bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–03–09
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
  2. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.
  3. Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.
  4. ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
  5. Ferroptosis in adipose tissue: A promising pathway for treating obesity?
  6. MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue.
  7. A cellular and molecular basis of leptin resistance.
  8. The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway.
  9. "Shunt-ing" down obesity with novel endogenous metabolites.
  10. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
  11. Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells.
  12. Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes.
  13. DNMT3A regulates murine megakaryocyte-biased hematopoietic stem cell fate decisions.
  14. Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission.
  1. Nat Commun. 2025 Mar 05. 16(1): 2229
    p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Shreeya Patel, Xue Lei, Adarsh Rajesh, Marcos G Teneche, Aaron P Havas, Armin Gandhi, Carolina Cano Macip, Jun Lyu, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Michael A LaPorta, Tianhui Liu, Nirmalya Dasgupta, Sha Li, Andrew Davis, Anatoly Korotkov, Erik Hultenius, Zichen Gao, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Andrei Seluanov, Vera Gorbunova, Susan M Kaech, Xiao Tian, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
    DOI:  https://doi.org/10.1038/s41467-025-57229-3
  2. Sci Adv. 2025 Mar 07. 11(10): eads4957
    Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.
    Zhangdan Xie, Moubin Lin, Beizi Xing, Hongmiao Wang, Haosong Zhang, Zimu Cai, Xinyu Mei, Zheng-Jiang Zhu.
      Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.
    DOI:  https://doi.org/10.1126/sciadv.ads4957
  3. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13763
    Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.
    Wagner S Dantas, Elizabeth C Heintz, Elizabeth R M Zunica, Jacob T Mey, Melissa L Erickson, Kathryn P Belmont, Analisa L Taylor, Gangarao Davuluri, Hisashi Fujioka, Ciarán E Fealy, Charles L Hoppel, Christopher L Axelrod, John P Kirwan.
       BACKGROUND: Activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D).
    METHODS: Fifty-eight sedentary adults (37 ± 12 years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow/Ob), or (3) T2D. Body composition, aerobic capacity, and insulin sensitivity were assessed during a 3-day inpatient stay. A fasted skeletal muscle biopsy was obtained to assess mitochondrial functions. C2C12 myoblasts were transfected with FLAG-HA-USP15 and FLAG-HA-USP30 and harvested to assess mitochondrial dynamics and cellular insulin action.
    RESULTS: Insulin sensitivity and aerobic capacity were lower in Ow/Ob (132% and 28%, respectively) and T2D (1024% and 83%, respectively) relative to HW. Patients with T2D presented with elevated skeletal muscle mitochondrial fission (3.2 fold relative to HW and Ow/Ob), decreased fusion, and impairments in quality control. Mitochondrial content was lower in Ow/Ob (26%) and T2D (56%). USP13 (84%), USP15 (96%) and USP30 (53%) expression were increased with decreased Parkin and Ub activation in T2D alone. USP15 (R2 = 0.55, p < 0.0001) and USP30 (R2 = 0.40, p < 0.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 (3.6 and 3.7 fold, respectively) while inhibiting AKT (96% and 81%, respectively) and AS160 (2.1 and 3.5 fold, respectively) phosphorylation.
    CONCLUSION: Mitochondrial fragmentation bypasses defects in mitophagy to sustain skeletal muscle quality control in patients with T2D.
    Keywords:  bioenergetics; fission; fusion; mitochondria; obesity; quality control; type 2 diabetes
    DOI:  https://doi.org/10.1002/jcsm.13763
  4. Nat Commun. 2025 Feb 28. 16(1): 2071
    ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
    Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li, Pingyu Liu.
      Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-57334-3
  5. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00057-9. [Epub ahead of print]37(3): 560-561
    Ferroptosis in adipose tissue: A promising pathway for treating obesity?
    John R Speakman.
      Using a high-fat-diet (HFD) mouse model and clinical samples, Wang et al.1 in this issue of Cell Metabolism report that ferroptotic signaling is involved in the expansion of adipose tissue and promotes adaptive thermogenesis in beige adipocytes. This finding may represent a promising new avenue for treating obesity.
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.029
  6. Adv Sci (Weinh). 2025 Mar 07. e2416598
    MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue.
    Xin-Yuan Zhao, Ben-Chi Zhao, Hui-Lin Li, Ying Liu, Bei Wang, An-Qi Li, Tian-Shu Zeng, Hannah Xiaoyan Hui, Jia Sun, Domagoj Cikes, Nele Gheldof, Jorg Hager, Jian-Xun Mi, D Ross Laybutt, Yin-Yue Deng, Yan-Chuan Shi, G Gregory Neely, Qiao-Ping Wang.
