Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Triterpene saponin from Ilex pubescens attenuates ferroptosis in myocardial ischemia/reperfusion injury by inhibiting the lncRNA Hmga2-as1/Sox10/GPX4 axis.
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Tian Xiaoyu, Lou Yanmei, Yao Xiaowei, Yang Ying, Gao Xiangyu, Liu Zhongqiu, Cheng Yuanyuan
Аннотация
BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) remains a key factor contributing to poor outcomes in acute myocardial infarction, with ferroptosis being a major mediator of cardiomyocyte death. Long non-coding RNAs and m6A modifications are vital epigenetic regulators, but their interaction in MI/RI-induced ferroptosis is poorly understood.
OBJECTIVE: This study aimed to investigate the role and molecular mechanism of lncRNA Hmga2-as1 in MI/RI and to screen for natural compounds with potential therapeutic value.
METHODS: Clinical samples from MI patients after PCI, a rat MI/RI model, and a H9c2 OGD/R model were utilized. Hmga2-as1 expression was quantified by qPCR, and cardiac specific knockdown was achieved using AAV9-shRNA. Mechanistic insights were obtained from subcellular fractionation, luciferase assays, EMSA, RIP, ChIP, and m6A mutagenesis. Triterpene saponins from Ilex pubescens were screened to identify inhibitors of Hmga2-as1.
RESULTS: Hmga2-as1 was significantly upregulated in post-PCI MI patients, MI/RI rat hearts, and OGD/R-treated H9c2 cells. Cardiac-specific Hmga2-as1 knockdown improved cardiac function, reduced infarct size, and lowered serum CK-MB levels in MI/RI rats. Knockdown selectively suppressed ferroptosis, as evidenced by elevated GSH, reduced MDA and lipid ROS, and upregulated GPX4 and xCT, without altering makers of apoptosis or pyroptosis, etc. Nuclear Hmga2-as1 interacted with the transcription factor Sox10, disrupting its binding to the conserved "CTGTGT" motif within the GPX4 promoter. MI/RI reduced m6A methylation of Hmga2-as1, which enhanced Hmga2-as1/Sox10 binding and impaired the Sox10-GPX4 promoter interaction. Mutagenesis of the Hmga2-as1 m6A site (GGACA→TCTGT) recapitulated these effects, confirming m6A-dependent regulation. Importantly, among the triterpene saponins from Ilex pubescens, IP-26 was identified as a potent Hmga2-as1 inhibitor. IP-26 bound Hmga2-as1 with moderate affinity (Kd=81.5 μM), upregulated GPX4 and xCT, alleviated ferroptosis, and protected against MI/RI both in vitro and in vivo. Overexpression of Hmga2-as1 blocked the cardioprotective effect of IP-26.
CONCLUSION: LncRNA Hmga2-as1 drives ferroptosis in MI/RI by inhibiting the Sox10/GPX4 transcriptional axis. The natural compound IP-26 likely exerts cardioprotective effects by inhibiting Hmga2-as1, highlighting a novel therapeutic strategy for MI/RI.
OBJECTIVE: This study aimed to investigate the role and molecular mechanism of lncRNA Hmga2-as1 in MI/RI and to screen for natural compounds with potential therapeutic value.
METHODS: Clinical samples from MI patients after PCI, a rat MI/RI model, and a H9c2 OGD/R model were utilized. Hmga2-as1 expression was quantified by qPCR, and cardiac specific knockdown was achieved using AAV9-shRNA. Mechanistic insights were obtained from subcellular fractionation, luciferase assays, EMSA, RIP, ChIP, and m6A mutagenesis. Triterpene saponins from Ilex pubescens were screened to identify inhibitors of Hmga2-as1.
RESULTS: Hmga2-as1 was significantly upregulated in post-PCI MI patients, MI/RI rat hearts, and OGD/R-treated H9c2 cells. Cardiac-specific Hmga2-as1 knockdown improved cardiac function, reduced infarct size, and lowered serum CK-MB levels in MI/RI rats. Knockdown selectively suppressed ferroptosis, as evidenced by elevated GSH, reduced MDA and lipid ROS, and upregulated GPX4 and xCT, without altering makers of apoptosis or pyroptosis, etc. Nuclear Hmga2-as1 interacted with the transcription factor Sox10, disrupting its binding to the conserved "CTGTGT" motif within the GPX4 promoter. MI/RI reduced m6A methylation of Hmga2-as1, which enhanced Hmga2-as1/Sox10 binding and impaired the Sox10-GPX4 promoter interaction. Mutagenesis of the Hmga2-as1 m6A site (GGACA→TCTGT) recapitulated these effects, confirming m6A-dependent regulation. Importantly, among the triterpene saponins from Ilex pubescens, IP-26 was identified as a potent Hmga2-as1 inhibitor. IP-26 bound Hmga2-as1 with moderate affinity (Kd=81.5 μM), upregulated GPX4 and xCT, alleviated ferroptosis, and protected against MI/RI both in vitro and in vivo. Overexpression of Hmga2-as1 blocked the cardioprotective effect of IP-26.
CONCLUSION: LncRNA Hmga2-as1 drives ferroptosis in MI/RI by inhibiting the Sox10/GPX4 transcriptional axis. The natural compound IP-26 likely exerts cardioprotective effects by inhibiting Hmga2-as1, highlighting a novel therapeutic strategy for MI/RI.