of Rho/ROCK in wild-type cells reproduced the mutant chromatin state, while inhibition of Rho/ROCK or BMP-SMAD signaling restored condensation to wild-type levels in mutant cells. Together, these findings establish that Acvr1 R206H enforces a pro-osteogenic chromatin landscape through convergent BMP-SMAD and Rho/ROCK signaling, predisposing progenitors to aberrant differentiation trajectories. Our study reframes FOP as a disorder of persistent, but reversible, chromatin states and identifies novel therapeutic opportunities to restore mesenchymal cell homeostasis and prevent pathological bone formation.
    Significance Statement: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a mutation in ACVR1/ALK2 drives progressive heterotopic ossification. However, how this mutation enforces a persistent pro-osteogenic state is unclear. Here, we show that the Acvr1 R206H mutation remodels chromatin architecture and accessibility through hyperactive BMP-SMAD and Rho/ROCK signaling, activating transcription factor networks that drive osteochondrogenic gene expression. These chromatin changes are dynamic and reversible with targeted pathway inhibition, revealing therapeutic potential to restore mesenchymal cell plasticity and prevent pathological bone formation.
    DOI:  https://doi.org/10.64898/2026.01.05.697733
  34. Small Sci. 2026 Jan;6(1): e202500440
    Chondrocyte-Targeted Nanoparticles Loaded with N-Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance.
    Shaoyi Wang, Fujian Zhang, Xiaocong Zhou, Jie Yang, Zhe Li, Songlin Li, Qunshan Lu, Houyi Sun, Peilai Liu.
      Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation. Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While N-acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte-targeted, chondroitin sulfate (CS)-modified PLGA nanoparticles (CS-NAC-NPs) is developed for sustained and localized delivery of NAC. These nanoparticles exhibit excellent physical and chemical properties, biocompatibility, and chondrocyte targeting capabilities. In vitro, CS-NAC-NPs attenuated mechanical stress-induced ROS accumulation, preserved mitochondrial integrity, restored GSH levels, and suppressed ferroptosis, as evidenced by increased GPX4 expression and improved chondrocyte viability. In a murine model of OA, intraarticular injection of CS-NAC-NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC-NPs. Notably, the therapeutic effect is abolished in GPX4-deficient mice, confirming that CS-NAC-NPs act via GPX4-mediated ferroptosis inhibition. Furthermore, in vivo tracking demonstrated excellent joint retention and no off-target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox-responsive delivery to modulate ferroptosis, offering a promising disease-modifying approach for OA treatment.
    Keywords:  N‐acetylcysteine; ferroptosis; glutathione; nanoparticle; osteoarthritis
    DOI:  https://doi.org/10.1002/smsc.202500440
  35. Sci Rep. 2026 Jan 11.
    Shen-Shuai-II-Recipe inhibits aerobic glycolysis through SIRT1 in 5/6 ablation/infarction renal failure model.
    Tianying Lan, Xinyue Zhang, Xiao Lyu, Ming Wu, Chen Wang, Liuyi Yang.
      Renal fibrosis is the common pathological feature of chronic kidney diseases, which is in parallel with increasing energy demand in proximal tubular epithelial cells during the metabolic shift from fatty acid oxidation to glycolysis. Shen-Shuai-II-Recipe (SSR) is a traditional Chinese medicine formula with known renal benefits in patients with chronic kidney disease (CKD) and has been shown to intervene in renal energy metabolism in a rodent model of CKD. We aimed to explore the mechanism underlying the protective effect of SSR against CKD. A 5/6 ablation/infarction (A/I) renal failure model was established in rats, followed by 8 weeks of gavage feeding with SSR or Losartan, a positive control. For in vitro experiments, normal rat kidney-52E (NRK-52E) cells were cultured under hypoxic condition (1% O2) or normoxic condition. The expression of fibrotic markers and aerobic glycolysis-related enzymes were determined by Western blotting analysis. The concentration of metabolites was also measured. The concentration of lactic acid was increased, and the concentration of pyruvic acid was decreased in vitro and in vivo models, which were correlated with increased expression of glycolysis-related enzymes Hexokinase2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), SSR treatment reversed the changes of renal glycolysis in cells and animals, which was associated with reduced expression of fibrotic markers such as fibronectin and α-SMA. Mechanistically, SSR treatment enhanced the expression of Sirtuin 1 (SIRT1) and reduced the expression of Hypoxia-Inducible Factor 1-alpha (HIF-1α) in vitro and in vivo models. Downregulation of SIRT1 by small interfering ribonucleic acid (siRNA) reversed the anti-fibrotic effect and anti-glycolysis effect of SSR in renal cells. SSR exerts an anti-fibrotic effect and inhibits renal aerobic glycolysis in CKD via the regulation of SIRT1/HIF-1α.
