bims-fibdiv Biomed News
on Fibroblast diversity
Issue of 2026–02–01
48 papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary
  1. Analysis of cranial tenocyte heterogeneity reveals a role for Wnt signaling in tendon attachments.
  2. Mesothelial Cells in Fibrosis: Focus on Intercellular Crosstalk.
  3. Anoikis: To Die or Not to Die?
  4. Role of FGF2 in promoting osteogenic differentiation for craniofacial bone regeneration.
  5. Exosomes in Hypertrophic Scars and Keloids: Mechanisms and Therapeutic Potentials-A Narrative Review.
  6. Exploring the Role of the Extracellular Matrix in Disease and Aging.
  7. Circular RNA circSmad4 controls pulmonary fibrosis.
  8. Targeting Cardiac Fibroblast Plasticity for Antifibrotic and Regenerative Therapy in Heart Failure.
  9. The Hippo pathway in cardiac fibrosis: mechanisms and therapeutic prospects.
  10. Molecular Mechanisms of Chondrocyte Hypertrophy Mediated by Physical Cues and Therapeutic Strategies in Osteoarthritis.
  11. Circulating Fibrocytes: Cellular Mediators of Tissue Fibrosis.
  12. Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis.
  13. Fibroblasts as Immunological Sentinels in Cutaneous Inflammation: A Review.
  14. Fibroblast Dynamics in Keloid Pathogenesis: Unraveling Cellular Crosstalk and Novel Therapeutic Targets.
  15. Tumour endothelial cells in cancer: Chemo-physical crosstalk and angiogenic signalling in the tumour microenvironment.
  16. Reframing fibrosis as a barrier to regeneration and gene delivery in muscular diseases.
  17. The Extracellular Matrix, the Silent 'Architect' of Glioma.
  18. Mechanostimulation-Induced Cell Adhesion and Interaction with the Extracellular Matrix.
  19. Tumor Microenvironment in Cancer Biology: A Comprehensive Review of Stromal, Immune, and Vascular Components Driving Malignancy.
  20. Nanofibrous scaffolds for bone and cartilage regeneration.
  21. The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy.
  22. A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction.
  23. Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.
  24. Mechanotransduction of Piezo1 in the cancer microenvironment: implications for NK cell-based immunotherapy.
  25. Tissue and extracellular matrix remodeling of the subchondral bone during osteoarthritis of knee joints as revealed by spatial mass spectrometry imaging.
  26. Exercise-Based Mechanotherapy: From Biomechanical Principles and Mechanotransduction to Precision Regenerative Rehabilitation.
  27. Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis.
  28. Decoding ECM remodeling: proteases as gatekeepers of Lysyl oxidase family-mediated crosslinking.
  29. Selective blockade of latent TGF-β1 activation suppresses tissue fibrosis with good safety.
  30. LncRNA P4HA2-AS1 drives renal interstitial fibrosis via trim32-mediated k63 ubiquitination of ULK1 and autophagic dysregulation.
  31. Mechanical Cues Regulate Estrogen and Progesterone-Induced Nascent ECM Deposition by Human Endometrial Stromal Fibroblasts.
  32. Transient Receptor Potential (TRP) Channels as Fundamental Regulators of Fibrosis and Pruritus-A New Therapeutic Target for Pathological Scar Management.
  33. TNFα and Endothelial IL-1 Receptor Signaling Drive Peritubular Capillary Regression and Fibrosis in Obstructive Kidney Injury.
  34. Bicuculline from Forsythia suspensa attenuates liver fibrosis via TLR4/MD2 inhibition and suppression of MyD88/NF-κB signaling.
  35. The TWEAK/FN14 axis influences the phenotype of cardiac fibroblasts during pathological cardiac remodeling through the regulation of EGR1.
  36. Extracellular Matrix Origin Directs Morphogenesis and Gene Regulation in Bioengineered Human Skin.
  37. Regression of fibrosis and portal hypertension in chronic liver disease: Endothelial perspectives and clinical implications.
  38. Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
  39. Perspectives on intrinsic articular cartilage interfaces.
  40. Nonthermal Atmospheric Plasma Modulates Palatal Wound Healing in Rats: A Morphometric, Histopathologic and Immunohistochemical Analysis.
  41. Matrix stiffness-driven cytoskeletal remodeling and tumor progression in anaplastic thyroid cancer via integrin-focal adhesion kinase signaling.
  42. Mechanisms of fibrotic tissue remodelling: insights from systemic sclerosis.
  43. Uncoupling TGFβ1 signalling from collagen protein synthesis in Dupuytren's disease.
  44. Sema3dhi Fibroblasts Promote Acute Kidney Injury Fibrotic Progression Through Confining Endothelial Cell Migration.
  45. LYVE1 ectodomain shedding blunts lymphatic transmigration and clearance of macrophages during kidney injury.
  46. Targeting LRRC15 in Cancer-Associated Fibroblasts Modifies the Extracellular Matrix and Enhances Tumor Immune Responses to Suppress Lung Cancer Progression.
  47. EVA1A responds to endoplasmic reticulum stress to regulate renal fibrosis by promoting TGF-β signaling pathway.
  48. Suppressing Endothelial-Mesenchymal Transition Through the Histone Deacetylase 1/GATA Binding Protein 4 Pathway: The Mechanism of Protocatechuic Acid Against Myocardial Fibrosis Revealed by an Integrated Study.
  1. Development. 2026 Jan 15. pii: dev205047. [Epub ahead of print]153(2):
    Analysis of cranial tenocyte heterogeneity reveals a role for Wnt signaling in tendon attachments.
    Arul Subramanian, Pavan K Nayak, Cameron L Miller, Daniel B Dranow, Ryan R Roberts, J Gage Crump, Thomas F Schilling.
      Tenocytes secrete the extracellular matrix (ECM) of tendons and ligaments in response to mechanical forces from the muscles and bones to which they attach. Although these tissues are often injured and weaken with age, we know little about the genetic mechanisms controlling their development or maintenance. Through single-cell RNA sequencing (scRNA-seq) of connective tissues in the embryonic zebrafish head, we identify distinct subpopulations of developing tenocytes and ligamentocytes. Spatially distinct transcriptional cell signatures, particularly for ECM genes, correlate with the type of tendon/ligament (i.e. longer load-bearing skeletal attachments versus soft tissue attachments) as well as tenocyte locations within tendons (i.e. skeletal entheses versus myotendinous junctions). Combinatorial in situ analyses confirm spatial co-expression of genes defining many of these subsets of tendon or ligament cells. From pathway analysis, the scRNA-seq data also suggest a role for canonical Wnt signaling in tenocyte development. Genetic and pharmacological Wnt manipulations alter tenocyte aggregation and cause ectopic cranial muscle attachments. These findings reveal previously unappreciated spatial and functional heterogeneity in tenocytes during embryogenesis and define a role for Wnt signaling in attachment patterning and morphogenesis.
    Keywords:  Enthesis; Ligamentocytes; Myotendinous junction; Tenocytes; Transcriptional heterogeneity; Zebrafish
    DOI:  https://doi.org/10.1242/dev.205047
  2. Biomolecules. 2026 Jan 05. pii: 85. [Epub ahead of print]16(1):
    Mesothelial Cells in Fibrosis: Focus on Intercellular Crosstalk.
    Nadezhda Bakalenko, Evdokiya Kuznetsova, Konstantin Dergilev, Irina Beloglazova, Anna Malashicheva.
      Mesothelial cells line serosal cavities and internal organs, playing a vital role in maintaining serosal integrity and homeostasis. Their remarkable plasticity and ability to undergo mesothelial-to-mesenchymal transition (MMT) position them as key regulators of tissue repair. However, when normal repair processes fail, mesothelial cells can acquire a profibrotic phenotype. They actively contribute to all stages of fibrosis development, including inflammation, fibrin accumulation, myofibroblast differentiation, and extracellular matrix (ECM) remodeling. Fibrotic progression involves multiple cell types, and communication among them is essential for its perpetuation. Mesothelial cells are implicated in bidirectional crosstalk with fibroblasts, macrophages, lymphocytes, and endothelial cells of the serosal microenvironment through direct contact, paracrine signaling, and extracellular vesicle exchange. These interactions regulate immune cell recruitment, cytokine balance, endothelial permeability, and ECM deposition, while, in turn, immune and endothelial cells modulate mesothelial activation, proliferation, and transition. Understanding this complex network of intercellular communication provides new insights into fibrosis pathogenesis and reveals promising targets for antifibrotic therapies.
    Keywords:  cell crosstalk; fibrosis; mesothelial cells; mesothelial-to-mesenchymal transition (MMT)
    DOI:  https://doi.org/10.3390/biom16010085
  3. Int J Mol Sci. 2026 Jan 06. pii: 579. [Epub ahead of print]27(2):
    Anoikis: To Die or Not to Die?
    Tomas Koltai, Larry Fliegel.
      Epithelial, endothelial, and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, these cells soon die by a mechanism called anoikis (homelessness). Anoikis is a programmed cell death of an apoptotic nature; however, it can, in certain cases, be overcome, and detached cells can survive in the absence of the correct signals from the ECM. This is the case of malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and would invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwining association between epithelial-mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of these anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them.
    Keywords:  anoikis; apoptosis; cancer; epithelial–mesenchymal transition; focal adhesion; integrins; metastasis
    DOI:  https://doi.org/10.3390/ijms27020579
  4. Regen Eng Transl Med. 2025 Jun 25.
    Role of FGF2 in promoting osteogenic differentiation for craniofacial bone regeneration.
    Xianrui Yang, Peter X Ma.
      Fibroblast growth factor II (FGF2), or basic fibroblast growth factor (bFGF), is an important regulator in bone and craniofacial development. FGF2 regulates cell survival, proliferation, migration, multilineage differentiation, and stemness in stromal cells. While there is broad interest in utilizing FGF2 for bone and craniofacial tissue repair and regeneration, the literature and reported data are often inconsistent or even controversial due to its multifunctional nature. Therefore, the outcomes are dependent on dose, duration, timing of administration, spatiotemporal pattern of the FGF2 delivery, and the microenvironment. This review paper aims to discuss FGF2 signaling and its related pathways, as well as mechanisms in vitro, in vivo, and in clinical applications of FGF2 in inducing osteogenic differentiation of human mesenchymal stromal cells (hMSCs) for craniofacial bone regeneration.
    Keywords:  Fibroblast growth factor II; craniofacial bone; drug delivery; mesenchymal stromal cells; tissue regeneration
    DOI:  https://doi.org/10.1007/s40883-025-00447-4
  5. J Cosmet Dermatol. 2026 Feb;25(2): e70705
    Exosomes in Hypertrophic Scars and Keloids: Mechanisms and Therapeutic Potentials-A Narrative Review.
    Mengke Wu, Jianfeng Zhang, Na Xiong, Yixiao Ma, Lingling Yong, Huaxu Liu, Qin Guo.
       BACKGROUND: Hypertrophic scars and keloids, types of pathological scars, arise from dysregulated wound healing, marked by abnormal fibroblast activation and excessive extracellular matrix (ECM) deposition. Current treatments have high recurrence rates and side effects, necessitating targeted therapies. Exosomes, extracellular vesicles mediating intercellular communication, offer multi-target regulatory potential to address scar formation complexities.
    METHODS: This narrative review synthesizes in vitro and in vivo studies (2020-2025) from PubMed and Scopus on exosomes' role in regulating hypertrophic scars and keloids, proposing innovative therapeutic approaches.
