Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Xuewen Yang,Yanwei Zhang,Xiaoping Leng,Yanying Wang,Manyu Gong,Dongping Liu,Haodong Li,Zhiyuan Du,Zhuo Wang,Lina Xuan,Ting Zhang,Han Sun,Xiyang Zhang,Jie Liu,Tong Liu,Tiantian Gong,Zhengyang Li,Shengqi Liang,Lihua Sun,Lei Jiao,Baofeng Yang,Ying Zhang
Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.
研究领域:
心脏病学
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分子生物学
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病理学
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药理学
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DOI
PubMed
高影响因子
EXCLI Journal
·
2026
·
IF 6.2
Yunxiao Lin,Fan Yang,Yingtian Zhang,Xiaoqin Zhang,Xiangyi Li,Zhiliang Chen,Xianglong Zhao,Yongzhi Wang,Hao Wu,Cong Huai,Qiange Xiao,Wei Bao,Minglei Yang,Ruoyu Chen,Zhongyu Cao,Jinhang Zhu,Zekun Yu,Zexiu Zhang,Shengying Qin
Liver cirrhosis represents a terminal stage of chronic liver disease with limited pharmacological options. Pien Tze Huang (PTH), a traditional Chinese medicine with established hepatoprotective properties, has shown therapeutic potential in liver fibrosis, yet its molecular mechanisms in cirrhosis remain poorly understood. Here, we investigated the anti-cirrhotic effects of PTH and underlying mechanisms through whole-transcriptome sequencing in a carbon tetrachloride (CCl 4 )-induced mouse model of cirrhosis. PTH treatment significantly attenuated liver injury and other cirrhotic phenotypes, as evidenced by reduced serum transaminases and improved histological features. Transcriptomic analysis identified 1,518 genes dysregulated in cirrhosis and reversed by PTH treatment, with functional enrichment implicating inflammatory and fibrotic pathways including NF-κB, TNF, and IL-17 signaling. Connectivity Map analysis revealed similarity between PTH-induced transcriptional signatures and those of statins and beta-blockers, drugs currently evaluated in cirrhosis clinical trials. Through integrative construction of competing endogenous RNA (ceRNA) networks, we identified a core regulatory module comprising 6 miRNAs, 8 mRNAs, and 27 circRNAs with reversed expression patterns following PTH treatment. Notably, the liver-specific miR-122-5p exhibited the highest network connectivity, targeting P4ha1 , a rate-limiting enzyme in collagen biosynthesis. Human proteome data confirmed liver-enriched expression of P4HA1 , which is a validated therapeutic target of Lufironil, a Phase II clinical trial drug for cirrhosis. Our findings suggest that PTH ameliorates cirrhosis through multi-pathway regulation of a P4ha1 -centered ceRNA network. Functional validation in hepatocytes confirmed that PTH modulates this network via the miR-122-5p/ P4HA1 axis, alleviating injury-induced miR-122-5p downregulation and consequent P4HA1 upregulation. These results provide experimental evidence for a mechanistic basis of PTH's therapeutic application and highlight P4ha1 as a promising biomarker for cirrhosis intervention. See also the graphical abstract (Fig. 1) .
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PubMed
高影响因子
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