    Keywords:  Aerobic glycolysis; CKD; Renal fibrosis; SIRT1
    DOI:  https://doi.org/10.1038/s41598-026-35061-z
  36. Small. 2026 Jan 15. e11914
    Acupuncture Mechanics, Stimulation, and Cellular Serotonin Detection by a Magneto-Responsive Nanomesh Sensor.
    Kai-Qi Jin, Qi-Yu Long, Jun-Lin Liu, Tian-Cai Sun, Kai-Kai Sheng, Yi Zhao, Wen-Ting Fan, Guo-You Huang, Wei-Hua Huang, Yan-Ling Liu.
      Acupuncture exerts its therapeutic effects through complex mechanical cues, including compressive forces from needle insertion and retention, and tensile stresses from extracellular matrix deformation during needle twisting. How these biomechanical stimuli regulate mast cell function at the molecular level remains poorly understood due to the lack of tools capable of replicating such multifaceted forces. Here, we report a magneto-responsive biosensor that enables multimodal simulation of stretching, compression, and combined loading in both static and cyclic modes. This allows for closely recapitulating the mechanical environment of mast cells during acupuncture, while simultaneously monitoring mechanically evoked cellular serotonin (5HT) release in real time. Using this sensor, we demonstrate that cyclic combined stimulation significantly amplifies cell responses by promoting both 5-HT release and intracellular biosynthesis. Furthermore, in vivo experiments at acupoints confirmed the "release-replenishment" phenomenon observed in vitro. Collectively, this study provides mechanistic insights into the molecular basis of acupuncture therapy and establishes a versatile tool for probing mechanobiological regulation in living systems.
    Keywords:  acupuncture; cell mechanotransduction; electrochemical sensor; magneto‐responsive; serotonin
    DOI:  https://doi.org/10.1002/smll.202511914
  37. Hepatology. 2026 Feb 01. 83(2): 197-198
    Fueling fibrosis: The PBX1-IL7R axis and its role in hepatic stellate cell activation.
    Hanna Erickson.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000001624
  38. Macromol Biosci. 2026 Jan;26(1): e00467
    Exploring the Role of Cartilage Hypertrophy in Osteoarthritis Progression: A Structural and Biochemical Analysis of Glycosaminoglycan Loss and ECM Integrity.
    Chandrashish Roy, Arti Sharma, Juhi Chakraborty, Soumik Siddhanta, Sourabh Ghosh.
      It is a matter of debate whether chondrocytse hypertrophy is an active driver of age-related Osteoarthritis (OA) or a passive consequence of OA. Understanding the progression of hypertrophy can be crucial in developing effective disease-modifying therapeutics. To clarify this, we investigated biochemical signatures associated with human healthy cartilage and hypertrophic reactivation in human OA cartilage using a multimodal spectroscopic approach. Healthy adult cartilage and OA samples spanning different disease stages were analyzed using ATR-FTIR, XPS, Raman spectroscopy, DMMB and hydroxyproline assays, along with histology. Across all modalities, OA cartilage exhibited distinct molecular features consistent with a hypertrophic-like shift: pronounced GAG depletion, collagen network disruption, loss of collagen-specific spectral peaks, and elevated oxidative modifications in the ECM. Quantitative assays confirmed reduced GAG and total collagen content, aligning with biochemical patterns observed during endochondral maturation. Raman profiles further captured molecular rearrangements linked to matrix mineralization pathways typically associated with hypertrophic differentiation. Histological evaluation validated the progressive ECM disorganization and GAG loss, reinforcing the spectroscopic findings. Overall, these integrated results suggest that in OA, chondrocyte hypertrophy is not merely a passive consequence, but OA reflects a modified reactivation of endochondral ossification.
