Acta Pharmaceutica Sinica B
·
2025
·
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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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2022
·Vol. 37
·期 1
·77-88
·
IF 6.388
Shuai Wang,Yifan Zhang,Jianwei Lou,Hui Yong,Shulin Shan,Zhidan Liu,Mingxue Song,Cuiqin Zhang,Ruirui Kou,Zhaoxiong Liu,Wenhao Yu,Xiulan Zhao,Fuyong Song
Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile-α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up-regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non-competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 μM BBE against ACR-induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR-intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR-poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1-dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1-dependent axonal destruction pathway.
研究领域:
神经科学
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药理学
·
毒理学
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PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-15
·
IF 17.694
Hou Yun Nan,Cai Yang,Li Wan Hua,He Wei Ming,Zhao Zhi Ying,Zhu Wen Jie,Wang Qiang,Mai Xinyi,Liu Jun,Lee Hon Cheung,Stjepanovic Goran,Zhang Hongmin,Zhao Yong Juan
Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is an autoinhibitory NAD-consuming enzyme that is activated by the accumulation of nicotinamide mononucleotide (NMN) during axonal injury. Its activation mechanism is not fully understood. Here, we generate a nanobody, Nb-C6, that specifically recognizes NMN-activated SARM1. Nb-C6 stains only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN, and partially activates SARM1 in vitro and in cells. Cryo-EM of NMN/SARM1/Nb-C6 complex shows an octameric structure with ARM domains bending significantly inward and swinging out together with TIR domains. Nb-C6 binds to SAM domain of the activated SARM1 and stabilized its ARM domain. Mass spectrometry analyses indicate that the activated SARM1 in solution is highly dynamic and that the neighboring TIRs form transient dimers via the surface close to one BB loop. We show that Nb-C6 is a valuable tool for studies of SARM1 activation.
研究领域:
分子生物学
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神经科学
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结构生物学
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细胞生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Chunyu Liu,Shun Wu,Chuang Wang,Zirui Zhou,Tianwei Cai,Wen Tao,Shidong Zuo,Chi Zhang,Yuhao Dong,Yi Feng,Qingbo Huang,Baojun Wang,Xin Ma,Haoli Ma,Xu Zhang,Yan Huang
Cellular senescence is a stable cell cycle arrest program with important therapeutic implications in cancer, yet how metabolic perturbations are translated into redox-dependent senescence remains incompletely understood. Here, we identify triosephosphate isomerase 1 (TPI1) as a critical regulator of senescence in clear cell renal cell carcinoma (ccRCC) through a customized CRISPR-Cas9 metabolic screen. TPI1 depletion induces a robust senescence phenotype characterized by mitochondrial redox imbalance, DNA damage, and stable growth arrest. Mechanistically, loss of TPI1 leads to accumulation of dihydroxyacetone phosphate (DHAP), which engages a SARM1-dependent signaling pathway, resulting in increased cyclic ADP-ribose (cADPR) production and intracellular Ca 2+ release. This cADPR-Ca 2+ axis drives mitochondrial ROS (mtROS) generation, thereby promoting DNA damage and activation of the p53-p21 pathway to enforce senescence. Pharmacological or genetic attenuation of calcium signaling, or mitochondrial ROS partially rescues these phenotypes, indicating that calcium-dependent redox stress is required for senescence induction. Importantly, this metabolic–redox signaling cascade is conserved across multiple cancer types. Collectively, our findings define a previously unrecognized TPI1–SARM1–cADPR–Ca 2+ axis that links glycolytic metabolite accumulation to mitochondrial redox stress and cellular senescence, highlighting a metabolite-driven redox vulnerability that may be therapeutically exploitable in cancer.
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高影响因子
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