bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–06–22
fifteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Relevance of GDF15 as a biomarker for clinical outcomes after bariatric surgery.
  2. Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
  3. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  4. Effect of hypoxia-inducible factor 1 on vascular endothelial growth factor expression in exercised human skeletal muscle: a systematic review and meta-analysis.
  5. Coordinated histone methylation loss and MYC activation promote translational capacity under amino acid restriction.
  6. VEGFB167 drives tumor progression by modulating the immune microenvironment.
  7. Role of leptin and adiponectin in immune response and inflammation.
  8. Targeting the hippo pathway as a potential regulator of immune checkpoints in cancer immunotherapy.
  9. Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
  10. Tumor-Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion.
  11. Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation.
  12. Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
  13. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
  14. Syndecan-4 promotes gastric cancer progression through activating TGF-β1 induced lipid reprogramming and contributes positive loop circuits.
  15. Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels.
  1. J Endocrinol. 2025 Jun 01. pii: JOE-25-0010. [Epub ahead of print]
    Relevance of GDF15 as a biomarker for clinical outcomes after bariatric surgery.
    Paula Urones, Paula Juiz-Valiña, Elena Outeiriño-Blanco, María Jesús García-Brao, Vanesa Balboa-Barreiro, Fernando Cordido, Susana Sangiao-Alvarellos.
      Bariatric surgery (BS) is the most effective long-term approach for weight loss and improvement of obesity-related comorbidities. Growth differentiation factor 15 (GDF15), a cytokine that enhances insulin sensitivity and reduces food intake, is a promising therapeutic target for obesity. This study assessed changes in circulating GDF15 levels in obesity and following BS, examining their associations with anthropometric, clinical, and biochemical parameters. Circulating GDF15 levels were measured in normal-weight individuals and patients with obesity prior to BS and at 3, 6 and 12 months post-surgery. Correlation analyses and linear mixed models were used to investigate variations in circulating GDF15 levels and to identify variables associated with GDF15 concentration. Circulating GDF15 levels were elevated in patients with obesity compared to normal-weight individuals and were higher in men than in women. In the combined cohort of obese and normal-weight individuals, circulating GDF15 levels positively correlated with weight, BMI, fat mass, glucose markers, C-reactive protein, transaminases, triglycerides, urea, creatinine and uric acid, and negatively correlated with apolipoprotein A and total, HDL and LDL cholesterol. In the obese cohort, however, circulating GDF15 levels showed a negative correlation with fat mass, while other associations persisted. After BS, circulating GDF15 levels significantly decreased, particularly in patients with hypertension or type 2 diabetes (T2D). One year post-surgery, ∆GDF15 was negatively associated with BMI and positively with excess weight loss and excess BMI loss. In conclusion, BS significantly reduces circulating GDF15 levels, particularly in patients with hypertension or T2D, indicating an association with clinical improvement after BS.
    DOI:  https://doi.org/10.1530/JOE-25-0010
  2. Redox Biol. 2025 Jun 09. pii: S2213-2317(25)00228-9. [Epub ahead of print]85 103715
    Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
    Rehna Paula Ginting, Hoang-Anh Pham-Bui, Choijamts Munkhzul, Siti Aisyah Fuad, Ahyeon Son, Jong-Seok Moon, Jaeseok Han, Mihye Lee, Min-Woo Lee.
      Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold-induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.
    DOI:  https://doi.org/10.1016/j.redox.2025.103715
  3. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  4. Am J Physiol Cell Physiol. 2025 Jun 16.
    Effect of hypoxia-inducible factor 1 on vascular endothelial growth factor expression in exercised human skeletal muscle: a systematic review and meta-analysis.
    Jerónimo Aragón-Vela, Rafael A Casuso.
      Aim: Within contracting human skeletal muscle (SKM), oxygen pressure significantly drops, which has been linked to the activation of a signaling cascade mediated by hypoxia-inducible factor 1α (HIF-1α). This cascade leads to SKM angiogenesis through vascular endothelial growth factor (VEGF). However, the role of HIF-1α in exercise-induced VEGF expression within SKM remains unclear. Methods: In this study, we systematically reviewed the literature to quantitatively synthesize all available evidence on HIF-1α activation in exercised human muscle. Results: We identified 21 studies providing 39 effect sizes of pre- and post-exercise SKM HIF-1α data from 235 subjects, with 15 of them also presenting data on VEGF mRNA levels. HIF-1α mRNA increased in response to high-intensity and resistance exercise, regardless of participants' physical fitness levels. Notably, meta-regression showed that exercise-induced VEGF expression is not modulated by HIF-1α mRNA levels. Similarly, when plotting exercise-induced fold changes of VEGF and HIF-1α no significant relationship was observed. Conclusion: Our findings demonstrate that HIF-1α is expressed in contracting SKM. However, the role of HIF-1α in the exercise-induced angiogenic response remains unclear, as most of the available evidence is limited to transcriptional data.