    Keywords:  X‐ray photoelectron spectroscopy (XPS) ; attenuated total reflectance‐fourier transform infrared spectroscopy (ATR‐FTIR); dimethyl methylene blue (DMMB) assay; extracellular matrix (ECM); glycosaminoglycans (GAGs); osteoarthritis (OA)
    DOI:  https://doi.org/10.1002/mabi.202500467
  39. Aging Med (Milton). 2025 Dec;8(6): 612-623
    Mechanism of RNA Oxidation and Its Inhibitor Involved in Ang II-Induced Cardiomyocyte Hypertrophy.
    Tong Liu, Jin Bian.
       Objectives: To explore the mechanism of RNA oxidation and its inhibitor MTHI involved in cardiomyocyte hypertrophy.
    Methods: The hypertrophic H9c2 cardiomyocytes were stimulated with different concentrations and times of Ang II (Ang II) to construct a model of hypertensive heart failure in vitro. Transfection of H9c2 cells with the MTH1 overexpression plasmid was performed. The mRNA expression of ANP, BNP, and β-MHC in each experimental group was detected by PCR. The expression of 8-oxoG in H9c2 cells was determined by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). The activation of the ERK-MAPK pathway and the amount of MTH1 protein were detected by WB semi-quantitative method.
    Results: Notably, RNA oxidation is a critical event in cellular senescence, and its accumulation is strongly linked to the aging process and the development of age-related diseases. In our model of cardiomyocyte hypertrophy, the oxidative damage of RNA was aggravated, and the expression of MTH1 was increased. At the same time, the sequence of ERK-MAPK pathway proteins was activated. It can be seen that the oxidative damage of RNA is related to the process of cardiomyocyte hypertrophy. After transfection of the MTH1 overexpression plasmid into the cardiomyocyte hypertrophy model, we found that the amount of 8-oxoG decreased, and the activation of ERK-MAPK signaling pathway proteins decreased, and H9c2 cell hypertrophy decreased. Therefore, we concluded that 8-oxoG may aggravate the hypertrophy of the cardiomyocyte hypertrophy model by activating the ERK-MAPK pathway.
    Conclusion: The oxidative damage of RNA is involved in the process of cardiomyocyte hypertrophy. The mechanism may be that 8-oxoG, a product of RNA oxidation, activates the downstream ERK-MAPK signaling pathway. These findings provide new perspectives for further exploration into the role of RNA oxidation in the pathogenesis of age-related diseases, particularly heart failure.
    Keywords:  8‐oxoG; ERK–MAPK; RNA oxidation; cardiomyocyte hypertrophy
    DOI:  https://doi.org/10.1002/agm2.70057
  40. Int J Mol Med. 2026 Mar;pii: 62. [Epub ahead of print]57(3):
    <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>.
    Chang Gao, Guiqing Chen, Hongyan Jia, Hong Zhu, Yun Cai, Dakai Yang, Kai Zhao.
      <p>Hepatic stellate cells (HSCs), specialized liver‑resident pericytes, play pivotal roles in both liver fibrogenesis and regeneration. Following hepatic injury, quiescent HSCs undergo activation and transdifferentiation into myofibroblasts, which drive tissue remodeling and scar formation. Recent advances have uncovered notable phenotypic and functional heterogeneity within HSC populations, with distinct subsets displaying context‑dependent activation states and specialized functions across diverse liver pathologies. The present review synthesizes current insights into the dynamic spectrum of HSC phenotypes and the molecular mechanisms governing their plasticity, emphasizing the mechanisms through which niche‑specific signaling, epigenetic regulation and metabolic reprogramming coordinate their functional diversity. The present review further discuss emerging therapeutic strategies that leverage this heterogeneity to selectively target pathogenic HSC subsets, while preserving their homeostatic roles, thereby opening new avenues for precision anti‑fibrotic therapies and liver regeneration.</p>.