    RESULTS: Therapeutic exosomes attenuate inflammation, promote wound healing, inhibit fibrosis, and modulate the scar microenvironment. They suppress fibroblast-to-myofibroblast transformation, regulate collagen synthesis, and inhibit fibrotic pathways, particularly via the Transforming Growth Factor-beta/Sma- and Mad-related protein (TGF-β/Smad) signaling pathway.
    CONCLUSION: Exosomes are a promising cell-free therapy for pathological scars due to their multi-target regulatory capabilities. Future research should optimize large-scale production, standardize protocols, and develop targeted delivery systems to enable clinical translation, with validation through clinical trials.
    Keywords:  TGF‐β/Smad; cell‐free therapy; exosome; fibrosis; hypertrophic scar; keloid; wound healing
    DOI:  https://doi.org/10.1111/jocd.70705
  6. Juntendo Med J. 2025 ;71(6): 372-374
    Exploring the Role of the Extracellular Matrix in Disease and Aging.
    Eri Arikawa-Hirasawa.
      Throughout my research career, I have focused on understanding the extracellular matrix (ECM) and its roles in disease pathogenesis and the aging process. My initial interest in muscular dystrophies gradually expanded to include various organs and systems, including the kidneys, brain, cartilage, skin, and eyes. During my tenure at the National Institutes of Health (NIH), I made substantial contributions to generating and analyzing conditional knockout mouse models for key ECM molecules, including laminin α1 and perlecan. These studies elucidated the roles of ECM components in hereditary diseases, embryonic development, and the functionality of the neuromuscular junction. Upon returning to Japan, I transitioned this foundational expertise into translational research across multiple fields, benefiting from a collaborative environment that bridges basic and clinical sciences. My recent work examines the impact of glycosylation on ECM remodeling. Reflecting on this scientific journey, I emphasize the importance of ECM as a structural component and as a dynamic regulator of cellular behavior. As I retire from active academic life, I aspire to support the next generation of scientists in exploring the extracellular space, an area rich with potential therapeutic opportunities.
    Keywords:  aging; extracellular matrix; laminin; muscular dystrophy; perlecan
    DOI:  https://doi.org/10.14789/ejmj.JMJ25-0033-P
  7. Korean J Physiol Pharmacol. 2026 Jan 28.
    Circular RNA circSmad4 controls pulmonary fibrosis.
    Anna Jeong, Taewon Kook, Yun-Gyeong Lee, Yongwoon Lim, Ayeong Han, Young-Kook Kim, Dongtak Jeong, Woo Jin Park, Duk-Hwa Kwon, Hyun Kook.
      Pulmonary fibrosis is a progressive and irreversible lung disease characterized by excessive fibroblast activation and extracellular matrix (ECM) deposition, leading to respiratory failure. Despite recent advances in understanding its molecular mechanisms, effective therapies remain limited. Circular RNAs have emerged as key regulators of gene expression, yet their role in pulmonary fibrosis is poorly understood. Here, we investigated circSmad4 and its therapeutic potential. Our results demonstrate that circSmad4 expression was markedly upregulated in bleomycininduced pulmonary fibrosis, suggesting a role in fibrotic progression. Silencing circ- Smad4 by siRNA significantly alleviated lung fibrosis, reducing lung weight, collagen deposition, and inflammatory cytokine expression. Mechanistically, we identified that circSmad4 exerted its pro-fibrotic effects through the miR-671-5p/Fgfr2 axis, suppressing miR-671-5p and increasing Fgfr2 expression, thereby enhancing fibroblast activation. Additionally, si-circSmad4 treatment also downregulated pro-inflammatory cytokines (IL-6, TNF-α, and TGF-β1) and inhibited ECM protein expression. Furthermore, in vitro experiments using TGF-β1-induced fibroblast activation models showed that circSmad4 knockdown mitigated fibroblast activation by lowering the expression of fibrosis-related genes (Acta2, Col1a1, Col3a1, Ctgf) and collagen secretion. Consistently, pharmacological inhibition of Fgfr2 with FGFR2-IN-1 also suppressed the pro-fibrotic effects of TGF-β1, mimicking si-circSmad4. These findings suggest that circSmad4 functions as a central regulator of pulmonary fibrosis by modulating fibroblast activation, ECM deposition, and inflammation. In conclusion, circSmad4 represents a novel driver of pulmonary fibrosis, and targeting circSmad4 may offer a promising therapeutic strategy.
    Keywords:  Extracellular matrix; Fgfr2 ; Pulmonary fibrosis; circSmad4; miR-671-5p
    DOI:  https://doi.org/10.4196/kjpp.25.123
  8. Cells. 2026 Jan 08. pii: 112. [Epub ahead of print]15(2):
    Targeting Cardiac Fibroblast Plasticity for Antifibrotic and Regenerative Therapy in Heart Failure.
    Suchandrima Dutta, Sophie Chen, Waqas Ahmad, Wei Huang, Jialiang Liang, Yigang Wang.
      Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF.
    Keywords:  antifibrotic therapy; direct fibroblast reprogramming; fibroblast heterogeneity; fibrosis; single-cell transcriptomics
    DOI:  https://doi.org/10.3390/cells15020112
  9. Hum Cell. 2026 Jan 27. 39(2): 39
    The Hippo pathway in cardiac fibrosis: mechanisms and therapeutic prospects.
    Yuting Qiu, Shanshan Hu, Hui Li, Jiatong Ren, Meixi Liao, Jie Huo, Zenan Luo, Lili Lu.
      Cardiac fibrosis is a prevalent pathological feature in the progression of various cardiovascular diseases, including heart failure, myocardial infarction, and dilated cardiomyopathy, particularly in their advanced stages. Its primary mechanism involves the abnormal activation of cardiac fibroblasts and excessive deposition of extracellular matrix, which ultimately results in decreased myocardial compliance and cardiac dysfunction. The Hippo signaling pathway, an evolutionary conserved kinase cascade, not only regulates organ development and tissue homeostasis but has also been shown to play a critical role in cardiac fibrosis. Notably, the Hippo pathway demonstrates cell-specific regulatory functions across different cardiac cell types, including cardiomyocytes, fibroblasts, and immune cells. This systematic review elucidates the molecular mechanisms by which the Hippo pathway influences cardiac fibrosis, emphasizing its cell type-dependent roles. It analyzes the complexity of its roles from the perspectives of cross-talk between pathways, various types of cardiac diseases, and different stages of disease progression. Additionally, it summarizes recent advancements in anti-fibrotic drugs that target this pathway, thereby providing a theoretical foundation for the development of novel therapeutic strategies in cardiac fibrosis.
    Keywords:  Cardiac fibrosis; Cell type-dependent; Fibrotic mechanism; Hippo signal pathway; Target therapeutic strategy
    DOI:  https://doi.org/10.1007/s13577-026-01352-w
  10. Int J Mol Sci. 2026 Jan 08. pii: 624. [Epub ahead of print]27(2):
    Molecular Mechanisms of Chondrocyte Hypertrophy Mediated by Physical Cues and Therapeutic Strategies in Osteoarthritis.
    Guang-Zhen Jin.
      Osteoarthritis (OA) is a multifactorial degenerative joint disease in which aberrant mechanical cues act in concert with metabolic dysregulation and chronic low-grade inflammation, with chondrocyte hypertrophy representing a key pathological event driving cartilage degeneration. Alterations in extracellular matrix (ECM) properties-including mechanical loading, stiffness and viscoelasticity, topological organization, and surface chemistry-regulate hypertrophic differentiation and matrix degradation in a zone-, stage-, and scale-dependent manner. Microscale measurements often reveal localized stiffening in superficial zones during early OA, whereas bulk tissue testing can show softening or heterogeneous changes in deeper zones or advanced stages, highlighting the context-dependent nature of ECM mechanics. These biophysical signals are sensed by integrin-based adhesion complexes, primary cilia, mechanosensitive ion channels (TRP/Piezo), and the actin cytoskeleton-nucleus continuum, and are transduced into intracellular pathways with zone- and stage-specific effects, governing chondrocyte fate under physiological and osteoarthritic conditions. Mechanism-based anti-hypertrophic strategies include biomimetic scaffold design for focal defects, dynamic mechanical stimulation targeting early OA, and multimodal approaches integrating mechanical cues with biochemical factors, gene modulation, drug delivery, or cell-based therapies. Collectively, this review provides an integrated mechanobiological framework for understanding cartilage degeneration and highlights emerging opportunities for disease-modifying interventions targeting chondrocyte hypertrophy.
    Keywords:  anti-hypertrophic therapeutic strategies; biophysical cues; chondrocyte hypertrophy; mechanotransduction; osteoarthritis
    DOI:  https://doi.org/10.3390/ijms27020624
  11. Int J Mol Sci. 2026 Jan 06. pii: 557. [Epub ahead of print]27(2):
    Circulating Fibrocytes: Cellular Mediators of Tissue Fibrosis.
    Xinya Guo, Jianyu Lu, Yiyao Du, Zhaofan Xia, Shizhao Ji.
      Fibrosis is a pathological condition resulting from an excessive tissue response during the repair process, often affecting various tissues such as the skin, organs, and joints, posing a significant threat to global health. Researchers have made substantial efforts to explore the endogenous mechanisms underlying fibrosis in recent years and have developed several therapeutic strategies to block this process. Historically, research on fibrotic diseases has focused on identifying highly relevant therapeutic targets and developing effective antifibrotic drugs. However, due to the complexity of the mechanisms of fibrosis and its effector cells, the effectiveness of antifibrotic therapies remains limited. With the advancement of high-throughput omics technologies and machine learning tools, we now have a clearer understanding of cellular heterogeneity, intercellular interactions, and the specific roles of cells in various biological processes. This enables tracking the trajectory of different cell types during the fibrotic process, facilitating early identification and discovery of new targets for fibrosis treatment, and conducting more precise targeted research. Supported by these novel technologies, numerous studies have revealed that, in addition to normal fibroblasts, a group of bone marrow-derived fibrocytes also contributes to the fibrosis of both parenchymal and non-parenchymal organs and tissues. Circulating fibrocytes are hematopoietic-derived cells that are recruited to injury sites during injury, disease, and aging, acting as participants in inflammation and tissue repair, and directly or indirectly promoting fibrosis in various tissues throughout the body. This review summarizes the general characteristics of circulating fibrocytes, the molecular mechanisms involved in their recruitment to different tissues, the process of their differentiation into fibroblasts, their potential roles in various diseases, and the latest research developments in this field. Given the key role of circulating fibrocytes in fibrosis across multiple tissues, they may serve as promising targets for the development of novel antifibrotic therapies.
    Keywords:  circulating fibrocytes; fibrosis
    DOI:  https://doi.org/10.3390/ijms27020557
  12. Front Endocrinol (Lausanne). 2025 ;16 1698404
    Bidirectional crosstalk between the bone extracellular matrix and lysosomes in bone remodeling and osteoporosis.
    Chang Zhou, Xinyue Hu, Yichen Jing, Jiaheng Zhang, Jing Tao, Xinyi Ouyang, Jiaqian Tang, Guomin Zhang, Huiping Liu.