    Keywords:  HIF-1; VEGF; angiogenesis; exercise; hypoxia; skeletal muscle; training
    DOI:  https://doi.org/10.1152/ajpcell.00297.2025
  5. Cancer Metab. 2025 Jun 16. 13(1): 29
    Coordinated histone methylation loss and MYC activation promote translational capacity under amino acid restriction.
    Chen Cheng, Trent Su, Marco Morselli, Siavash K Kurdistani.
       BACKGROUND: Cells adapt to nutrient fluctuations through both signaling and epigenetic mechanisms. While amino acid (AA) deprivation is known to suppress protein synthesis via mTORC1 inactivation, the epigenetic pathways that support cellular adaptation and recovery remain poorly understood. We investigated how chromatin and transcriptional changes contribute to maintaining translational capacity during AA restriction and priming cells for growth upon AA repletion.
    METHODS: Human cells were cultured under amino acid-replete or -depleted conditions, and global histone methylation levels were assessed by Western blotting and ChIP-seq. RNA-seq and chromatin-associated RNA-seq (chromRNA-seq) were used to evaluate gene expression and transcriptional output. Ribosome profiling and [35S]-methionine/cysteine or O-propargyl-puromycin (OPP) incorporation assays measured protein synthesis. Functional contributions of SETD8 and MYC were tested through knockdown and overexpression experiments.
    RESULTS: AA deprivation induced a selective, genome-wide loss of H4K20me1, particularly from gene bodies, and led to increased MYC expression and binding at promoter regions. These changes were most pronounced at genes encoding ribosomal proteins and translation initiation factors. Although overall protein synthesis declined during AA restriction, these cells showed increased translational capacity evidenced by accumulation of monomeric ribosomes and enhanced translation upon AA repletion. Loss of H4K20me1 was independent of mTORC1 signaling and partly driven by SETD8 protein downregulation. While MYC overexpression alone was insufficient to upregulate translation-related genes, its combination with SETD8 knockdown in nutrient-rich conditions was both necessary and sufficient to induce expression of these genes and enhance protein synthesis.
    CONCLUSIONS: Our findings reveal a chromatin-based mechanism by which cells integrate metabolic status with transcriptional regulation to adapt to amino acid limitation. Loss of H4K20me1 and increased MYC activity act in parallel to prime the translational machinery during AA deprivation, enabling rapid recovery of protein synthesis upon nutrient restoration. This mechanism may help explain how cells maintain competitive growth potential under fluctuating nutrient conditions and has implications for understanding MYC-driven cancer progression.
    Keywords:  Amino acid restriction; Cancer; Epigenetic adaptation; H4K20me1; Histone modifications; MYC; Translational capacity
    DOI:  https://doi.org/10.1186/s40170-025-00399-x
  6. Int Immunopharmacol. 2025 Jun 12. pii: S1567-5769(25)01038-0. [Epub ahead of print]161 115048
    VEGFB167 drives tumor progression by modulating the immune microenvironment.
    Yaowu Zheng, Quangang Chen, He Zhang, Xin Li, Salah Adlat, Yanan Yu, Noor Bahadar, Rajiv Kumar Sah, Wei Xu, Ankang Hu, Xiaodan Lu, Renjin Chen, Yang Chen.
