EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Manman Yuan,Jing Ye,Xiangqiao Sun,Zhiwu Tong,Tingting Wang,Renxiang Tan,Xingxin Wu
Acaudiolide ameliorates liver fibrosis in mice • Acaudiolide inhibits TGF-β1/SMAD signaling in HSCs • Acaudiolide inhibits the nuclear translocation of p-SMAD2/3 • Acaudiolide weakens the interaction between SMAD4 and p-SMAD2/3 • SMAD4 is a candidate covalent target of acaudiolide Hepatic stellate cell (HSC) activation is a central driver of fibrosis progression in metabolic dysfunction-associated steatohepatitis (MASH), yet effective antifibrotic pharmacotherapies remain limited. Here, we identify acaudiolide, a sulfur-bridged symmetric dimeric macrodiolide isolated from the fungus Acaulium sp. H-JQSF, as a natural-product lead that suppresses HSC activation and experimental liver fibrosis. In a Western diet (WD)/CCl 4 murine model of MASH, acaudiolide reduced collagen deposition, alpha-smooth muscle actin (α-SMA) expression and fibrogenic gene expression. Transcriptomic profiling of HSCs showed that acaudiolide antagonized transforming growth factor-β1 (TGF-β1)-driven profibrotic programs. Mechanistically, acaudiolide did not measurably alter SMAD2/3 phosphorylation but markedly reduced the nuclear accumulation of phosphorylated SMAD2/3 (p-SMAD2/3). Integration of Connectivity Map (CMap) analysis with isotopic tandem orthogonal proteolysis-activity-based protein profiling (isoTOP-ABPP) chemical proteomics nominated SMAD4 as a candidate covalent target of acaudiolide. Covalent docking suggested Cys363 as a potential engagement site, and co-immunoprecipitation showed that acaudiolide weakened the association of SMAD4 with p-SMAD2/3. These findings support a model in which acaudiolide interferes with SMAD complex assembly, thereby attenuating TGF-β-dependent profibrotic transcription and HSC activation. Collectively, our data nominate acaudiolide as a preclinical antifibrotic lead and SMAD4 as a potentially tractable downstream node for pharmacological modulation of TGF-β signaling in MASH-related fibrosis. Download: Download high-res image (386KB) Download: Download full-size image
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DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2024
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IF 2.5
Juanjuan Zhu,Wenmin Tang,Xian Wu,Mao Mu,Quan Zhang,Xueke Zhao
Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
LIFE SCIENCES
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2026
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IF 6.4
Gaoxuan Shao,Chenceng Sun,Chenhao Ye,Ying Liu,Jiashu Pan,Yujing Liu,Lu Lu,Lei Wang,Zemin Lin,Fan Yang,Guang Ji,Hanchen Xu
Luteolin significantly reduces tumor burden and fibrosis in a MASH-HCC mouse model. • Luteolin attenuates hepatic lipid accumulation by inhibiting de novo lipogenesis. • The protective effects of luteolin are mediated via the AMPK/ACC signaling pathway. • Inhibition of AMPK abolishes the lipid-lowering benefits of luteolin in hepatocytes. Aims Metabolic dysfunction-associated steatohepatitis (MASH) is a primary driver of hepatocellular carcinoma (HCC), yet effective therapeutic interventions remain limited. While luteolin is known for its anti-inflammatory properties, its efficacy and underlying mechanism in the MASH-HCC transition are not fully understood. This study investigated the protective effects of luteolin against MASH-HCC and the role of the AMPK/ACC signaling pathway in this process. Materials and methods In vivo , a MASH-HCC mouse model was established using diethylnitrosamine (DEN) combined with a high-fat, high-cholesterol (HFHC) diet. Mice were treated with vehicle or luteolin (50 or 100 mg/kg) for 26 weeks. Progression was monitored via serum alpha-fetoprotein (AFP), histological analysis, and Western blotting. In vitro , HepG2 and Huh-7 cells were challenged with cholesterol and treated with luteolin. The AMPK inhibitor BAY-3827 was employed to verify whether the metabolic benefits of luteolin were pathway-dependent. Key findings Luteolin treatment significantly reduced tumor burden, lowered serum AFP levels, and attenuated hepatic lipid accumulation and fibrosis in MASH-HCC mice. In vitro results mirrored these findings, showing that luteolin reduced cholesterol-induced lipid loading. Mechanistically, luteolin increased the phosphorylation of AMPK and its downstream target, ACC. Furthermore, pharmacological inhibition of AMPK with BAY-3827 abolished the lipid-lowering effects of luteolin in hepatic cells, confirming that its therapeutic benefits are mediated through AMPK activation. Significance Luteolin suppresses the progression of MASH to HCC by activating the AMPK/ACC signaling pathway and subsequently inhibiting de novo lipogenesis. These findings highlight luteolin as a promising potential therapeutic candidate for the prevention and treatment of MASH-related liver cancer. Download: Download high-res image (314KB) Download: Download full-size image