      Osteoporosis is a systemic skeletal disorder characterized by progressive loss of bone mass and deterioration of microarchitectural integrity. Traditionally, its pathogenesis has been attributed primarily to an imbalance in the number and activity of osteoblasts and osteoclasts. However, emerging evidence has uncovered a critical bidirectional interdependence between the integrity of the extracellular matrix (ECM) and the functional homeostasis of the intracellular lysosomal system-an axis increasingly recognized as the "bone matrix-lysosome crosstalk." Despite its apparent importance, the central role of this regulatory circuitry in bone homeostasis and the mechanisms through which it becomes disrupted under pathological conditions remain insufficiently defined.This review synthesizes current advances regarding the cell type-specific functions of lysosomes across distinct bone cell populations and further examines how the ECM, as a dynamic microenvironment, exerts reciprocal control over lysosomal biogenesis and activity. We highlight how the biochemical composition and biophysical properties of the ECM govern lysosomal acidification, metabolic coupling, and degradative capacity with remarkable precision. During the progression of osteoporosis, structural compromise of the ECM and lysosomal dysfunction reinforce one another, establishing a self-amplifying pathological loop that accelerates the collapse of the bone microenvironment. Recognizing this reciprocal deterioration, we propose that restoring the dynamic equilibrium of the "ECM-lysosome axis" may represent a mechanistic pivot for reversing osteoporotic degeneration. Interventions targeting lysosomal function, reconstructing the bone ECM, and employing nanomedicine-enabled organelle-specific delivery hold particular promise for advancing precision therapeutics in osteoporosis.
    Keywords:  bone ECM; lysosome; osteoblast; osteoclasts; osteocytes; osteoporosis
    DOI:  https://doi.org/10.3389/fendo.2025.1698404
  13. J Clin Med. 2026 Jan 09. pii: 556. [Epub ahead of print]15(2):
    Fibroblasts as Immunological Sentinels in Cutaneous Inflammation: A Review.
    Taihao Quan.
      Fibroblasts, traditionally viewed primarily as structural cells responsible for extracellular matrix production and tissue architecture, have emerged as important immunomodulatory players in inflammation. These cells actively participate in inflammatory processes through multiple mechanisms: recognizing and responding to inflammatory stimuli, producing diverse inflammatory mediators, and engaging in complex interactions with various immune cells. This review explores the multifaceted immunomodulatory functions of fibroblasts, including their capacity to sense inflammatory signals, secrete inflammatory mediators, modulate immune cell behavior, and establish a pro-inflammatory microenvironment. Understanding the dynamic role of fibroblasts in inflammatory processes provides insights into inflammatory pathology and may inform the development of novel therapeutic strategies targeting fibroblast-mediated immune modulation.
    Keywords:  fibroblasts; inflammation; inflammatory mediators; skin
    DOI:  https://doi.org/10.3390/jcm15020556
  14. Dermatol Res Pract. 2026 ;2026 2528205
    Fibroblast Dynamics in Keloid Pathogenesis: Unraveling Cellular Crosstalk and Novel Therapeutic Targets.
    Ziad Alkouz, Ala'a Al Suwait, Lian Zhang, Rehab Alhejairi, Freddy Gahimbare, Mahmoud Qalalwa, Bin Yang.
      Keloid scars represent a complex fibroproliferative disorder characterized by abnormal wound healing and excessive collagen deposition. Central to keloid pathogenesis are dynamic fibroblast populations that undergo extensive phenotypic transitions, including heterogeneous subpopulation differentiation, enhanced migration, myofibroblast transdifferentiation, and sustained activation states. This review examines fibroblast dynamics as the central orchestrator of keloid formation, analyzing how these cells interact with keratinocytes, immune cells, endothelial cells, and melanocytes to drive pathological scarring. We focus on key signaling pathways that directly regulate fibroblast function, including TGF-β/Smad, VEGF, Wnt, and emerging regulators such as miR-3606-3p that integrate multiple fibrotic cascades. Current therapeutic approaches show variable efficacy, with surgical excision alone resulting in 45%-100% recurrence rates, while combination therapies incorporating radiation, intralesional injections, and novel molecular targets achieve improved outcomes. Emerging strategies include COX-2 inhibition for dual antiproliferative and proapoptotic effects on keloid fibroblasts, stem cell therapies, and precision medicine approaches based on molecular profiling. Through deeper understanding of fibroblast dynamics and their regulatory networks, more effective therapeutic strategies can be developed to improve patient outcomes and quality of life.
    Keywords:  TGF-β signaling; cellular heterogeneity; fibroblast dynamics; keloid fibroblasts; precision medicine; therapeutic targets
    DOI:  https://doi.org/10.1155/drp/2528205
  15. Cell Signal. 2026 Jan 23. pii: S0898-6568(26)00041-0. [Epub ahead of print]141 112391
    Tumour endothelial cells in cancer: Chemo-physical crosstalk and angiogenic signalling in the tumour microenvironment.
    Arian Ansardamavandi, Mohammad Tafazzoli-Shadpour.
      The tumour microenvironment (TME) represents a complex, dynamic ecosystem comprising cellular and acellular elements that collectively facilitate tumour progression, invasion, and metastasis through intricate chemo-mechanical interactions. Cancer cells drive TME remodelling by recruiting and reprogramming stromal components, including cancer-associated fibroblasts (CAFs) that alter extracellular matrix (ECM) composition and stiffness, tumour-associated macrophages (TAMs) that promote immunosuppressive conditions, and tumour endothelial cells (TECs) that establish aberrant vascular networks. This review synthesises current literature on the pivotal role of TECs in tumour angiogenesis, emphasising their bidirectional crosstalk with cancer and stromal cells via chemical signals (e.g., growth factors under hypoxia) and mechanical cues (e.g., ECM stiffness and topography) that modulate cellular contractility, adhesion, and biochemical release. Key findings reveal how TECs integrate these multifaceted stimuli to orchestrate vascular remodelling, enhance permeability, and foster metastatic dissemination, often through dysregulated pathways distinct from normal endothelium. Ultimately, elucidating these mechanisms offers promising avenues for developing targeted therapies that selectively inhibit TEC-mediated angiogenesis while preserving physiological vascular function.
    Keywords:  Angiogenesis; Cancer; Cellular cross-talk; Chemical and mechanical stimuli; Tumour endothelial cells; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112391
  16. FEBS J. 2026 Jan 29.
    Reframing fibrosis as a barrier to regeneration and gene delivery in muscular diseases.
    Hasan Basri Kiliç, Y Çetin Kocaefe.
      Gene replacement therapies for muscular dystrophies show promise in preclinical models but often fail in clinical settings. A major difference between animal models and human pathology is the extent of fibrosis observed. Progressive and irreversible fibrosis needs to be targeted before or alongside genetic strategies. Fibrosis limits muscle function through a collagen-rich extracellular matrix (ECM) that forms a stiff barrier impeding penetration of gene therapy vectors, such as adeno-associated viruses (AAVs). It disrupts the satellite cell niche, compromising activation, proliferation, and differentiation. Even with successful gene delivery, regeneration in fibrotic muscle is severely impaired. Recent reports of acute liver toxicity leading to deaths in gene therapy trials using the AAVrh74 vector underscore the risks associated with high systemic AAV doses. If fibrosis can be alleviated, effective transduction might be achieved with lower vector quantities in a single therapeutic dose, reducing the systemic risks. Anti-fibrotic agents are being explored to counteract disease progression. Modulators of ECM maturation offer novel therapeutic targets. However, pleiotropic and context-dependent roles of these mediators complicate translation. Therapies must target pathological ECM remodeling without disrupting essential physiology elsewhere. In this Review, we examine therapeutic efforts targeting skeletal muscle dystrophies and emphasize fibrosis as a major barrier to gene and regenerative therapies. We highlight the need for a deeper investigation into fibrotic pathways, modulators, and extracellular maturation processes and propose that these underexplored areas may yield novel therapeutic targets for muscular dystrophies. A fibrosis-aware therapeutic framework that integrates insights across systems and pathologies is critical for improving treatment outcomes in skeletal muscle disorders.
    Keywords:  Duchenne Muscular Dystrophy (DMD); adeno‐associated virus (AAV); fibrosis; gene therapy; transforming growth factor‐beta (TGF‐β)
    DOI:  https://doi.org/10.1111/febs.70427
  17. Biomedicines. 2026 Jan 17. pii: 205. [Epub ahead of print]14(1):
    The Extracellular Matrix, the Silent 'Architect' of Glioma.
    Carmen Rubio, Javier Pérez-Villavicencio, Nadia F Esteban-Román, Ángel Lee, Gervith Reyes-Soto, Moisés Rubio-Osornio.
      The brain's extracellular matrix (ECM) serves as a dynamic and instructive regulator of glioma progression. The ECM provides structural support while integrating pharmacological and mechanical signals that influence glioma initiation, progression, and treatment resistance. Deviant ECM remodeling fosters tumor heterogeneity, invasion, and immune evasion by altering stiffness, composition, and cellular matrix signaling. We proposed that ECM remodeling in gliomas not only facilitates tumor growth and heterogeneity but also establishes advantageous biophysical and metabolic conditions that foster treatment resistance and recurrence. Our objective is to analyze current findings regarding the structural, biochemical, and mechanical roles of the brain ECM in glioma growth, emphasizing its contribution to tumor heterogeneity, mechanotransduction, immunological modulation, and its potential as a therapeutic target.
    METHOD: A comprehensive literature review was conducted using scientific databases including PubMed, Web of Science, and Scopus. Peer-reviewed literature published between 2000 and 2025 was selected for its relevance to ECM composition, stiffness, remodeling enzymes, extracellular vesicles, and mechanobiological processes in gliomas.
    RESULTS: Recent investigations demonstrate that glioma cells actively alter the ECM by secreting collagens, laminins, and metalloproteinases, establishing a feedback loop that facilitates invasion and resistance.
    DISCUSSION: Mechanical variables, such as ECM stiffness and solid stress, influence glioma growth, metabolism, and immune exclusion. Moreover, extracellular vesicles facilitate significant extracellular matrix remodeling and improve communication between tumors and stromal cells. The disruption of ependymal and subventricular extracellular matrix niches enhances invasion and cerebrospinal fluid-mediated signaling. The remodeling of the ECM influences glioma growth through interconnected biochemical, mechanical, and immunological mechanisms. Examining ECM stiffness, crosslinking enzymes, and vesicle-mediated signaling represents a potential therapeutic approach. Integrative methodologies that combine mechanobiology, imaging, and multiomics analysis could uncover ECM-related vulnerabilities to improve glioma treatment.
    Keywords:  ECM reorganization; extracellular matrix; glioma advancement; mechanotransduction; therapeutic resistance; tumor diversity
    DOI:  https://doi.org/10.3390/biomedicines14010205
  18. Biomolecules. 2025 Dec 30. pii: 60. [Epub ahead of print]16(1):
    Mechanostimulation-Induced Cell Adhesion and Interaction with the Extracellular Matrix.
    Kazuo Katoh.
      Cells sense and transmit mechanical forces exerted by their environment to the nucleus via adhesion sites and the cytoskeleton. The nucleus interprets these mechanical inputs and determines cell fate and behavior by regulating gene expression. This review addresses how force-generated signals at the cell-extracellular matrix (ECM) interface influence adhesion, signaling, nuclear function, and tissue remodeling. Disruption of these mechanotransduction pathways contributes to the development of diseases such as cancer, fibrosis, and cardiovascular disorders. Advances in technologies that enable the investigation of the underlying mechanisms will support the development of novel treatment strategies for such diseases.
    Keywords:  cell adhesion; focal adhesion; mechanostimulation; signal transduction
    DOI:  https://doi.org/10.3390/biom16010060
  19. Cureus. 2025 Dec;17(12): e100320
    Tumor Microenvironment in Cancer Biology: A Comprehensive Review of Stromal, Immune, and Vascular Components Driving Malignancy.
    Sushma T A, Sudarshan Gupta, Priyanka Kiyawat, Yashodha Darshan, Kumar Sambhav, Saiyad Shabbirali Shamshadali.