      Vascular endothelial growth factor B (VEGFB), a member of VEGF family, shares the VEGFR1 receptor with VEGFA. VEGFB has two isoforms, VEGFB167 and VEGFB186, whose distinct biological roles remain poorly characterized. To elucidate the isoform-specific functions of VEGFB in tumorigenesis, we utilized transgenic mouse models, including VEGFB overexpression (aP2-Vegfb167, aP2-Vegfb186) and VEGFB knockout (Vegfb-/-), along with tumor cell lines (B16-F10, U14 and LLC). Our findings revealed that VEGFB167 acts as a potent promoter of tumor growth. VEGFB inactivation significantly retards tumor growth and tumor cell metastasis. Mechanistically, VEGFB deficiency alters the tumor microenvironment by shifting tumor-associated macrophages (TAMs) from a pro-tumor M2 phenotype to an anti-tumor M1 phenotype, thereby enhancing anti-tumor immunity. Notably, the impact of VEGFB on tumor growth and metastasis surpasses that of VEGFA, highlighting its potential as a promising therapeutic target. These findings establish VEGFB167 as a key regulator of tumor progression and suggest that targeting VEGFB signaling could provide novel strategies for VEGFB-sensitive cancers.
    Keywords:  Macrophage; STAT3; Tumor microenvironment; VEGFB; VEGFR1
    DOI:  https://doi.org/10.1016/j.intimp.2025.115048
  7. Int Immunopharmacol. 2025 Jun 13. pii: S1567-5769(25)01072-0. [Epub ahead of print]161 115082
    Role of leptin and adiponectin in immune response and inflammation.
    Chang Liu, Xiaojiao Li.
      Adipose tissue has gained significant attention for its role in immune response and inflammation through the secretion of adipokines. Adipokines, such as leptin and adiponectin, are secreted by adipose tissue and have been implicated in various physiological processes, with a focus on their role in modulating immune responses and inflammation. Leptin and adiponectin are the most abundant adipokines in human, playing a crucial role in regulating functions of the heart, skeletal muscle, growth, and inflammation. Leptin, a pro-inflammatory adipokine, is involved in controlling food intake and energy expenditure, and it influences immune cell activation and cytokine production. In contrast, adiponectin, an anti-inflammatory adipokine, circulates at high levels in the plasma and modulates immune cell functions, counteracting the effects of leptin. Here we provided an overview of the role of adipokines in immune response and inflammation. In addition，The leptin-adiponectin ratio (Adpn/Lep) has emerged as a significant indicator of various metabolic diseases and conditions. Further research is needed to fully elucidate the mechanisms by which adipokines influence immune responses and to identify potential therapeutic targets for inflammatory and metabolic disorders.
    Keywords:  Adipokines; Adiponectin; Inflammation; Leptin
    DOI:  https://doi.org/10.1016/j.intimp.2025.115082
  8. Int Immunopharmacol. 2025 Jun 14. pii: S1567-5769(25)01057-4. [Epub ahead of print]161 115067
    Targeting the hippo pathway as a potential regulator of immune checkpoints in cancer immunotherapy.
    Yu-Ying Meng, Xin Chang, Si-Si Cao, Ping Ma, Yi Ou-Yang, Min Dong.
      The Hippo pathway is a conserved signaling cascade in mammals, known for its critical role in regulating cellular functions, including cell growth, differentiation, and organ size. These functions are largely mediated by the transcriptional effectors YAP and TAZ, which regulate gene expression through interactions with TEAD family transcription factors. Aberrant Hippo pathway signaling has been implicated in various aspects of cancer progression, including tumorigenesis, invasion and metastasis. This review explores the Hippo pathway has been implicated in the regulation of immune checkpoint (IC) expression and the role of the Hippo pathway in the tumor microenvironment (TME). Specifically, the Hippo pathway regulates the TME by influencing T-cell function, myeloid-derived suppressor cell (MDSC) activity, and macrophage polarization and recruitment. Furthermore, we also discuss how the Hippo pathway regulates immune checkpoint inhibitors (ICIs) and its potential for enhancing immunotherapy efficacy while reducing associated adverse effects.
    Keywords:  Genetic biomarker,immunotherapy; Hippo pathway; Immune checkpoint inhibitors; cancer
    DOI:  https://doi.org/10.1016/j.intimp.2025.115067
  9. Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373
    Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
    Fan Gao, Kang Sun, Sicheng Wang, Xiaozhen Zhang, Xueli Bai.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.
    Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
  10. Adv Sci (Weinh). 2025 Jun 18. e2416501
    Tumor-Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion.
    Jing-Yan Cheng, Hsiu-Hui Tsai, Jung-Tung Hung, Tsai-Hsien Hung, Chun-Cheng Lin, Chien-Wei Lee, Zi-Chi Lo, Jing-Rong Huang, Shih-Pin Chiou, Yenlin Huang, Shih-Hsiang Chen, Chun-Nan Yeh, John Yu, Alice L Yu.