    Keywords:  hepatic stellate cells; heterogeneity; precision targeting; spatial‑temporal regulation
    DOI:  https://doi.org/10.3892/ijmm.2026.5733
  41. ACS Biomater Sci Eng. 2026 Jan 14.
    Thermosensitive Hydrogel Derived from a Human Amniotic Membrane Promotes Diabetic Wound Healing.
    Pratibha Jaipal, Sunil Gujjar, Shubhanshi Ranjan, Manisha Kumari, Bhisma N Panda, Priyanka Sharma, Jagadish C Sharma, Anil K Pandey, Santosh Mathapati.
      Extracellular matrix (ECM) hydrogels are recognized as promising biomaterials for regenerative medicine owing to their ability to recapitulate the native tissue microenvironment. The human amniotic membrane (AM), readily available and posing little to no ethical concerns, is rich in ECM components with inherent wound-healing potential. This study aimed to develop and characterize thermosensitive hydrogels derived from a decellularized AM and assess their therapeutic potential for diabetic wound healing. The native AM was subjected to detergent-enzymatic decellularization to remove the cellular content while preserving the essential ECM. The resulting acellular AM was lyophilized, cryomilled, and digested with pepsin under acidic conditions at three different concentrations. The pregel solutions were neutralized and thermally induced to form AM ECM hydrogels at 37 °C. The physicochemical properties, including gelation kinetics, swelling, porosity, mechanical stiffness, and biodegradation, were evaluated. The biological evaluation was assessed using fibroblasts, keratinocytes, and endothelial cells through live/dead staining, the MTS assay, and analyses of ROS production, apoptosis, cytoskeletal organization, and cell migration. Proteomic profiling was conducted to identify the retained matrisome proteins. The in vivo performance was tested in a diabetic murine full-thickness wound model. AM ECM hydrogels exhibited temperature-dependent gelation (t1/2: ∼12.75-27 min), high water content (>97%), and >60% porosity. All formulations supported >70% cell viability at 24 h and >300% proliferation at 72 h, with negligible ROS production, minimal apoptosis, and preserved cytoskeletal integrity. The proteomic analysis confirmed the maintenance of matrisome proteins related to epithelial differentiation, angiogenesis, and tissue repair. The in vivo study demonstrated that the AM ECM hydrogel accelerated wound healing, evidenced by early wound closure, along with vascular stabilization, regulated inflammatory response, and ECM stabilization compared to those of the control group. These findings collectively demonstrate that AM ECM hydrogel treatment in diabetic mice ameliorates wound pathology, as evidenced by reduced severity, a modulated inflammatory response, and decreased fibrotic burden.
    Keywords:  amniotic membrane; biomimetic; cell–matrix interaction; extracellular matrix (ECM); placenta
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c01299
  42. Toxicon. 2026 Jan 14. pii: S0041-0101(25)00744-5. [Epub ahead of print] 108969
    Selectivity screening of cytotoxicity evoked by viper venoms and their toxins after nanofractionation.
    Haifeng Xu, Mátyás A Bittenbinder, Julien Slagboom, Nicholas R Casewell, Paul Jennings, Jeroen Kool.
      Cytotoxicity is a major pathological effect that can occur during snakebite envenoming. To better understand the underlying biochemical and molecular mechanisms behind snake venom-induced cytotoxicity, it is essential to use appropriate in vitro tools for bioassaying cytotoxicity evoked by snake venoms. Identifying the toxins causing cytotoxicity is also important in this regard, particularly in the context of developing more effective snakebite treatments. Cytotoxicity induced by venom toxins can result in local pathologies in snakebite victims, which can result in long-term morbidity, and is frequently observed after bites by medically important vipers. In the present study, we optimized and applied an analytical cytotoxicity profiling platform for in vitro cytotoxicity assessment of viper venoms. Using four cell lines (RPTEC/TERT1, HepaRG, iPSC-EC, HaCat), we applied an imaging analysis assay together with resazurin reduction to identify the mechanisms of cytotoxicity at the level of cell necrosis, extracellular matrix (ECM) degradation and/or cell apoptosis. Strong cytotoxic peaks are consistent with ECM-associated cytotoxic effects, as reflected by pronounced reductions in cell area and monolayer integrity. These cytotoxicity bioassays were integrated into nanofractionation analytics and high throughput venomics, which allowed for the identification of viper venom cytotoxins at the biological and chemical levels. Venom profiling showed ECM degradation as the main cytotoxic mechanism, except for Daboia russelii, which induced necrosis and apoptosis in three cell lines. Cytotoxicity largely disappeared after reversed-phase separation, prompting use of non-denaturing SEC in nanofractionation analytics, which revealed strong cytotoxic peaks for Bothrops jararaca and Calloselasma rhodostoma in RPTEC/TERT1 cells. The methodology presented here combined analytical and biochemical tools allowing rapid cytotoxicity profiling of viper venom toxins in parallel with toxin identification.