      The tumor microenvironment (TME), comprising the extracellular matrix (ECM), stromal cells, immune cells, and vascular components, plays a decisive role in cancer growth, metastasis, and treatment response. Although cancer research has traditionally focused on tumor cells, increasing evidence shows that the TME actively influences tumor behavior. This narrative review synthesizes recent findings on the stromal, immune, and vascular elements of the TME, drawing on advanced approaches such as single-cell RNA sequencing and AI-assisted imaging. Cancer-associated fibroblasts (CAFs) promote tumor progression through ECM remodeling and immune suppression, while vascular abnormalities limit drug delivery and contribute to therapeutic resistance. Emerging TME-targeted strategies, including anti-angiogenic agents, immune checkpoint inhibitors, and stromal-directed therapies, show promise but remain challenged by TME heterogeneity and tumor adaptability. The evidence indicates that targeting the TME represents a major shift in cancer therapy and offers important opportunities to develop more effective and personalized treatment strategies.
    Keywords:  angiogenesis; extracellular matrix; immune evasion; stromal cells; tumor microenvironment
    DOI:  https://doi.org/10.7759/cureus.100320
  20. Appl Phys Rev. 2025 Sep;pii: 031319. [Epub ahead of print]12(3):
    Nanofibrous scaffolds for bone and cartilage regeneration.
    Rafael Correia Cavalcante, Xianrui Yang, Kemao Xiu, Chuan-Ju Liu, Peter X Ma.
      Bone, cartilage, and their composites in various joints are the most important components that form the skeletal structure and enable motion and movements of the body. Their disease and/or loss are most debilitating and afflict millions of Americans, reducing productivity and deteriorating quality of life. Due to limited treatments, scientists, engineers, and clinical doctors are investigating new tissue engineering solutions. In tissue engineering approaches, scaffolds are artificially designed temporary matrices that accommodate stem/progenitor cells and provide both physical and biological signals to guide cell differentiation and 3D tissue regeneration but eventually degrade and leave behind regenerated functional tissues or organs. Therefore, scaffolds often substantially benefit from mimicking certain features of the natural extracellular matrix (ECM) and designing certain engineered features to facilitate cell repopulation, mass transportation, and mechanical and biological cues for cells to regenerate tissue. This review article focuses on the design, synthesis, fabrication, and functionalization of nanofibrous materials to mimic the ECM, deliver biological signals, and integrate various engineering design features such as pore shape, size, connectivity, tissue architectures, and anatomic tissue/organ shapes to guide 3D tissue regeneration. In addition to biological and physical principles of scaffold design and fabrication, we also provide several examples of specific applications of these advanced nanofibrous scaffolds for bone, cartilage, and their associated composite tissue regeneration in osteochondral defects. We also discuss the interdisciplinary and multidisciplinary nature of these research directions, the importance of collaborations across disciplines, and the perspectives of future developments in the field.
    Keywords:  Bone; cartilage; cells; joint; nanofibrous scaffold; tissue regeneration
    DOI:  https://doi.org/10.1063/5.0225639
  21. Curr Oncol. 2026 Jan 19. pii: 59. [Epub ahead of print]33(1):
    The Role of Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in the Tumor Microenvironment and Their Impact on Ovarian Cancer Survival and Therapy.
    Alena A McQuarter, Joseph Cruz, Celina R Yamauchi, Mariem Chouchen, Cody S Carter, Tonya J Webb, Salma Khan.
      Ovarian cancer is the deadliest gynecologic cancer, mainly because it is often diagnosed late and resists standard treatments. The tumor microenvironment (TME) plays a major role in disease progression and therapy failure. Two key components of the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), create conditions that facilitate tumor growth and immune evasion. CAFs are highly diverse and originate from sources like fibroblasts and stem cells. They support cancer by remodeling the extracellular matrix, promoting angiogenesis, and releasing cytokines and growth factors that aid tumor survival. TAMs, which are usually in an M2 state, also promote metastasis and suppress immune responses by secreting immunosuppressive molecules. Together, CAFs and TAMs interact with cancer cells to activate pathways such as the TGF-β, IL-6, and PI3K/AKT pathways, which drive resistance to therapy. New treatments aim to block these interactions by targeting CAFs and TAMs through depletion, reprogramming, or pathway inhibition, often combined with immunotherapy. Advances such as single-cell sequencing and spatial transcriptomics now enable more precise identification of CAF and TAM subtypes, enabling more targeted therapies. This review summarizes their roles in epithelial ovarian cancer and explores how targeting these cells could improve outcomes.
    Keywords:  cancer-associated fibroblasts; epithelial ovarian cancer; extracellular matrix; single-cell sequencing; stromal remodeling; targeted therapies; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/curroncol33010059
  22. Int J Mol Sci. 2026 Jan 12. pii: 745. [Epub ahead of print]27(2):
    A New Perspective on Osteogenesis Imperfecta: From Cellular Mechanisms to the Systemic Impact of Collagen Dysfunction.
    Emma Lugli, Ludovica Gaiaschi, Maria Grazia Bottone, Fabrizio De Luca.
      Osteogenesis imperfecta (OI) is a rare genetic disease caused by mutations in collagen type I, leading to defective protein folding and an impaired extracellular matrix structure and remodelling. Beyond skeletal fragility, these molecular defects trigger a network of intracellular stress responses with multiorgan implications: the accumulation of misfolded collagen can induce persistent endoplasmic reticulum stress, which can in turn compromise mitochondrial function and autophagy or lead to cell death activation, and it can even promote widespread redox imbalance and inflammation. The interplay between intracellular stress, widespread oxidative damage and inflammation not only underlies cellular dysfunction but also the multisystemic manifestations of osteogenesis imperfecta. Targeting these interconnected pathways may result in new insights for a better understanding of OI and possibly offer novel therapeutic strategies designed to restore proteostasis and improve cell homeostasis and overall patient outcomes, highlighting the need for an integrated understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease and their translation into patient-centred therapeutic interventions.
    Keywords:  ER stress; autophagy; cell death; collagen dysfunction; in vivo models; intracellular stress; mitochondrial stress; osteogenesis imperfecta; redox imbalance; systemic inflammation
    DOI:  https://doi.org/10.3390/ijms27020745
  23. Toxicol Appl Pharmacol. 2026 Jan 24. pii: S0041-008X(26)00032-3. [Epub ahead of print] 117736
    Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.
    Jingwen Zhang, Xin Jin, Yajiao Sun, Rongyao Xia, Fuhui Chen.
      Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.
    Keywords:  BDKRB1; Epithelial-Mesenchymal Transition (EMT); Idiopathic Pulmonary Fibrosis (IPF); TFAP2A; Transcriptional Regulation
    DOI:  https://doi.org/10.1016/j.taap.2026.117736
  24. Front Oncol. 2025 ;15 1729588
    Mechanotransduction of Piezo1 in the cancer microenvironment: implications for NK cell-based immunotherapy.
    Xinmu Cui, Binbin Zhang, Jianan Zhao, Huajie Tian.
      Natural Killer (NK) cells serve a critical function in antitumor immunity. However, their effectiveness is often hampered by the biomechanical properties of the solid tumor microenvironment (TME), such as the stiffness of the extracellular matrix. This review focuses on the mechanosensitive ion channel Piezo1 and its role in enhancing NK cell function. Studies have shown that tumor cell stiffness, as a key physical cue, directly influences the responsiveness of NK cells. In three-dimensional (3D) matrices, the stiffening of the extracellular matrix (ECM) can activate Piezo1, leading to calcium influx that substantially boosts NK cells' cytotoxicity and tumor infiltration ability. Remarkably, similar to Yoda1, a specific Piezo1 agonist, short-term Piezo1 activation significantly enhances NK cells' cytotoxicity and infiltration capacity. Whether such benefits persist under prolonged stimulation without inducing functional exhaustion remains to be determined. Unlike broader review articles that discuss TME biomechanics, this study focuses on uncovering the signal transduction mechanism of the Piezo1-NK cell axis, providing new perspectives and strategies for addressing immunotherapy resistance. This mechanobiology-based framework, through detailed analysis of the Piezo1-NK cell signaling transduction mechanism, is expected to overcome bottlenecks in NK cell immunotherapy. Its application prospects are not limited to the field of oncology but can also be extended to other diseases sensitive to mechanical signals.
    Keywords:  Piezo1; TME; cancer immunotherapy; immunotherapy; matrix stiffness; mechanobiology; mechanotransduction; natural killer cells
    DOI:  https://doi.org/10.3389/fonc.2025.1729588
  25. Bone Res. 2026 Jan 26. 14(1): 14
    Tissue and extracellular matrix remodeling of the subchondral bone during osteoarthritis of knee joints as revealed by spatial mass spectrometry imaging.
    Charles A Schurman, Joanna Bons, Jonathon J Woo, Cristal Yee, Qi Liu, Nannan Tao, Tamara Alliston, Peggi Angel, Birgit Schilling.
      Osteoarthritis (OA) is a degenerative skeletal condition marked by the loss of articular cartilage and changes to subchondral bone homeostasis. Treatments for OA beyond full joint replacement are lacking primarily due to gaps in molecular knowledge of the biological drivers of disease. Mass Spectrometry Imaging (MSI) enables molecular spatial mapping of the proteomic landscape of tissues. Histologic sections of human tibial plateaus from knees of human OA patients and cadaveric controls were treated with collagenase III to target extracellular matrix (ECM) proteins prior to MS Imaging of bone and cartilage proteins. Spatial MS imaging of the knee identified distinct areas of joint damage to the subchondral bone underneath areas of lost cartilage. This damaged bone signature extended underneath remaining cartilage in OA joints, indicating subchondral bone remodeling could occur before full thickness cartilage loss in OA. Specific ECM peptide markers from OA-affected medial tibial plateaus were compared to their healthier lateral halves from the same patient, as well as to healthy, age-matched cadaveric knees. Overall, 31 peptide candidates from ECM proteins, including Collagen alpha-1(I), Collagen alpha-1(III), and surprisingly, Collagen alpha-1(VI) and Collagen alpha-3(VI), exhibited significantly elevated abundance in diseased tissues. Additionally, highly specific hydroxyproline-containing collagen peptides, mainly from collagen type I, dominated OA subchondral bone directly under regions of lost cartilage but not areas where cartilage remained intact. A separate analysis of synovial fluid from a second cohort of OA patients found similar regulation of collagens and ECM proteins via LC-MS/MS demonstrating that markers of subchondral bone remodeling discovered by MALDI-MS may be detectable as biomarkers in biofluid samples. The identification of specific protein markers for subchondral bone remodeling in OA advances our molecular understanding of disease progression in OA and provides potential new biomarkers for OA detection and disease grading.
    DOI:  https://doi.org/10.1038/s41413-025-00495-0
  26. Int J Mol Sci. 2026 Jan 09. pii: 694. [Epub ahead of print]27(2):
    Exercise-Based Mechanotherapy: From Biomechanical Principles and Mechanotransduction to Precision Regenerative Rehabilitation.
    Guang-Zhen Jin.