      Adenosine signaling is a crucial immunosuppressive pathway within the tumor microenvironment, making it a promising target for cancer therapy. In this study, it is demonstrated that Globo H ceramide (GHCer), the most prevalent tumor-associated glycosphingolipid, influences the tumor microenvironment by activating adenosine signaling, which results in dual immunosuppressive effects on T cells. It is demonstrated that GHCer interacts with the adenosine receptor 2A (A2AR), triggering cyclic AMP (cAMP) and protein kinase A (PKA) signaling. This interaction leads to a reduction in the proliferation of CD4+ T cells while simultaneously promoting the differentiation of regulatory T cells (Tregs). Furthermore, GHCer enhances the suppressive capacity of Treg cells by upregulating inhibitory molecules such as Lymphocyte-activation gene 3 (LAG3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Programmed cell death 1 ligand 1 (PD-L1), and it stimulates the secretion of the immunosuppressive cytokine Interleukin 35 (IL-35). Additionally, GHCer-induced Tregs express CD39 and CD73, which further enhances adenosine production and creates a positive feedback loop in the adenosinergic pathway and A2AR signaling. Mechanistically, it is found that GHCer forms a complex with TRAX (translin-associated factor-X) and the C-terminus of A2AR, which facilitates the activation of A2AR and promotes an immunosuppressive tumor microenvironment.
    Keywords:  Adenosine receptor 2A; Globo H ceramide; TRAX; Treg
    DOI:  https://doi.org/10.1002/advs.202416501
  11. Cell Metab. 2025 Jun 17. pii: S1550-4131(25)00269-4. [Epub ahead of print]
    Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation.
    Xiaohui Zhang, Zhongliang Nie, Shuang Wang, Yuxi Ma, Dan Han, Ting Hu, Liu Liu, Liying Men, Tao Zhang, Xiaoting Wu, Xu Li, Sheng Hu, Meng Yuan, Liu Liu, Chaoqun Wang, Ping Xu, Limin Xiang, Jiao Liu, Yong Zhang, Dahai Zhu, Hehua Lei, Limin Zhang, Xiangpan Li, Yanxia Zhao, Wei Yan.
      Radiotherapy reduces the risk of cancer recurrence and death, but the fact that it's accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify that cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles to trigger skeletal muscle weakness upon radiotherapy. Mechanistically, irradiation-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of the SRM protein, facilitating SRM packaging into extracellular vesicles from the primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon radiotherapy, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of radiotherapy-mediated muscle weakness when combined with losartan treatment.
    Keywords:  extracellular vesicles; fibrosis; polyamine metabolism; radiotherapy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.013
  12. Clin Exp Immunol. 2025 Jun 14. pii: uxaf028. [Epub ahead of print]
    Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
    Christine C A van Linge, Erik H A Michels, Liza Pereverzeva, Regina de Beer, Augustijn M Klarenbeek, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, W Joost Wiersinga, Peter I Bonta, Jouke T Annema, Tom van der Poll, Alex F de Vos.
       INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require oxidative phosphorylation. However, which nutrients AMs use to fuel their energy demand during inflammatory responses, is still unknown. The present study aimed to determine the contribution of three key metabolic pathways; fatty acid oxidation, glutaminolysis, and glycogenolysis, to the inflammatory response of AMs.
    METHODS: Primary AMs were isolated from healthy human volunteers and stimulated with lipopolysaccharide (LPS). After 24 hours, cells were subjected to analyses of metabolic flux, expression of genes involved in these metabolic pathways, and inflammatory cytokine secretion in the presence of metabolic inhibitors.
    RESULTS: The results of our study show that human AMs display expression of genes involved in fatty acid and glutamine metabolism and are capable of metabolizing oleic acid and glutamine during homeostasis, but do not use these metabolites to fuel the production of inflammatory cytokines. We demonstrate that AMs, while residing in a glucose-deprived environment, contain glycogen and use glycogenolysis to fuel inflammatory cytokine secretion, as reflected by reduced TNF, IL-1βand IL-6 levels in supernatant of LPS-stimulated AMs treated with the glycogenolysis inhibitor CP316819. Moreover, AMs display marked expression of genes involved in glycogenesis, including FBP1 and GYS.