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Huimin Qiu,Xinqi Tan,Quan Sheng,Na Yang,Chunming Jiang,Lulu Wang
Metabolic dysfunction-associated steatohepatitis (MASH) frequently induces renal injury, forming a “liver-kidney axis” vicious cycle. Current therapies primarily target hepatic lesions, failing to interrupt the cross-organ injury cascade, creating an urgent need for novel strategies. To explore dapagliflozin’s therapeutic efficacy and core mechanism in MASH and associated renal injury, we utilized in vitro models (free fatty acid [FFA]-induced HepG2 hepatocyte MASH model, HK2 renal tubular epithelial cell injury model, Transwell co-culture system) and an in vivo MASH mouse model induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Results showed dapagliflozin dose-dependently improved dysregulated lipid metabolism, suppressed inflammation, and alleviated fibrosis in vitro and in mouse liver/kidney tissues, while upregulating SIRT1/PPARα and downregulating SREBP-1c to restore lipid homeostasis. Molecularly, dapagliflozin specifically bound to ferroptosis key regulator solute carrier family 7 member 11 (SLC7A11), upregulated its abnormally reduced expression, and inhibited PI3K/AKT pathway hyperactivation—an effect mediated via a “liver-kidney axis” paracrine mechanism with β-hydroxybutyrate (β-HB) as the key mediator. Additionally, SLC7A11 knockdown in cells conversely confirmed that the lipid-lowering effect of dapagliflozin is mediated by SLC7A11.Collectively, dapagliflozin forms hydrogen bonds with SLC7A11, modulates the SIRT1/PPARα/SREBP-1c axis, and inhibits PI3K/AKT, thereby exerting therapeutic effects on MASH and associated renal injury.
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DOI
PubMed
高影响因子
ACS Nano
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2024
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IF 15.8
Chenshuang Zhang,Yilong Teng,Xin Bai,Maoping Tang,William Stewart,Jake Jinkun Chen,Xiaoyang Xu,Xue-Qing Zhang
Chronic exposure of the liver to multiple insults culminates in the development of metabolic dysfunction-associated steatohepatitis (MASH), a complicated metabolic syndrome characterized by hepatic steatosis and inflammation, typically accompanied by progressive fibrosis. Despite extensive clinical evaluation, there remain challenges in MASH drug development, which are primarily due to unsatisfactory efficacy and limited specificity. Strategies to address the unmet medical need for MASH with fibrosis before it reaches the irreversible stage of decompensated cirrhosis are critically needed. Herein, we developed an mRNA-mediated liver-specific antibody therapy for MASH and hepatic fibrosis using a targeted lipid nanoparticle (LNP) delivery system. When encapsulated with IL-11 single-chain variable fragment (scFv)-encoded mRNA, the targeted AA3G LNP (termed mIL11-scFv@AA3G) specifically accumulated in the liver and secreted IL-11 scFv to neutralize overexpressed IL-11 in hepatic environments, thus inhibiting the IL-11 signaling pathway in hepatocytes and hepatic stellate cells. As a preventative regimen, systemic administration of mIL11-scFv@AA3G reversed MASH and prevented the progression to fibrosis in a murine model of early MASH. Notably, mIL11-scFv@AA3G exhibited superior efficacy compared to systemic administration of IL-11 scFv alone, attributed to the sustained antibody expression in the liver, which lasted 18-fold longer than that of IL-11 scFv. When tested in the MASH model with fibrosis, mIL11-scFv@AA3G effectively ameliorated steatosis and resolved fibrosis and inflammation. These findings present a versatile LNP platform targeting liver cell subtypes for the sustained expression of therapeutic antibodies to treat MASH and fibrosis. The developed mRNA-mediated liver-specific antibody therapy offers a promising approach for addressing MASH and holds the potential for expansion to various other diseases.
CAS / MDL:
研究领域:
肝病学
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药理学
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分子生物学
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治疗学
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DOI
PubMed
高影响因子
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