      Mechanical loading generated during physical activity and exercise is a fundamental determinant of musculoskeletal development, adaptation, and regeneration. Exercise-based mechanotherapy, encompassing structured movement, resistance training, stretching, and device-assisted loading, has evolved from empirical rehabilitation toward mechanism-driven and precision-oriented therapeutic strategies. At the macroscopic level, biomechanical principles governing load distribution, stress-strain relationships, and tissue-specific adaptation provide the physiological basis for exercise-induced tissue remodeling. At the molecular level, mechanical cues are transduced into biochemical signals through conserved mechanotransduction pathways, including integrin-FAK-RhoA/ROCK signaling, mechanosensitive ion channels such as Piezo, YAP/TAZ-mediated transcriptional regulation, and cytoskeleton-nucleoskeleton coupling. These mechanisms orchestrate extracellular matrix (ECM) remodeling, cellular metabolism, and regenerative responses across bone, cartilage, muscle, and tendon. Recent advances in mechanotherapy leverage these biological insights to promote musculoskeletal tissue repair and regeneration, while emerging engineering innovations, including mechanoresponsive biomaterials, 4D-printed dynamic scaffolds, and artificial intelligence-enabled wearable systems, enable mechanical loading to be quantified, programmable, and increasingly standardized for individualized application. Together, these developments position exercise-informed precision mechanotherapy as a central strategy for prescription-based regenerative rehabilitation and long-term musculoskeletal health.
    Keywords:  exercise-based mechanotherapy; mechanotransduction; musculoskeletal tissues; precision rehabilitation
    DOI:  https://doi.org/10.3390/ijms27020694
  27. Biochim Biophys Acta Mol Basis Dis. 2026 Jan 24. pii: S0925-4439(26)00017-7. [Epub ahead of print]1872(4): 168169
    Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis.
    Yongjuan Wang, Xiaoli Xie, Jiajun Tian, Xiaoyu Jiang, Huiqing Jiang.
       BACKGROUND: Goosecoid (GSC) is a transcription factor implicated in epithelial-mesenchymal transition (EMT) during embryogenesis and cancer, but its function in organ fibrosis remains poorly understood. This study investigates the role and mechanistic targets of GSC in hepatic stellate cell (HSC) EMT during liver fibrogenesis.
    METHODS: We analyzed GSC and EMT marker expression in primary HSCs isolated from murine liver fibrosis models induced by carbon tetrachloride (CCl₄) or bile duct ligation (BDL), and in TGF-β-stimulated LX-2 cells. The functional role of GSC was validated via in vitro and in vivo GSC knockdown, while chromatin immunoprecipitation sequencing (ChIP-seq) combined with experimental verification was used to identify its target genes and regulatory mechanisms.
    RESULTS: GSC expression was significantly upregulated in activated HSCs from fibrotic mouse models and TGF-β-induced LX-2 cells, which was closely associated with enhanced EMT (downregulation of epithelial markers, upregulation of mesenchymal markers). Functional assays confirmed that GSC knockdown suppressed HSC EMT in vitro and ameliorated liver fibrosis in vivo via AAV-mediated HSC-specific GSC silencing. Mechanistically, we found that GSC undergoes increased nuclear translocation during HSC activation. ChIP-seq analysis identified Serum- and glucocorticoid-induced protein kinase 1 (SGK1) as a direct transcriptional target of GSC. Further validation revealed that SGK1, in turn, promotes HSC EMT by activating the NF-κB signaling pathway.
    CONCLUSION: This study uncovers a novel mechanism by which GSC promotes HSC EMT and liver fibrosis through direct transcriptional activation of SGK1, followed by downstream NF-κB pathway activation.
    SUMMARY: GSC is markedly upregulated in activated HSCs from murine fibrosis models (CCl₄/BDL) and during TGF-β-induced EMT. HSC-specific GSC knockdown attenuated liver fibrosis progression. Mechanistically, GSC translocates to the nucleus where it binds the SGK1 promoter to enhance transcription, subsequently driving HSC EMT and promoting fibrogenesis through the NF-κB signaling pathway.
    Keywords:  EMT; GSC; HSCs; Liver fibrosis; SGK1
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168169
  28. FEBS J. 2026 Jan 28.
    Decoding ECM remodeling: proteases as gatekeepers of Lysyl oxidase family-mediated crosslinking.
    Ashutosh Joshi, Abhi Dutta, Antara Roy, Bhaskar Mondal, Trayambak Basak.
      Proteases hydrolyze the amide bond of a polypeptide chain, which can influence protein synthesis and function. This activity has been predominantly observed in the post-translational processing of lysyl oxidase (LOX) and lysyl-oxidase-like (LOXL) family proteins, which are indispensable for the remodeling of the extracellular matrix (ECM). Of the four classes, metallo- and serine proteases are known to catalyze the hydrolysis of pro-LOX and pro-LOXL family proteins into their processed forms. These LOX family proteins play instrumental roles in ECM remodeling by oxidatively deaminating the lysine and 5-hydroxy lysine residues, primarily in collagens and elastin, thus facilitating the formation of lysyl-derived covalent crosslinking that stabilizes the extracellular matrix assembly. Previous studies have established the presence of different proteolytic sites and the corresponding proteases for different LOX family proteins. However, the underlying mechanism of this protease-mediated processing of the LOX family in fibrotic tissue remodeling has remained elusive. In this review, we summarize the critical role of ECM crosslinking reactions catalyzed by the LOX family and provide an overview of proteolytic sites and corresponding proteases in fibrosis. Moreover, we discuss the potential catalytic mechanisms of bone morphogenetic protein-1, a metalloprotease, and Factor Xa, a serine protease, on LOX and LOXL2, respectively.
    Keywords:  crosslinking; fibrosis; lysyl oxidases; matrix remodeling; proteases
    DOI:  https://doi.org/10.1111/febs.70418
  29. Commun Med (Lond). 2026 Jan 28.
    Selective blockade of latent TGF-β1 activation suppresses tissue fibrosis with good safety.
    Masakazu Kanamori, Izumi Sato, Christine Xing'er Koo, Yang Sun, Hiroki Kawauchi, Kenji Nakagawa, Atsuko Murai, Kentaro Asanuma, Siok Wan Gan, Chai Ling Pang, Yuichiro Shimizu, Meiri Shida-Kawazoe, Chisako Kanamaru, Yoko Kayukawa, Natsuko Hada, Ken Ohmine, Takehisa Kitazawa, Junichi Nezu, Tomoyuki Igawa, Hideaki Shimada.
       BACKGROUND: Fibrosis is a hallmark of organ failure observed after chronic epithelial injury and inflammation. The transforming growth factor beta (TGF-β) is the master regulator of fibrogenesis, so blockade of the TGF-β pathway is a potential treatment strategy for fibrosis; however, the therapeutic potential of pan-TGF-β blockade is limited by side effects.
    METHODS: We generated SOF10, a humanized antibody that targets latent TGF-β1 and selectively blocks protease- and integrin αvβ8-mediated latent TGF-β1 activation. We conducted gene expression and histological analyses in nonalcoholic steatohepatitis (NASH)/liver fibrosis and renal interstitial fibrosis models. We also evaluated the combination effect of SOF10 with an immune checkpoint inhibitor in a syngeneic mouse model and performed safety studies in mice and monkeys.
    RESULTS: Here we show that SOF10 reduces fibrosis in NASH/liver fibrosis and renal interstitial fibrosis models and improves renal function in a chronic kidney disease model. Furthermore, the combination of SOF10 with an anti-PD-L1 antibody decreases tumor growth in a syngeneic mouse model. SOF10 demonstrates safety in both mice and monkeys.
    CONCLUSIONS: Selective blockade of latent TGF-β1 activation represents a promising approach for treating a broad range of fibrotic diseases and cancers. By specifically targeting TGF-β1, SOF10 may offer a safer and more effective therapeutic option compared to non-selective TGF-β inhibitors. This strategy has the potential to transform the treatment paradigm for fibrosis-related conditions.
    DOI:  https://doi.org/10.1038/s43856-026-01408-w
  30. Commun Biol. 2026 Jan 29.
    LncRNA P4HA2-AS1 drives renal interstitial fibrosis via trim32-mediated k63 ubiquitination of ULK1 and autophagic dysregulation.
    Zhou Pan, Fei Xiao, Wei Hu, Ting Liu, Wenjing Shu, Yan Leng, Qingqing Yi, Yan Zeng, Fan Cheng, Hengcheng Zhu, Kang Yang.
      Renal interstitial fibrosis (RIF), the central pathological driver of chronic kidney disease (CKD) progression, remains mechanistically incompletely defined. While long non-coding RNAs (lncRNAs) are emerging as critical regulators of CKD, their roles in RIF pathogenesis are poorly understood. Here, we identify the fibrosis-associated lncRNA P4HA2-AS1 as a key modulator of RIF through integrated analyses of unilateral ureteral obstruction (UUO) mice and TGF-β-stimulated human renal tubular epithelial cells (HK-2), combined with RNA sequencing, RNA pull-down, ubiquitination profiling, and autophagic flux assays. P4HA2-AS1 was markedly upregulated in fibrotic kidneys, and its suppression attenuated fibrotic phenotypes in vivo and in vitro while restoring autophagic flux. Mechanistically, P4HA2-AS1 directly binds the E3 ubiquitin ligase TRIM32, impeding its proteasomal degradation. This stabilization enhances TRIM32-mediated K63-linked ubiquitination of ULK1, a master autophagy initiator, leading to aberrant autophagic activation and fibrotic progression. Our study uncovers a previously unrecognized P4HA2-AS1/TRIM32/ULK1 axis that couples dysregulated autophagy to RIF, proposing lncRNA-protein interaction targeting as a therapeutic strategy against renal fibrosis.
    DOI:  https://doi.org/10.1038/s42003-026-09618-7
  31. J Biomed Mater Res A. 2026 Feb;114(2): e70038
    Mechanical Cues Regulate Estrogen and Progesterone-Induced Nascent ECM Deposition by Human Endometrial Stromal Fibroblasts.
    Grace K Hinds, Arina Velieva, Joshua Yu-Chung Liu, Avinava Roy, Rima Chavali, Claudia Loebel.
      The endometrium, the mucosal lining of the uterus, is a highly regenerative tissue that undergoes cyclic remodeling guided by tightly regulated levels of estrogen and progesterone. Stromal cells, including fibroblasts, are embedded within the connective tissue of the endometrium and contribute to the rapidly changing extracellular matrix (ECM). During the secretory phase, high levels of progesterone induce decidualization of endometrial fibroblasts, which changes their morphology and protein secretion. While it has been shown that the mechanical properties of endometrial tissue, such as the elastic modulus, also contribute to tissue homeostasis and pathology, the interplay between hormones and tissue modulus in contributing to ECM remodeling remains unknown. To address this, we used hydrogels of varying elastic moduli (5 and 15 kPa) to induce decidualization of endometrial fibroblasts. Using metabolic labeling of glycosylated nascent ECM proteins, we then visualized and measured the deposition of newly secreted (nascent) ECM proteins during decidualization. In addition, we designed an automated ImageJ-based workflow for unbiased quantification of nascent ECM deposition. Our results demonstrate that both 5 and 15 kPa hydrogels support decidualization of endometrial stromal fibroblasts as shown by an increase in cell flattening and prolactin secretion. While increased hydrogel modulus alone enhances nascent ECM deposition, decidualization produces an additional increase that converges to similar levels regardless of the initial hydrogel modulus. Collectively, these findings demonstrate that endometrial stromal fibroblasts deposit nascent ECM that is enhanced during decidualization. These observations may provide new insights toward future studies addressing the mechanisms of ECM remodeling in endometrial tissue.
    DOI:  https://doi.org/10.1002/jbma.70038
  32. Int J Mol Sci. 2026 Jan 14. pii: 815. [Epub ahead of print]27(2):
    Transient Receptor Potential (TRP) Channels as Fundamental Regulators of Fibrosis and Pruritus-A New Therapeutic Target for Pathological Scar Management.