    Keywords:  High-throughput venomics; In vitro human cell line; Nanofractionation analysis; Toxicovenomics; Viper snake venom
    DOI:  https://doi.org/10.1016/j.toxicon.2025.108969
  43. FEBS J. 2026 Jan 14.
    The ALS-associated E425K mutation uncouples DNAJC7 from the Hsp70 chaperone cycle.
    Bar Elmaleh, Ofrah Faust, Rina Rosenzweig.
      DNAJC7, a member of the J-domain protein (JDP/Hsp40) family, plays a key role in protein homeostasis by regulating Hsp70 activity and preventing protein aggregation. Mutations in DNAJC7 have been linked to amyotrophic lateral sclerosis (ALS); yet, the molecular mechanisms by which these variants impair chaperone function remain poorly understood. DNAJC7 is a conserved chaperone featuring both a canonical J-domain, essential for Hsp70 activation, and three TPR domains, which serve as protein-protein binding interfaces. Here, we investigate the structural and functional consequences of the ALS-associated E425K mutation located within the conserved J-domain. Using NMR spectroscopy, we show that although the E425K mutation does not alter the structure of the protein, it significantly disrupts the conserved J-domain-Hsp70 interaction. We further identify a second Hsp70-binding interface within the TPR domains, which interacts with the C-terminal EEVD motif of Hsp70. This TPR-EEVD interaction is preserved in the E425K mutant but cannot compensate for the loss of J-domain binding or restore DNAJC7-dependent Hsp70 activation. Functionally, we show that the TPR domains of DNAJC7 directly bind TDP-43 and prevent its aggregation and that this holdase activity is retained in the E425K mutant. However, the mutant fails to support client transfer to Hsp70 and the subsequent Hsp70-mediated substrate refolding. Together, these findings demonstrate that DNAJC7 requires coordinated action of both J-domain and TPRs to regulate Hsp70 function and that disruption of J-domain-mediated activation uncouples DNAJC7 from the Hsp70 cycle, providing a mechanistic basis for its dysfunction in ALS.
    Keywords:  ALS; DNAJC7; Hsp70; Molecular chaperones; NMR spectroscopy
    DOI:  https://doi.org/10.1111/febs.70395
  44. Cancer Med. 2026 Jan;15(1): e71498
    Krüppel-Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment.
    Min Tang, Binle Tian, Jingyi Zhou, Di Ma, Rongze Sun, Qi Li.
       OBJECTIVE: Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays context-dependent roles in cancer. It functions as either a tumor suppressor or an oncogene depending on tumor type and cellular context. This review aimed to comprehensively summarize the roles of KLF4 in the tumor microenvironment (TME) and evaluate its potential as a therapeutic target.
    METHODS: We conducted a comprehensive literature review to elucidate the expression patterns, regulatory mechanisms, and functional roles of KLF4 across different TME components, including cancer cells, immune cells, cancer-associated fibroblasts, pericytes, and extracellular matrix.
    RESULTS: KLF4 exhibits dual roles in cancer cells, acting as a tumor suppressor in gastric, lung, and pancreatic cancers while promoting oncogenesis in breast, colorectal, and prostate cancers. In the TME, KLF4 regulates macrophage polarization (M1/M2), T-cell exhaustion, NK cell activity, and MDSC recruitment. Additionally, KLF4 modulates CAF activation and ECM remodeling. KLF4 expression is regulated by miRNAs, lncRNAs, and epigenetic modifications. Emerging therapeutic strategies targeting KLF4, such as APTO-253, show promise in preclinical and early clinical trials.