    CONCLUSION: Taken together, these results indicate that primary human AMs are equipped to use different nutrients to fuel their metabolic demands. Moreover, our findings suggest that glycogenolysis is critical for the inflammatory response of AMs.
    Keywords:  Cellular Immunology; Lipopolysaccharide; Macrophage; Metabolism
    DOI:  https://doi.org/10.1093/cei/uxaf028
  13. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
    The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
    Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  14. Discov Oncol. 2025 Jun 14. 16(1): 1104
    Syndecan-4 promotes gastric cancer progression through activating TGF-β1 induced lipid reprogramming and contributes positive loop circuits.
    Guangjie Liu, Ru Jia, Heng Deng, Xiaoshan Wang.
       BACKGROUND: Syndecan-4 (SDC4) plays a pivotal role in tumorigenesis through cell signaling, adhesion and matrix interactions. Lipid reprogramming is a core strategy for malignant tumors to drive progression and invasion through reshaping immunity, stromal and vascular ecology in microenvironment. However, the regulatory mechanism of SDC4 in lipid reprogramming has not yet been elucidated. Therefore, it is important to investigate underlying mechanisms and develop novel therapeutic targets for gastric cancer (GC).
    METHODS: Clinicopathological data and corresponding immunohistochemistry were collected to explore the role of SDC4 in patients with GC. Functional experiments were performed to assess tumor progression and lipid reprogramming. Moreover, western blot assay was performed to verify the molecular mechanisms. In addition, cholesterol-induced lipotoxic environments both in vivo and in vitro were constructed to explore the underlying positive loop circuit.
    RESULTS: SDC4 expression was upregulated in tumor tissues compared to normal gastric tissues and was associated with differentiation grades. Patients with high SDC4 expression were positively correlated with high circulating tumor cell (CTC) levels, vascular endothelial growth factor (VEGF) levels and poor prognosis. Moreover, SDC4 significantly promoted tumor progression by activating transforming growth factor-beta 1 (TGF-β1/TGFB1)-induced lipid reprogramming and contributed a positive loop circuit in GC cells. However, the core of this circuit was dependent on Smad3. In addition, a cholesterol-induced lipotoxic environment upregulated SDC4 expression by activating the RAS signaling pathway and further indicated a positive loop circuit between SDC4 and lipid reprogramming in GC.
    CONCLUSIONS: These findings highlight SDC4 as a therapeutic target for GC and identify actionable positive loop circuits.
    Keywords:  Cell progression; Lipid reprogramming; SDC4; Smad3; TGF-β1
    DOI:  https://doi.org/10.1007/s12672-025-02975-5
  15. Diabetologia. 2025 Jun 20.
    Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels.
    Niki F Brisnovali, Isabelle Franco, Amira Abdelgawwad, Hio Lam Phoebe Tsou, Thong Huy Cao, John McDonald, Antonio Riva, Guy A Rutter, Elina Akalestou.
       AIMS/HYPOTHESIS: Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive.
    METHODS: To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high-fat-diet-fed control mice, mice treated chronically with dapagliflozin, and total-body Slc5a2-knockout mice.
    RESULTS: SGLT2-null mice exhibited better glucose tolerance and insulin sensitivity (blood glucose during IPGTT AUC 0-90 min 1175 ± 57.4 mmol/l × min, mean ± SEM) compared with control (AUC 0-90 min 1857 ± 117.9 mmol/l × min, p=0.05) or dapagliflozin-treated mice (AUC 0-90 min 1506 ± 68.72 mmol/l × min, p=0.09), independent of glycosuria and body weight. Moreover, SGLT2-null mice demonstrated physiological regulation of corticosterone secretion, with lower morning levels than control mice (p<0.01). Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly IL-6. Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 treatment increased SGLT2 expression in human kidney HK2 cells, suggesting a role for cytokines in the effects of hyperglycaemia.
    CONCLUSIONS/INTERPRETATION: Collectively, our data elucidate a potential interplay between SGLT2 activity, immune modulation and metabolic homeostasis, as well as a potential feedback loop between SGLT2 expression and cytokine concentration.
    Keywords:  Corticosterone; Cytokines Glutathione; IL6; SGLT2
    DOI:  https://doi.org/10.1007/s00125-025-06467-7
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