    Yuchen Tang, Zheng Zhang, Yixin Zhang.
      Pathological scars (PSs), which encompass hypertrophic scars (HSs and keloids, pose significant challenges in the realm of plastic surgery due to their characteristics of excessive fibrosis and persistent pruritus. This fibrosis can lead to both functional limitations and aesthetic issues, while pruritus often indicates ongoing scar development and greatly impacts quality of life. Although the underlying cause of both conditions is linked to dysregulated inflammation, the specific connections between fibrosis and pruritus are not well understood. Transient receptor potential channels (TRP), known for their roles in systemic fibrotic diseases and as mediators of chronic pruritus in skin disorders, may play a crucial role in the environment of pathological scars. This review compiles existing research to investigate the idea that certain TRP subfamilies (TRPA1, TRPV1, TRPV3, TRPV4) could link fibrosis and pruritus in pathological scars by interacting with common inflammatory mediators. We suggest that these channels might act as central molecular hubs that connect the signaling pathways of fibrosis and pruritus in these scars. Therefore, targeting TRP channels pharmacologically could be a promising approach to simultaneously alleviate both fibrosis and pruritus, potentially leading to a new dual-pathway treatment strategy for managing pathological scars. Our review also critically examines the current landscape of TRP-targeted therapies, pointing out challenges such as limited selectivity for specific subtypes and the lack of clinical trials focused on pathological scars, while emphasizing the necessity for interdisciplinary advancements in this area. In conclusion, while TRP channels are attractive targets for therapeutic intervention in pathological scars, their effective clinical application necessitates a more profound understanding of the mechanisms specific to scars and the creation of targeted delivery methods.
    Keywords:  fibrosis; pathological scars; pharmacotherapy; pruritus; targeted therapy; transient receptor potential channels
    DOI:  https://doi.org/10.3390/ijms27020815
  33. bioRxiv. 2025 Dec 30. pii: 2025.12.30.697039. [Epub ahead of print]
    TNFα and Endothelial IL-1 Receptor Signaling Drive Peritubular Capillary Regression and Fibrosis in Obstructive Kidney Injury.
    Charmain F Johnson, Kate Wheeler, Jun Xie, Jenna Chan, George E Davis, Courtney T Griffin.
      Capillary regression destabilizes tissue homeostasis and contributes to chronic organ dysfunction, yet the inflammatory pathways that drive pathological vessel loss remain incompletely defined. We previously identified the inflammatory cytokines TNFα and IL-1 as conserved mediators of physiological vessel regression in the neonatal mouse eye, but whether these cytokines contribute to pathological capillary regression in adult mice is unknown. In this study, we investigated the capillary regression that occurs along with inflammation in murine kidneys following irreversible unilateral ureteral obstruction (UUO) surgical challenge. Mice lacking genes encoding global TNFα, the endothelial IL-1 receptor IL-1R1, or both (double knockout, DKO) were examined at 10 days after UUO surgery. While loss of the individual genes did not affect peritubular capillary (PTC) regression, PTC regression was significantly reduced in DKO mice. This reduction in PTC regression correlated with less expression of the tubular epithelial injury marker KIM-1. DKO kidneys also displayed less fibrosis by Picrosirius Red and Masson's trichrome staining. These findings demonstrate that TNFα and endothelial IL-1R1 cooperatively drive pathological capillary regression in the irreversible UUO model of chronic kidney injury and that preservation of PTCs correlates with less renal tubular injury and fibrosis at 10 days after injury.
    NEW & NOTEWORTHY: Pathological PTC regression drives progressive kidney injury, but its inflammatory triggers are unclear. Using the UUO model, this study identifies cooperative TNFα and endothelial IL-1R1 signaling as key drivers of capillary loss. While deletion of either pathway alone was insufficient, combined loss preserved PTCs, reduced tubular injury, and attenuated fibrosis. These findings highlight synergistic inflammatory signaling in microvascular loss and suggest dual targeting may help preserve PTC integrity in chronic kidney disease.
    DOI:  https://doi.org/10.64898/2025.12.30.697039
  34. Comput Struct Biotechnol J. 2026 ;31 363-376
    Bicuculline from Forsythia suspensa attenuates liver fibrosis via TLR4/MD2 inhibition and suppression of MyD88/NF-κB signaling.
    Xiaozheng Zhang, Guicai Wu, Sili Peng, Haoran Xu, Kai Li, Tingjuan Huang, Zhizhen Liu.
      Liver fibrosis, a cardinal feature of chronic liver injury, involves hepatic stellate cells (HSCs) activation and excessive extracellular matrix (ECM) deposition. Upon liver fibrosis, TLR4 is highly expressed on HSCs and Kupffer cells. TLR4 activation induces liver inflammation followed by exacerbated fibrosis. Inhibition of TLR4 signaling represents a validated anti-liver fibrosis therapeutic approach. In the realm of liver fibrosis treatment, traditional Chinese medicine (TCM) has demonstrated certain anti-fibrotic effects in clinical practice after long-term application. However, due to the complex composition of TCM, understanding the underlying biological mechanisms and controlling drug quality remain challenging. To address these issues, this study developed a database of potential active ingredients from TCM against liver fibrosis and conducted virtual screening based on TLR4/MD2. It is worth noting that bicuculline, a known GABAA receptor antagonist, is a newly identified MD2 ligand that confers protection against liver fibrosis via disruption of TLR4 signaling. Bicuculline exhibits prominent anti-liver fibrosis activity in activated HSCs and effectively reduces fibrosis in bile duct ligation (BDL) and CCl4-induced mouse liver fibrosis models. Concomitantly, the upregulation of MyD88, phosphorylated NF-κB (p-NF-κB), and downstream cytokines (TNF-α, IL-1β, and IL-6) in activated HSCs and liver fibrosis models could be effectively attenuated by bicuculline treatment. Molecular dynamics simulations further revealed that bicuculline binds to the LPS-binding pocket of MD2, which may inhibit TLR4 dimerization and subsequent production of pro-inflammatory factors. This study endeavors to overcome the limitations of TCM treatment and explore novel anti-liver fibrosis drugs.
    Keywords:  Liver fibrosis; Molecular dynamics simulation; TCM prescription mining; Toll-like receptor 4
    DOI:  https://doi.org/10.1016/j.csbj.2025.12.026
  35. Eur J Pharmacol. 2026 Jan 22. pii: S0014-2999(26)00050-6. [Epub ahead of print]1015 178568
    The TWEAK/FN14 axis influences the phenotype of cardiac fibroblasts during pathological cardiac remodeling through the regulation of EGR1.
    Wenqiang Han, Qingsu Lan, Runtian Zhang, Zimeng Shen, Jingquan Zhong, Li Hao.
       BACKGROUND: Pathological cardiac remodeling is a critical process in the progression of cardiovascular diseases. To investigate the role and underlying mechanisms of the TWEAK/FN14 axis in cardiac fibrosis, we conducted both in vivo and in vitro experiments.
    METHODS AND RESULTS: Transcriptomic analysis and Western blotting revealed that FN14 expression was upregulated in animal models of pathological cardiac remodeling. Knockdown of FN14 using adeno-associated virus in spontaneously hypertensive rats significantly attenuated cardiac remodeling. In cardiac fibroblasts, FN14 knockdown and overexpression, validated by Western blotting, wound healing assay, and EdU assay, confirmed that the TWEAK/FN14 axis regulates fibroblast phenotypes. Activation of the TWEAK/FN14 axis increased the expression of pro-fibrotic genes and extracellular matrix deposition. Furthermore, inhibitor and rescue experiments demonstrated that EGR1 functions as a critical downstream mediator in the TWEAK/FN14 axis-induced regulation of fibrosis.
    CONCLUSIONS: These findings suggest that targeting the TWEAK/FN14 axis in cardiac fibroblasts may provide a novel therapeutic strategy for preventing and treating cardiac fibrosis and adverse remodeling.
    Keywords:  Cardiac remodeling; EGR1; FN14; Fibrosis; TWEAK
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178568
  36. Adv Healthc Mater. 2026 Jan 28. e04765
    Extracellular Matrix Origin Directs Morphogenesis and Gene Regulation in Bioengineered Human Skin.
    Francesco Galardo, Giorgia Imparato, Costantino Casale, Francesco Urciuolo, Luca Mannino, Antonio Federico, Dario Greco, Paolo Antonio Netti.
      The cellular microenvironment plays a pivotal role in directing tissue development, repair, and homeostasis through a complex interplay of biochemical and mechanical cues. The extracellular matrix (ECM) serves as a key instructive component, guiding transcriptional programs that determine cell fate, function, and identity. In this study, we investigated the impact of microenvironmental context on the biofabrication of human skin equivalents, comparing constructs based on endogenous versus exogenous ECMs. Specifically, we compared collagen-based full-thickness skin models with full-thickness skin models based on a fibroblast-assembled endogenous ECM. Our RNA sequencing analyses reveal that ECM origin profoundly influences transcriptional trajectories, highlighting the importance of a native-like microenvironment in supporting appropriate gene expression profiles and morphogenetic processes. Notably, skin equivalents featuring endogenously produced ECMs exhibit physiologically relevant architecture, including a well-organized dermal-epidermal junction (DEJ), whereas constructs based on exogenous matrices, such as animal-derived collagen, display abnormal epithelial expansion and fail to replicate key structural features. These findings underscore the necessity of recapitulating the native ECM to achieve functional tissue constructs in vitro and raise critical considerations regarding scaffold choice in regenerative medicine and tissue engineering applications.
    Keywords:  ECM; RNA‐Seq, transcriptomics; full‐thickness skin equivalent; gene expression profiling; organotypic culture
    DOI:  https://doi.org/10.1002/adhm.202504765
  37. Ann Hepatol. 2026 Jan 23. pii: S1665-2681(25)00399-0. [Epub ahead of print] 102174
    Regression of fibrosis and portal hypertension in chronic liver disease: Endothelial perspectives and clinical implications.
    Yuly P Mendoza, Raül Pastó, Sonia E Selicean, Jordi Gracia-Sancho.
      Chronic liver disease (CLD) remains a major global health burden, driven by persistent hepatic injury that triggers inflammation, vascular dysfunction and progressive extracellular matrix (ECM) deposition. These processes disrupt the liver architecture, leading to advanced liver fibrosis or cirrhosis and increasing the risk of severe complications such as portal hypertension, hepatocarcinoma and even death. While fibrosis and cirrhosis were historically regarded as irreversible, accumulating experimental and clinical evidence now support the potential for fibrosis and even cirrhosis regression once the etiological insult is controlled. Nevertheless, fibrosis regression is not universally observed: about 25% of patients with advanced CLD and sustained hepatitis B virus suppression and over one-third of those with metabolic dysfunction-associated steatotic liver disease after bariatric surgery fail to experience fibrosis regression. Notably, fibrosis regression is often partial and slower in advanced CLD or cirrhosis, especially in decompensated stages, highlighting the need for a better understanding of the cellular and molecular mechanisms that either facilitate or restrict hepatic tissue repair. This review summarizes current knowledge on the dynamics of liver fibrosis regression, with a particular emphasis on the liver sinusoidal endothelial cell (LSEC) as a central regulator of the microenvironment. We discuss how LSEC phenotype determines interactions with hepatic stellate cells (HSCs), immune cells, and hepatocytes, thereby shaping the balance between fibrogenesis and resolution. Mechanisms such as endothelial capillarization, macrophage-driven inflammation, HSC activation and hepatocyte regeneration are examined in the context of both disease progression and regression. Special attention is given to vascular alterations, which represent a major limiting factor for recovery in advanced CLD. We also highlight recent experimental advances, including insights from extracellular vesicle-mediated communication, microenvironmental stiffness, transcriptomic studies of LSEC plasticity during regression, and novel biomarkers of fibrosis regression. Understanding the spatiotemporal orchestration of these processes may inform novel therapeutic strategies aimed at restoring vascular and parenchymal homeostasis, ultimately enabling fibrosis reversal, portal pressure reduction, and improved clinical outcomes in patients with advanced CLD.