    CONCLUSIONS: KLF4 serves as a hub gate orchestrating cell crosstalk within the TME. Understanding its context-dependent functions may facilitate the development of KLF4-targeted therapies for precision oncology.
    Keywords:  KLF4; cancer; immune cells; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.71498
  45. CPT Pharmacometrics Syst Pharmacol. 2026 Feb;15(2): e70183
    Development of a Physiologically Based Model of Bilirubin Metabolism in Health and Disease and Its Comparison With Real-World Data.
    Ahenk Zeynep Sayin, Lars Kuepfer.
      Bilirubin is a breakdown product of erythrocytes and plays a crucial role in elimination of heme-containing proteins. After its synthesis in the reticuloendothelial system, unconjugated bilirubin is released into plasma and taken up into the liver. In hepatocytes, bilirubin is conjugated and excreted into the gastrointestinal tract via bile, where it is further converted to urobilinoids. There are various genetic factors causing abnormal bilirubin levels in plasma, such as Gilbert syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, and Rotor syndrome. To better understand bilirubin metabolism and its disorders, this study develops a physiologically based computational model incorporating published literature as well as real-world clinical data from the Explorys database. The model simulates bilirubin levels in both healthy individuals and patients with disorders of bilirubin metabolism. Population simulations show that Gilbert syndrome requires a substantial reduction in UDP-glucuronosyltransferase 1A1 activity, while Crigler-Najjar syndrome requires near-complete loss of its function. In contrast, Dubin-Johnson syndrome is characterized by a significant impairment of multidrug resistance-associated protein 2 activity. To also illustrate model behavior under targeted perturbations, we simulated administration of atazanavir in healthy individuals and patients with Gilbert syndrome to investigate its effect on bilirubin levels. Relative to baseline, unconjugated bilirubin maximum concentration (Cmax) increased by 34% in healthy individuals but by 67% in Gilbert syndrome. Overall, this study provides a conceptual and mechanistically informed framework for studying bilirubin homeostasis and the functional consequences of drug administration in health and disease.
    Keywords:  PBPK; bilirubin; disorders of bilirubin metabolism; interindividual variability; population simulation; real‐world data
    DOI:  https://doi.org/10.1002/psp4.70183
  46. Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 63
    Degradation of Elastic Fiber Triggers Lacrimal Gland Dysfunction in Marfan Syndrome Mice.
    Bing Xiao, Leyi Hu, Xinyu Zhang, Liyan Liu, Charlotte Young, Xinxin Liu, Qian Ye, Danying Zheng, Lingyi Liang, Guangming Jin.
       Purpose: Elastic fibers constitute essential elements of the extracellular matrix (ECM) in the lacrimal gland (LG), yet their influence on tear secretion is not fully elucidated. This study examined the impact of elastic fibers on LG secretory function in a Marfan syndrome (MFS) mouse model, characterized by inherent elastic fiber defects.
    Methods: Alterations of the ocular surface in female MFS mice along with their control strains were assessed using a phenol red test for tear production and fluorescein staining for corneal integrity. The LGs were harvested and processed for histology, immunohistochemistry, transcriptional profiling, and Western blotting.
    Results: MFS mice exhibited reduced tear production and corneal epithelial defects. Morphologically, a yellow-brown appearance was observed, along with vacuole formation, atrophied acini with dense collagen deposition, and increased infiltration of inflammatory cells in the LG. Furthermore, a decrease in elastic fiber integrity, accompanied by collagen fiber accumulation within the ECM of LG, was noted. Additionally, decreased expression of vesicle-trafficking GTPase (Rab3D) and α<@150>smooth muscle actin in the acini of MFS mice was associated with impaired lacrimal secretion. Notably, TGF-β signaling was activated in the LG of MFS mice. RNA sequencing analysis revealed immune activation and ECM dysfunction as core pathological features.
    Conclusions: Abnormalities of elastic fibers in LG ECM due to fibrillin-1 deficiency can lead to inflammatory and fibrotic disorders and ultimately LG dysfunction.
    DOI:  https://doi.org/10.1167/iovs.66.15.63
  47. Methods Mol Biol. 2026 ;3008 171-198
    An In Vitro Ubiquitination Assay to Study Phytoplasmal Effector Function.