      Stimulating adipose tissue thermogenesis has emerged as a promising strategy for combating obesity, with uncoupling protein 1 (UCP1) playing a central role in this process. However, the mechanisms that suppress adipose thermogenesis and energy dissipation in obesity are not fully understood. This study identifies mitochondrial carrier homolog 2 (MTCH2), an obesity susceptibility gene, as a negative regulator of energy homeostasis across flies, rodents, and humans. Notably, adipose-specific MTCH2 depletion in mice protects against high-fat-diet (HFD)-induced obesity and metabolic disorders. Mechanistically, MTCH2 deficiency promotes energy expenditure by stimulating thermogenesis in brown adipose tissue (BAT) and browning of subcutaneous white adipose tissue (scWAT), accompanied by upregulated UCP1 protein expression, enhanced mitochondrial biogenesis, and increased lipolysis in BAT and scWAT. Using integrated RNA sequencing and proteomic analyses, this study demonstrates that MTCH2 is a key suppressor of thermogenesis by negatively regulating autophagy via Bcl-2-dependent mechanism. These findings highlight MTCH2's critical role in energy homeostasis and reveal a previously unrecognized link between MTCH2, thermogenesis, and autophagy in adipose tissue biology, positioning MTCH2 as a promising therapeutic target for obesity and related metabolic disorders. This study provides new opportunities to develop treatments that enhance energy expenditure.
    Keywords:  adipose tissue; autophagy; mitochondrial carrier homolog 2 (MTCH2); obesity; thermogenesis
    DOI:  https://doi.org/10.1002/advs.202416598
  7. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00001-4. [Epub ahead of print]37(3): 723-741.e6
    A cellular and molecular basis of leptin resistance.
    Bowen Tan, Kristina Hedbacker, Leah Kelly, Zhaoyue Zhang, Alexandre Moura-Assis, Ji-Dung Luo, Joshua D Rabinowitz, Jeffrey M Friedman.
      Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.
    Keywords:  POMC; diet-induced obesity; leptin; leptin resistance; mTOR; rapamycin
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.001
  8. Exp Mol Med. 2025 Mar 03.
    The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway.
    Jong Yoen Park, Eun Sun Ha, Jimin Lee, Pierre-Jacques Brun, Yeri Kim, Sung Soo Chung, Daehee Hwang, Seung-Ah Lee, Kyong Soo Park.
      Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RBP4 in brown adipose tissue and its metabolic significance remain unclear. Here we generated and studied transgenic mice that express human RBP4 (hRBP4), specifically in brown adipocytes (UCP1-RBP4 mice), to better understand these uncertainties. When fed a chow diet, these mice presented significantly lower body weights and fat mass than their littermate controls. The UCP1-RBP4 mice also showed significant improvements in glucose clearance, enhanced energy expenditure and increased thermogenesis in response to a cold challenge. This was associated with increased lipolysis and fatty acid oxidation in brown adipose tissue, which was attributed to the activation of canonical adrenergic signaling pathways. In addition, high-performance liquid chromatography analysis revealed that plasma RBP4 and retinol levels were elevated in the UCP1-RBP4 mice, whereas their hepatic retinol levels decreased in parallel with a chow diet. Steady-state brown fat levels of total retinol were significantly elevated in the UCP1-RBP4 mice, suggesting that their retinol uptake was increased in RBP4-expressing brown adipocytes when fed a chow diet. These findings reveal a critical role for RBP4 in canonical adrenergic signaling that promotes lipid mobilization and oxidation in brown adipocytes, where the harnessed energy is dissipated as heat by adaptive thermogenesis.
    DOI:  https://doi.org/10.1038/s12276-025-01411-6
  9. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00063-4. [Epub ahead of print]37(3): 564-565
    "Shunt-ing" down obesity with novel endogenous metabolites.
    Victor J Pai, Alan Saghatelian.
      Obesity is a growing public health issue that has recently been transformed through the advent of new medicines. However, our understanding of the pathways and mechanisms that regulate energy balance in mammals is still developing. Recent discoveries on this front include an exciting new finding that there exists a novel class of metabolites in humans and mice that can regulate obesity in rodents.
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.005
  10. Nature. 2025 Mar 05.
    Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
    Laetitia Coassolo, Niels B Danneskiold-Samsøe, Quennie Nguyen, Amanda Wiggenhorn, Meng Zhao, David Cheng-Hao Wang, David Toomer, Jameel Lone, Yichao Wei, Aayan Patel, Irene Liparulo, Deniz Kavi, Lianna W Wat, Saranya Chidambaranathan Reghupaty, Julie Jae Kim, Tina Asemi, Ewa Bielczyk-Maczynska, Veronica L Li, Maria Dolores Moya-Garzon, Nicole A J Krentz, Andreas Stahl, Danny Hung-Chieh Chou, Liqun Luo, Katrin J Svensson.
      Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1)1,2. However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.
    DOI:  https://doi.org/10.1038/s41586-025-08683-y
  11. Nat Commun. 2025 Mar 02. 16(1): 2109
    Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells.
    Wenyang Li, Robert P Sparks, Cheng Sun, Yang Yang, Lorena Pantano, Rory Kirchner, Nahid Arghiani, Arden Weilheimer, Benjamin J Toles, Jennifer Y Chen, Sean P Moran, Victor Barrera, Zixiu Li, Peng Zhou, Meghan L Brassil, David Wrobel, Shannan J Ho Sui, Gary Aspnes, Michael Schuler, Jennifer Smith, Benjamin D Medoff, Chan Zhou, Carine M Boustany-Kari, Jörg F Rippmann, Daniela M Santos, Julia F Doerner, Alan C Mullen.
      Hepatic stellate cells (HSCs) are activated with chronic liver injury and transdifferentiate into myofibroblasts, which produce excessive extracellular matrices that form the fibrotic scar. While the progression of fibrosis is understood to be the cause of end-stage liver disease, there are no approved therapies directed at interfering with the activity of HSC myofibroblasts. Here, we perform a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts to identify gene products necessary for the fibrotic phenotype of HSCs. We find that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient in Abhd17b are also protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, our data suggest that ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include interaction with MYO1B to modulate gene expression and HSC migration. Together, our results provide an analysis of the phenotypic consequences for siRNAs targeting RNAs from >9500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-025-56900-z
  12. Nat Commun. 2025 Feb 28. 16(1): 2064
    Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes.
    Junyoung Park, Andrés Peña-Tauber, Lia Talozzi, Michael D Greicius, Yann Le Guen.
      Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.
    DOI:  https://doi.org/10.1038/s41467-025-57315-6
  13. Blood Adv. 2025 Mar 06. pii: bloodadvances.2024015061. [Epub ahead of print]
    DNMT3A regulates murine megakaryocyte-biased hematopoietic stem cell fate decisions.
    Sarah M Waldvogel, Virginia Camacho, Dandan Fan, Anna Guzman, Alejandra Garcia-Martell, Elmira Khabusheva, Jacey Rodriguez Pridgen, Josephine De La Fuente, Rachel E Rau, Ashlyn Laidman, Maria N Barrachina, Estelle Carminita, Justin Andrew Courson, Michael Williamson, Joanne Ino Hsu, Chun-Wei Chen, Jaime Reyes, Subhashree Pradhan, Rolando Rumbaut, Alan Burns, Benjamin Deneen, Jianzhong Su, Kellie R Machlus, Margaret A Goodell.
      Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of the peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but few differential regulatory mechanisms have been identified. In this work, we explored the role of the DNA methyltransferase 3A (DNMT3A) in the megakaryocyte-biased HSC population, which is thought to reside at the top of the hematopoietic hierarchy. We demonstrate that heterozygous loss of DNMT3A (Dnmt3a+/-) in these megakaryocyte-biased HSCs has consequences distinct from the rest of the HSC pool. These megakaryocyte-biased HSCs become delayed in their lymphoid-repopulating ability but can ultimately regenerate all lineages. We further demonstrate that Dnmt3a+/- mice have increased numbers of megakaryocytes in the bone marrow. Analysis of DNA methylation differences between WT and Dnmt3a+/- HSC subsets, megakaryocyte-erythroid progenitors (MEP), and megakaryocytes revealed that DNA methylation is eroded in the mutants in a cell type-specific fashion. While transcriptional differences between the WT and Dnmt3a+/- megakaryocyte-biased HSCs are subtle, the pattern of DNA methylation loss in this HSC subset is almost completely different from that in non-megakaryocyte-biased HSCs. Together, our findings establish the role of epigenetic regulation in the fate of megakaryocyte-biased HSCs and their downstream progeny and suggest that the outcomes of DNMT3A loss might vary depending on the identity of the HSC that acquires the mutation.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015061
  14. Stem Cell Res Ther. 2025 Mar 05. 16(1): 116
    Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission.
    Yifei Chen, Fuji Yang, Yanjin Wang, Yujie Shi, Likang Liu, Wei Luo, Jing Zhou, Yongmin Yan.
       BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission.
    METHODS: We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice.
    RESULTS: We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation.
    CONCLUSIONS: The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD.
    Keywords:  DRP1; MASLD; MSC; Mitochondrial fission; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s13287-025-04228-2
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