    Keywords:  Cirrhosis; LSEC; cirrhosis regression; fibrosis regression; liver endothelium; liver sinusoidal endothelial cell
    DOI:  https://doi.org/10.1016/j.aohep.2025.102174
  38. Oncol Res. 2026 ;34(2): 10
    Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications.
    Yang Wu, Dong Xu, Run Shi, Mingwei Zhan, Shaohui Xu, Xin Wang, Jianpeng Zhang, Zhaokai Zhou, Weizhuo Wang, Yongjie Wang, Minglun Li, Zihao Xu, Kaifeng Su.
      Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, largely due to therapy resistance and metastatic progression. Increasing evidence highlights the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), as a critical determinant of disease behavior. CAFs constitute a heterogeneous population originating from fibroblasts, mesenchymal stem cells, endothelial cells, epithelial cells undergoing epithelial-mesenchymal transition (EMT), and adipose tissue. Through dynamic crosstalk with tumor, immune, endothelial, and adipocyte compartments, CAFs orchestrate oncogenic processes including tumor proliferation, invasion, immune evasion, extracellular matrix remodeling, angiogenesis, and metabolic reprogramming. This review comprehensively summarizes the cellular origins, phenotypic and functional heterogeneity, and spatial distribution of CAFs within the prostate TME. We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance, and critically evaluate emerging strategies to therapeutically target CAF-mediated signaling, metabolic, and immune pathways. By integrating recent advances from single-cell and spatial transcriptomics (ST), our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.
    Keywords:  Prostate cancer; cancer-associated fibroblasts; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2025.073265
  39. Ann Anat. 2026 Jan 27. pii: S0940-9602(26)00020-8. [Epub ahead of print] 152799
    Perspectives on intrinsic articular cartilage interfaces.
    Sandeep Silawal, Gundula Schulze-Tanzil.
       INTRODUCTION: According to the current concept the joint is an organ composed of multiple tissues forming manifold communicating interfaces. Moreover, cartilage itself presents typical intrinsic zonal interfaces. Since the healthy joint cartilage is not vascularized, soluble mediators are distributed by the synovia fluid flow in the cartilage extracellular matrix (ECM) of the joint compartments. This distribution is dependent on intermittent mechanical loading and water flow in the joint. Hence, soluble factors play a pivotal role in articular cartilage interfacial communication. These mediators must traverse the cartilage ECM, whose permeability and binding capacity for growth factors and signaling molecules vary according to its structural integrity (e.g. pathology) and homeostasis.
    MAIN PART: Cartilage lesions, e.g., due to osteoarthritis (OA), substantially alter the interfacial communication. Chondrocyte phenotype, subpopulations and cartilage ECM density changes in OA. Superficial zones, and during disease progression, deep zones, are lost over time. OA is closely linked to metabolic disorders like type 2 diabetes mellitus (T2DM), characterized by hyperglycemia. Elevated glucose levels promote aberrant glycosylation of cellular and ECM glycoproteins, formation of advanced glycation end products (AGEs), excessive ECM cross-linking, reduced elasticity, and chondrocyte aging associated with the senescence-associated secretory phenotype (SASP). Cartilage immunobiology comprises a dysregulation of complement split fragments and pro-/anti-inflammatory mediators: their release influences chondrocyte phenotype.
    CONCLUSIONS: Intrinsic cartilage interface communication changes in joint cartilage disorders such as OA and associated systemic diseases. The role of immunobiological complement factors and pleiotrophic cytokines is still to be elucidated in articular cartilage in vivoand in OA patients.
    Keywords:  Complement; Human Anatomy; Human Biology; Intrinsic cartilage interface; Joint interfaces; Musculoskeletal Disease; Osteoarthritis; Perspective
    DOI:  https://doi.org/10.1016/j.aanat.2026.152799
  40. Biomedicines. 2026 Jan 01. pii: 89. [Epub ahead of print]14(1):
    Nonthermal Atmospheric Plasma Modulates Palatal Wound Healing in Rats: A Morphometric, Histopathologic and Immunohistochemical Analysis.
    Basak Kusakci Seker, Hakan Ozdemir, Suna Karadeniz Saygili.
      Background/Objectives: Non-thermal atmospheric plasma (NTAP) has recently gained attention as a promising tool for tissue regeneration due to its ability to modulate cellular signaling and enhance wound repair. However, its effects on oral mucosal healing and associated molecular pathways remain insufficiently characterized. This study aimed to investigate the histological and immunohistochemical effects of NTAP on palatal wound healing in rats and to evaluate key biomarkers involved in angiogenesis, proliferation, and extracellular matrix remodeling. Methods: Sixty rats were randomly assigned to three groups: Saline Control Group (SCG), Chlorhexidine Gluconate Group (CHG), and NTAP-Treated Group (NTAPG). Standardized full-thickness excisional wounds were created in the central palatal mucosa. Animals were sacrificed on postoperative days 7, 14, and 21. Histological assessments included vascularization, inflammatory cell infiltration, collagen fiber organization, and epithelial gap measurements. Immunohistochemical analyses were performed using antibodies targeting VEGF-A, TGF-β, FGF-2, CD34, α-SMA, and Ki67 to evaluate angiogenesis, fibroblast activity, and cellular proliferation. Results: NTAP treatment significantly elevated TGF-β levels at all time points and increased α-SMA-positive cell counts on days 7 and 14. FGF-2 expression was the highest in NTAPG, while VEGF-A and CD34 levels were significantly elevated, indicating robust angiogenic activity. NTAP also reduced inflammatory cell infiltration relative to the other groups. NTAPG exhibited enhanced fibroblast proliferation, increased collagen deposition, improved vascularization, and accelerated re-epithelialization compared with SCG and CHG. Conclusions: NTAP significantly promoted palatal wound healing by enhancing proliferative activity, stimulating growth factor expression, and accelerating tissue repair. These findings suggest that NTAP may serve as an effective therapeutic approach for improving oral mucosal wound healing.
    Keywords:  angiogenesis; fibroblast; growth factors; non-thermal atmospheric plasma; oral mucosa; plasma medicine; plasma-induced regeneration; wound healing
    DOI:  https://doi.org/10.3390/biomedicines14010089
  41. Oncogene. 2026 Jan 28.
    Matrix stiffness-driven cytoskeletal remodeling and tumor progression in anaplastic thyroid cancer via integrin-focal adhesion kinase signaling.
    Chenyao Li, Yingying Sun, Xu Shan, Tianxue Yang, Guang Chen.
      Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC aggressiveness through mechanotransduction mediated by the Integrin α6β4/Focal Adhesion Kinase (FAK) axis. By engineering collagen-coated polyacrylamide hydrogels with tunable rigidity, we demonstrated that high ECM stiffness (60 kPa) markedly enhanced ATC cell proliferation, clonogenicity, migration, and invasion. Mechanistically, stiff matrices induced cytoskeletal reorganization, activated RhoA/Rac1/Cdc42 signaling, and upregulated Integrin α6β4-FAK pathway components, as validated by transcriptomic, proteomic, and functional assays. Pharmacological inhibition of FAK reversed stiffness-dependent tumor-promoting effects in vitro. In vivo, mice injected with tumor cells pre-cultured on high-stiffness ECM-mimicking hydrogels exhibited accelerated subcutaneous tumor growth and increased lung metastatic burden, which were significantly attenuated by FAK-targeted therapy. These findings establish ECM stiffness as a biomechanical determinant of ATC progression and metastasis, offering novel insights into microenvironment-driven malignancy and highlighting FAK as a promising therapeutic target to disrupt mechanosignaling in ATC.
    DOI:  https://doi.org/10.1038/s41388-025-03674-9
  42. Nat Rev Rheumatol. 2026 Jan 26.
    Mechanisms of fibrotic tissue remodelling: insights from systemic sclerosis.
    Jörg H W Distler, David Launay, Carol Feghali-Bostwick, Alexandru-Emil Matei, Maria Trojanowska, Johann E Gudjonsson.
      Systemic sclerosis (SSc) is a prototypical systemic immune-mediated fibrosing disease that affects the skin, the lungs, the heart, the kidneys and the intestinal tract. Similar to many other fibrotic diseases, SSc is associated with high morbidity and mortality and therapeutic options are limited. Fibrosis arises from a complex interplay of vascular damage, inflammation and prolonged, misdirected repair responses. The progressive accumulation of extracellular matrix perturbs the physiological tissue architecture and commonly leads to failure of the affected organs. Understanding the mechanisms of fibrotic tissue remodelling can lead to the identification of preclinical targets. Novel fibrosis-promoting cell subpopulations, the interplay of fibroblasts with B cells and macrophages, the nerve-fibroblast axis, matrikines and matricryptins, senescence, profibrotic transcription factors, developmental pathways and epigenetic tissue memory are all important drivers of fibrotic tissue remodelling that might offer potential for novel therapies to improve outcomes for patients with SSc and possibly other fibrotic conditions.
    DOI:  https://doi.org/10.1038/s41584-025-01349-z
  43. J Pathol. 2026 Jan 26.
    Uncoupling TGFβ1 signalling from collagen protein synthesis in Dupuytren's disease.
    Gabriella Cooper, Jade A Gumbs, Sahem Alkharabsheh, Katie J Lee, Alan Carter, Hannah Coleman, Niamh S O'Heneghan-Yates, Rama Ijaz, Emma Beamish, Lisa A Menezes, Triantafillos Liloglou, Peter D Clegg, Elizabeth G Canty-Laird.
      Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, potentially due to continual production of matrisomal proteins. Here, metabolic labelling and proteomics identified differences in the new synthesis and composition of matrisomal proteins between Dupuytren's tissue and normal PF. Dupuytren's tissue actively synthesised type I collagen, fibronectin (FN1), matrix metalloproteinases-2 and -3 (MMP2, MMP3) and tissue inhibitor of metalloproteinases 2 (TIMP2). Both tissues actively synthesised insulin-like growth factor binding protein 7 (IGFBP7). Label-free analysis implicated the transforming growth factor-β (TGFβ) pathway in the matrisomal profile of Dupuytren's tissue. The effect of TGFβ isoforms on COL1 mRNA expression was first tested in cultured young and aged equine tenocytes. COL1A1 mRNA responded to treatment with all TGFβ isoforms and was more highly expressed in cells from aged samples. In aged human cells, COL1A1 and COL1A2 mRNA was higher in cells derived from Dupuytren's tissue than normal PF and in response to TGFβ1, but no changes in COL1A1 or COL1A2 CpG methylation were detected. TGFβ1 treatment only resulted in increased type I collagen protein accumulation in the media of Dupuytren's nodule cells. In three-dimensional cultures, COL1A1 mRNA was lower in normal PF than in Dupuytren's cells, but TGFβ1 treatment only increased type I collagen accumulation in the media of normal PF cultures, and TGFβ1 inhibition did not alter new collagen protein synthesis. TGFβ1 inhibition in Dupuytren's tissue explants did not alter the proportion of homotrimeric type I collagen, nor was this changed in skin or tendon of the tight-skin (TSK) mouse, a naturally occurring model of indirect TGFβ1 activation. Therefore, the role of TGFβ in Dupuytren's disease may be predominantly related to myofibroblast phenoconversion and contractility rather than directly altering collagen protein synthesis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  Dupuytren's; TGF‐beta; collagen; fibrosis; metabolic labelling; proteomics
    DOI:  https://doi.org/10.1002/path.70020
  44. Int J Biol Sci. 2026 ;22(3): 1283-1305
    Sema3dhi Fibroblasts Promote Acute Kidney Injury Fibrotic Progression Through Confining Endothelial Cell Migration.