    Margot Raffeiner.
      The attachment of one or more ubiquitin molecules onto a target substrate, ubiquitination for short, is a posttranslational modification that determines its correct further processing within a eukaryotic cell. Ubiquitination was shown to be a central player in the regulation of many cellular processes from protein degradation to protein sorting (e.g., endocytosis), DNA repair, or other non-proteolytic pathways. Because of its importance in maintaining cellular homeostasis, it is not surprising that, in the course of evolution, pathogens, including plant pathogens such as phytoplasma, have developed strategies to manipulate ubiquitination of host targets to their own benefit. Manipulation includes the translocation of so-called effector proteins that themselves ubiquitinate host targets, thereby mediating their subsequent degradation to dampen host immune responses.The identification and characterization of phytoplasmal effector proteins that ubiquitinate target substrates, as well as the detection of a target ubiquitination is crucial to understand phytoplasma-associated pathogenesis.Here, we provide an easy-to-follow protocol adapted from a method described by Furlan and Trujillo (2017) to study the in vitro E3 ligase activity potential of phytoplasma effector proteins. Additionally, this protocol allows to study the in vitro ubiquitination of putative target substrates by phytoplasma effectors.
    Keywords:  Effector proteins; Effector targets; In vitro ubiquitination; Phytoplasma; Posttranslational modification; Ubiquitin
    DOI:  https://doi.org/10.1007/978-1-0716-5104-9_14
  48. bioRxiv. 2026 Jan 07. pii: 2026.01.06.697990. [Epub ahead of print]
    Genetic deletion of cytoglobin exacerbates cardiac hypertrophy and inhibits cardiac fibroblast activation independent of changes in blood pressure.
    Le Gia Cat Pham, Kurrim Gilliard, Frances Jourd'heuil, Sarahann Mistretta, John J Schwarz, Harold A Singer, David Jourd'heuil.
      Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressure. The present work aims to determine the role of Cygb in angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in the mouse.
    Methods: Males and females global Cygb knockout (Cygb -/- ), and wildtype ( Cygb +/+ ) mice were treated with Ang II (1.5 µg/kg/day) for two weeks via subcutaneous osmotic minipumps. Cardiac function was assessed through echocardiography, and hearts were analyzed for changes in hypertrophy, fibrosis, and gene expression. Functional studies were also performed in isolated cardiac fibroblasts.
    Results: Cygb-/- mice from both sexes showed an increase in cardiac hypertrophy over Cygb +/+ mice. Cardiac functions were also depressed in Cygb -/- males with no changes in females. Importantly, genetic deletion of Cygb did not affect systemic blood pressure in mice, at baseline or after Ang II treatment. We established that Cygb was expressed in fibroblasts and pericytes in humans and mice hearts. Finally, we found that Cygb -/- cardiac fibroblast did not upregulate the expression of genes associated with myofibroblasts following treatment with Ang II. This was reversed following expression of human cytoglobin.
    Conclusions: Our findings indicate that Cygb plays a protective role in the mouse heart during Ang II-induced cardiac stress. This is the first study detailing the function of Cygb in the heart as a regulator of cardiac hypertrophy. This study also reveals a role for Cygb in regulating cardiac fibroblast activation by Ang II.
    NEW & NOTEWORTHY: We identified cytoglobin as an important globin in cardiac pathophysiology. Genetic deletion of cytoglobin led to exacerbation of angiotensin II-mediated cardiac hypertrophy in the absence of any effect on systemic blood pressure. Cytoglobin is expressed in cardiac fibroblasts and pericytes and is required for cardiac fibroblast activation to myofibroblast. The present study reveals for the first time a role for cytoglobin in regulating angiotensin II signaling.
    DOI:  https://doi.org/10.64898/2026.01.06.697990
  49. J Agric Food Chem. 2026 Jan 14.
    Dietary Quercetin-3-Glucuronide Mitigates Oxidative Stress, Inflammation, and Fibroblast Transition by Regulating Nrf2 and Autophagy in Pulmonary Fibrosis.
    Pei-Rong Yu, Chiao-Yun Tseng, Yu-Hsuan Liang, Yu-Ci Chang, Jing-Hsien Chen, Hui-Hsuan Lin.
