依帕司他是一种醛糖还原酶抑制剂，通过抑制糖代谢减轻阿霉素诱导的心脏毒性。

Epalrestat, an aldose reductase inhibitor, mitigates doxorubicin-induced cardiotoxicity by inhibiting glycometabolism.

作者信息

Zhu Jian, Wang Huihui, Guan Yue, Wang Yijun, Tan Wuping, Wang Jun

机构信息

Department of Cardiology, The First Affiliated Hospital of Bengbu Medical University, 233004 Bengbu, Anhui, China.

West China Hospital, Sichuan University, Chengdu 610041, China.

出版信息

Int Immunopharmacol. 2025 Jun 26;162:115106. doi: 10.1016/j.intimp.2025.115106.

DOI:10.1016/j.intimp.2025.115106

PMID:40577965

Abstract

BACKGROUND

Doxorubicin (DOX) is a powerful chemotherapeutic drug with limited clinical effectiveness due to the risk of cardiotoxicity and glycometabolic disorders at high dosages. Epalrestat (EPS), a potent AKR1B1 inhibitor, has been extensively documented for its remarkable efficacy in treating glycometabolic disorders. We aimed to investigate the protective effects of EPS against DOX-induced cardiotoxicity and elucidate the underlying mechanisms.

METHODS

C57BL/6 mice (24) were divided into the saline-treated control, EPS-treated, DOX-treated, and DOX plus EPS-treated groups. Cardiotoxicity was induced via intraperitoneal DOX administration (cumulative dose: 20 mg/kg), and EPS (100 mg/kg/day) was administered for four weeks.

RESULTS

DOX treatment increased creatine kinase isoenzyme-MB, lactate dehydrogenase, and brain natriuretic peptide levels, indicating cardiotoxicity. EPS treatment notably ameliorated DOX-induced adverse effects in a dose-dependent manner, with decreased apoptosis-related protein expression, reduced reactive oxygen species (ROS) levels, and preserved mitochondrial membrane potential. In protein expression analyses, EPS suppressed proapoptotic gene expression (Bax and caspase-3) while upregulating antiapoptotic gene expression (Bcl-2). Additionally, EPS reduced ROS levels, suppressed proinflammatory cytokine production, and preserved mitochondrial integrity by inhibiting nuclear factor kappa B (NF-κB) expression. Furthermore, EPS increased serum antioxidant enzyme levels, highlighting its potential as an antioxidative agent. The protective effect of EPS on mitochondrial integrity was visually confirmed by transmission electron microscopy. Transcriptomic analysis identified key biological processes and signaling pathways implicated in DOX-induced cardiotoxicity, emphasizing the significant contributions of the advanced glycation end product-receptor for advanced glycation end products (AGE-RAGE) signaling pathway and endocrine resistance.

CONCLUSION

EPS is a promising pharmacological agent for protection against DOX-induced cardiotoxicity due to its antioxidative and antiapoptotic effects and its ability to inhibit AGE/RAGE/NF-κB signaling.

摘要

背景

阿霉素（DOX）是一种强效化疗药物，但由于高剂量使用时有心脏毒性和糖代谢紊乱风险，其临床疗效有限。依帕司他（EPS）是一种有效的醛糖还原酶1B1（AKR1B1）抑制剂，已被广泛证明在治疗糖代谢紊乱方面具有显著疗效。我们旨在研究EPS对DOX诱导的心脏毒性的保护作用，并阐明其潜在机制。

方法

将24只C57BL/6小鼠分为生理盐水处理对照组、EPS处理组、DOX处理组和DOX加EPS处理组。通过腹腔注射DOX（累积剂量：20mg/kg）诱导心脏毒性，并给予EPS（100mg/kg/天）四周。

结果

DOX治疗增加了肌酸激酶同工酶-MB、乳酸脱氢酶和脑钠肽水平，表明存在心脏毒性。EPS治疗以剂量依赖方式显著改善了DOX诱导的不良反应，凋亡相关蛋白表达降低，活性氧（ROS）水平降低，线粒体膜电位得以保留。在蛋白质表达分析中，EPS抑制促凋亡基因表达（Bax和半胱天冬酶-3），同时上调抗凋亡基因表达（Bcl-2）。此外，EPS降低了ROS水平，抑制了促炎细胞因子的产生，并通过抑制核因子κB（NF-κB）表达维持了线粒体完整性。此外，EPS提高了血清抗氧化酶水平，突出了其作为抗氧化剂的潜力。通过透射电子显微镜直观地证实了EPS对线粒体完整性的保护作用。转录组分析确定了与DOX诱导的心脏毒性相关的关键生物学过程和信号通路，强调了晚期糖基化终产物受体（AGE-RAGE）信号通路和内分泌抵抗的重要作用。