    Qiuyu Xie, Xiaohong Xin, Weijian Yao, Zehua Li, Yuanyuan Ma, Lei Qu, Yiyi Ma, Chengang Xiang, Suxia Wang, Gang Liu, Ying Chen, Li Yang.
      Acute kidney injury (AKI) often leads to incomplete recovery of renal function, progressing to chronic kidney disease (CKD). Key pathological features in the AKI-CKD transition include microvascular rarefaction and fibrosis. However, the direct effects of activated fibroblasts on microvasculature and endothelial cells remain unclear. We constructed a single-cell RNA sequencing (scRNA-seq) database from unilateral ischemia reperfusion injury (uIRI) mouse model and identified five heterogeneous fibroblast subpopulations, with C0-Sema3dhi fibroblasts significantly increasing post-injury and correlating with reduced endothelial cells. Conditioned medium from Sema3dhi-NRK49F cells inhibited focal adhesion formation and induced cytoskeletal collapse in human umbilical vein endothelial cells (HUVECs), preventing migration and angiogenesis. Mechanistically, Sema3dhi fibroblasts secrete Sema3d, activating the endothelial Plexin D1 receptor, leading to Arf6 activation and integrin β1 internalization, thus suppressing endothelial function. Systemic administration of Sema3d-shRNA using adeno-associated virus serotype 9 (AAV9) effectively reduced Sema3d levels and significantly alleviated renal fibrosis in mice. The presence of SEMA3D+ fibroblasts was confirmed by analyzing human scRNA-seq data and through immunofluorescence staining of kidney sections from patients with kidney diseases. This study reveals new target for mitigating renal fibrosis and microvascular loss, suggesting that targeting the Sema3d signaling pathway may provide a novel strategy for preventing AKI fibrotic progression.
    Keywords:  Sema3d; acute kidney injury; angiogenesis; endothelial cell; fibroblast; migration
    DOI:  https://doi.org/10.7150/ijbs.124971
  45. JCI Insight. 2026 Jan 22. pii: e195176. [Epub ahead of print]
    LYVE1 ectodomain shedding blunts lymphatic transmigration and clearance of macrophages during kidney injury.
    Jing Liu, Yuqing Liu, Wenqian Zhou, Saiya Zhu, Jianyong Zhong, Haichun Yang, Annet Kirabo, Valentina Kon, Chen Yu.
      Although renal fibrosis is predominantly driven by the accumulated inflammatory cells that secrete pro-inflammatory factors within the kidney, the key mechanisms underlying macrophage clearance from the kidney are not well understood. The interaction of hyaluronan (HA) with lymphatic endothelial hyaluronan receptor 1 (LYVE1) constitutes a critical initial step in macrophage adhesion and removal by lymphatic vessels. This study investigates alterations in LYVE1 during kidney disease and elucidates its role in macrophage trafficking. Three renal fibrosis models demonstrated a reduction in full-length LYVE1 and an increase in the soluble LYVE1 fragment. Immunostaining of fibrotic kidneys showed significantly reduced expression of soluble LYVE1 compared with intracellular fragment (Cyto-LYVE1), demonstrating ectodomain shedding of LYVE1 in vivo and in vitro. Functionally, human lymphatic endothelial cells exposed to TGF-β1 exhibited significant decrease in macrophage adhesion and transendothelial migration compared to controls. Mechanistic analyses identified increased matrix metalloproteinase (MMP)9 in renal injury as a key upstream regulator of LYVE1 shedding. MMP9 inhibitors reduced LYVE1 shedding, enhanced macrophage adhesion and trafficking, and mitigated macrophage accumulation and disease progression. In conclusion, MMP9-induced LYVE1 shedding is linked to progressive kidney fibrosis and macrophage accumulation. LYVE1 shedding inhibitors offer potential as therapeutic agents for mitigating immune overload and kidney fibrosis.
    Keywords:  Fibrosis; Inflammation; Lymph; Macrophages; Nephrology; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.195176
  46. Cancer Res. 2026 Jan 27.
    Targeting LRRC15 in Cancer-Associated Fibroblasts Modifies the Extracellular Matrix and Enhances Tumor Immune Responses to Suppress Lung Cancer Progression.
    Lu Qi, Guohui Dang, Xinnan Ling, Yuhui Miao, Yufei Bo, Yuhang Zhai, Xiaowei Chen, Qianting Zhai, Liangtao Zheng, Yu Zhang, Yanjie Li, Chang Liu, Hongtao Fan, Wen Si, Dan Tong, Zhenlin Yang, Xueda Hu, Dongfang Wang, Sijin Cheng, Zemin Zhang, Linnan Zhu.
      Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the tumor microenvironment (TME) and driving tumor progression. While single-cell transcriptomics has revealed the phenotypic and functional heterogeneity of CAFs, effective therapeutic strategies targeting CAFs remain urgently needed. Here, we identified LRRC15+ CAFs as a tumor-specific CAF subset in lung cancer and proposed LRRC15 as a potential therapeutic target. LRRC15 deficiency suppressed lung cancer progression in mice by modulating macrophage polarization and enhancing CD8+ T cell activation. Mechanistically, LRRC15 deficiency inhibited CD206+ macrophage polarization by reducing extracellular matrix (ECM) production in CAFs, leading to increased CD8+ T cell cytotoxicity. Finally, development of a bispecific antibody targeting LRRC15 and TGF-β enabled effective downregulation of LRRC15 expression in CAFs and limited tumor progression in mice. This study highlights LRRC15 as a promising therapeutic target and provides insights into CAF-directed cancer treatment strategies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2871
  47. J Adv Res. 2026 Jan 25. pii: S2090-1232(26)00089-5. [Epub ahead of print]
    EVA1A responds to endoplasmic reticulum stress to regulate renal fibrosis by promoting TGF-β signaling pathway.
    Qiongdan Gao, Zhenkun Wang, Yuting Fu, Shuyi Lin, Haiping Liu, Yuanyuan Zhou, Yifei Wei, Zhenyu Ju, Lili Zhou, Bo Liu.
       INTRODUCTION: Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD), and ultimately leads to end-stage renal disease. ER-stress and TGF-β signaling pathway activation play critical roles in renal fibrosis, but the precise mechanisms underlying the intricate interplay between ER-stress and TGF-β signaling pathway remain ambiguous. Our previous study has demonstrated that EVA1A responds to ER-stress to regulate hematopoietic stem cell regeneration; However, the function of EVA1A in renal fibrosis remains unexplored.
    OBJECTIVES: To elucidate the role of EVA1A in TGF-β signaling regulation and renal fibrosis.
    METHODS: We characterized EVA1A expression changes in chronic kidney disease through single-cell RNA-seq data analysis, immunohistochemical staining and Western blot analysis. Eva1a conditional knockout mouse subjected to unilateral-ischemia-reperfusion-injury (UIRI) and unilateral-ureteral-obstruction (UUO), two well-established and widely used fibrosis-related CKD mouse models, were used to investigate the role of EVA1A in renal fibrosis. Subsequently, we characterized the interaction of EVA1A and TGF-β receptor type Ⅱ (TGFBR2) by co-immunoprecipitation and bimolecular-fluorescence-complementation (BiFC) assays to clarify the regulatory mechanism of EVA1A in TGF-β signaling.
    RESULTS: We found that EVA1A was significantly upregulated in fibrotic kidneys from CKD patients and mice with UUO or UIRI treatment. Deletion of Eva1a significantly attenuated kidney fibrosis and damage in mice with UUO or UIRI treatment. Overexpression of EVA1A enhanced fibrosis levels in mice with UUO treatment and upregulated the expression of fibrosis-related proteins in cultured renal epithelial cells. Mechanistically, we found that ER stress upregulates EVA1A expression via CHOP in CKD mouse model. Subsequently, EVA1A interacted with BIP to stabilize and facilitate the secretion of TGFBR2 from ER to plasma membrane, thereby promoting TGF-β signaling activation and renal fibrosis.
    CONCLUSION: During the progression of CKD, EVA1A serves as a sensor for ER stress and regulates renal fibrosis by promoting TGF-β signaling pathway activity.
    Keywords:  ER stress; EVA1A; Renal fibrosis; TGF-β signaling; TGFBR2
    DOI:  https://doi.org/10.1016/j.jare.2026.01.064
  48. Biology (Basel). 2026 Jan 22. pii: 206. [Epub ahead of print]15(2):
    Suppressing Endothelial-Mesenchymal Transition Through the Histone Deacetylase 1/GATA Binding Protein 4 Pathway: The Mechanism of Protocatechuic Acid Against Myocardial Fibrosis Revealed by an Integrated Study.
    Chengsi Jin, Chongyu Shao, Guanfeng Xu, Haitong Wan.
       BACKGROUND: Myocardial fibrosis, a central pathological process leading to heart failure, lacks specific mechanism-based therapies. Although the anti-inflammatory activity of the natural compound protocatechuic acid is recognized, its direct anti-fibrotic mechanism, particularly concerning the critical role of endothelial-mesenchymal transition (EndMT), remains unexplored. This study aimed to investigate the protective effects and underlying mechanisms of protocatechuic acid.
    METHODS: The study employed both in vivo and in vitro models. For in vivo evaluation, a rat model of myocardial fibrosis was induced by isoproterenol hydrochloride (ISO). For in vitro analysis, human umbilical vein endothelial cells (HUVECs) were stimulated with angiotensin II (Ang II) and subjected to siRNA-mediated histone deacetylase 1 (HDAC1) knockdown, alongside a co-culture model involving HUVECs and the AC16 human cardiomyocyte cells. Additionally, molecular docking and dynamics simulations were performed to evaluate the binding affinity and stability of protocatechuic acid with the target protein, HDAC1.
    RESULTS: In vivo, protocatechuic acid significantly improved cardiac function, attenuated pathological injury, and reduced collagen deposition in ISO-induced fibrotic rats. It also potently suppressed inflammatory responses and inhibited the EndMT process. These beneficial effects were associated with decreased HDAC1 and increased GATA binding protein 4 (GATA4) expression in perivascular regions, which suggests the modulation of the HDAC1/GATA4 pathway. In vitro, protocatechuic acid suppressed Ang II-induced endothelial inflammation in HUVECs. This effect was replicated by HDAC1 knockdown, thus confirming that the HDAC1/GATA4 pathway mediates its anti-inflammatory action at the cellular level. Furthermore, molecular docking and dynamics simulations indicated that protocatechuic acid stably binds to a key target, HDAC1.
    CONCLUSIONS: Protocatechuic acid alleviates inflammation and EndMT by inhibiting the HDAC1/GATA4 signaling pathway, thereby preserving cardiac function and retarding the progression of myocardial fibrosis. These findings provide a theoretical and experimental foundation for the potential application of protocatechuic acid in treating cardiovascular diseases.
    Keywords:  EndMT; HDAC1/GATA4; myocardial fibrosis; protocatechuic acid
    DOI:  https://doi.org/10.3390/biology15020206
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