      Pulmonary fibrosis involves oxidative stress, inflammation, and fibroblast-to-myofibroblast transition (FMT). Quercetin-3-glucuronide (Q3G) exhibits antioxidant and anti-inflammatory properties; however, its antifibrotic effects remain unclear. This study aimed to investigate the protective role of Q3G in epithelial injury-induced fibroblast activation, with a focus on nuclear factor erythroid 2-related factor 2 (Nrf2) and autophagy regulation. First, the decreased expressions of Nrf2 and an autophagy marker LC3 were detected in human emphysema compared with normal subjects. Further results demonstrated Q3G enhanced both coexpressions, while suppressing reactive oxygen species (ROS), interleukin (IL)-1β, IL-6, and extracellular matrix (ECM) deposition. The protective effects of Q3G were significantly reversed by Nrf2 silencing or autophagy inhibition. The Q3G-induced colocalization of Nrf2 and LC3 suggests a functional coupling between these pathways, which contributes to redox homeostasis and the attenuation of fibrosis. These findings indicate that Q3G mitigates oxidative stress, inflammation, and FMT via the coordinated activation of Nrf2 and autophagy, highlighting its therapeutic potential in pulmonary fibrosis.
    Keywords:  autophagy; fibroblast-to-myofibroblast transition (FMT); nuclear factor erythroid 2−related factor 2 (Nrf2); pulmonary fibrosis; quercetin-3-glucuronide (Q3G)
    DOI:  https://doi.org/10.1021/acs.jafc.5c13444
  50. J Mol Histol. 2026 Jan 13. 57(1): 48
    Danshen/Huanglian-loaded gelatin/Bletilla striata gum dressings accelerate wound healing in anal fistula by promoting angiogenesis through TGF-β/Smad pathway activation.
    Houdong Wang, Shuxian Shao, Wenjie Shen, Zhong Shen, Rongchao He.
      Anal fistula (AF) is a common anorectal disease that significantly impairs patients' quality of life. Dressings were frequently used for therapeutic wound healing. In this study, Danshen/Huanglian-loaded gelatin/Bletilla striata gum (DH-GB) dressings were prepared. The aim was to investigate its therapeutic effects and potential mechanism in AF. DH-GB, Danshen-loaded gelatin/Bletilla striata gum (D-GB), and GB dressings were prepared. AF models were constructed using wire surgery method, with dressing treatment for two weeks. Wound healing rate and blood flow were detected during this period. HE staining, MASSON staining, and immunohistochemistry for Angiopoietins-1 (Ang-1) expression were performed. In vitro, rat primary skin flbroblast cells (PRSFs) were randomized into Control, immersion solution of dressings (Danshen/Huanglian), Danshen/Huanglian + small interfering RNA-negative control (si-NC), and Danshen/Huanglian + siRNA targeting transforming growth factor-β (si-TGF-β) groups. Cell viability and cell proliferation were assessed by CCK8 and EdU assay. Additionally, both in vivo and in vitro, ELISA for VEGF levels and Western blot for TGF-β/Smad pathway-related expression were conducted. In AF rats, DH-GB treatment up-regulated wound healing rate, collagen deposition, and blood flow, increased VEGF, Ang-1, TGF-β, p-Smad2/Smad2, p-Smad3/Smad3, and p-Smad4/Smad4 expression, and improved pathological damage. Notably, DH-GB dressings exhibited enhanced efficacy in promoting wound healing compared to D-GB and GB dressings. Moreover, in rat PRSFs, Danshen/Huanglian promoted cell viability, cell proliferation, and enhanced VEGF, TGF-β, p-Smad2/Smad2, p-Smad3/Smad3, and p-Smad4/Smad4 expression, which were reversed by si-TGF-β. Our study revealed that DH-GB dressings promoted AF wound healing by stimulating angiogenesis through up-regulating TGF-β/Smad pathway, offering scientific foundation for its clinical application in AF.
    Keywords:  Anal fistula; Angiogenesis; Danshen/Huanglian; Dressing; TGF-β/Smad pathway; Wound healing
    DOI:  https://doi.org/10.1007/s10735-025-10699-7
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