GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2026-02-01 Epub Date: 2026-01-10 DOI:10.1016/j.taap.2026.117713

Yucong Zhang , Ruihan Zheng , Minne Xie , Yunxuan Chen , Binbin Xia , Zexin Yang , Zhuoning Li , Yuzheng Li , Li Luo , Weijian Huang , Shanshan Dai , Bozhi Ye , Wenli Zhang

{"title":"GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction","authors":"Yucong Zhang , Ruihan Zheng , Minne Xie , Yunxuan Chen , Binbin Xia , Zexin Yang , Zhuoning Li , Yuzheng Li , Li Luo , Weijian Huang , Shanshan Dai , Bozhi Ye , Wenli Zhang","doi":"10.1016/j.taap.2026.117713","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms.</div></div><div><h3>Methods</h3><div>In vivo, wild-type and Gsdmd<sup>−</sup>/<sup>−</sup> mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM.</div></div><div><h3>Results</h3><div>GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release.</div></div><div><h3>Conclusion</h3><div>GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117713"},"PeriodicalIF":3.6000,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X26000098","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective

This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms.

Methods

In vivo, wild-type and Gsdmd⁻/⁻ mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM.

Results

GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release.

Conclusion

GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.

Abstract Image

查看原文本刊更多论文

GSDMD抑制剂GI-Y1通过抑制线粒体功能障碍减轻阿霉素诱导的心脏毒性。

目的：探讨GI-Y1 （GSDMD抑制剂）对多柔比星（Dox）诱导的心脏毒性（DIC）的保护作用，并阐明其分子机制。方法：在体内，野生型和Gsdmd-/-小鼠分别给予Dox（5 mg/kg/周，持续4 周）和GI-Y1（10或20 mg/kg/天）。aav9介导的GSDMD过表达证实了目标特异性。超声心动图评估心功能；通过H&E染色、TUNEL试验和血清生物标志物（CK-MB、LDH、cTnT）检测心肌损伤。在体外，用Dox（0.5 μg/mL）和GI-Y1（10或20 μM）处理HL-1心肌细胞。采用Western blot、ELISA、JC-1染色和TEM检测焦亡标志物（GSDMD裂解、IL-1β分泌、LDH释放）和线粒体功能。结果：GI-Y1改善了dox处理小鼠的存活率和心功能。降低血清心肌损伤生物标志物，减轻心肌组织学损伤。在体内和体外，GI-Y1抑制dox诱导的心肌细胞焦亡，表现为GSDMD切割减少，IL-1β分泌减少，细胞死亡减少。在机制上，GI-Y1结合GSDMD，损害其脂质结合和成孔能力。它还通过降低线粒体GSDMD-N、恢复MMP、促进ATP和抑制mtDNA释放来缓解dox诱导的线粒体功能障碍。结论：GI-Y1通过直接靶向GSDMD减轻DIC，抑制热亡和线粒体损伤。本研究强调GI-Y1是化疗相关心脏损伤的一种有前景的治疗方法，也是研究心血管疾病焦亡的一种有价值的工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.