Tetramethylpyrazine ameliorates 5-fluorouracil-Induced cardiotoxicity by inhibiting PANoptosis and suppressing the p38 MAPK/JNK/ERK signaling pathway

作者：Yi Xie, Aling Shen, Huiyun Lin, Huifang Zheng, Guosheng Lin, Youqin Chen, Ying Zhong, Hong Liu, Ying Cheng, Meizhu Wu, Lihui Wei, Qingquan Li, Jun Peng · 发表于：European Journal of Pharmacology · 年份：2025 · DOI：10.1016/j.ejphar.2025.178180 · 被引用次数：4 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Cancer Treatment and Pharmacology、Melanoma and MAPK Pathways

Cardiac injury is a severe complication of 5-fluorouracil (5-FU) treatment in patients with gastrointestinal tumors, underscoring the urgent need for effective therapeutic strategies. Tetramethylpyrazine (TMP), a bioactive compound derived from traditional Chinese medicine, has demonstrated promising potential for alleviating 5-FU-induced cardiotoxicity. However, the precise mechanisms underlying its cardioprotective effects remain poorly understood. This study aimed to investigate the cardioprotective effects of TMP on 5-FU-induced cardiac injury and elucidate the underlying molecular mechanisms. TMP intervention significantly alleviated 5-FU-induced cardiac injury in both in vivo and in vitro models, as evidenced by improved cardiac function, reduced histological damage, and decreased levels of injury markers (creatine kinase MB (CKMB), cardiac Troponin I (cTn-I), N-terminal pro-B-type natriuretic peptide (NT-proBNP)). RNA sequencing revealed that TMP suppressed the activation of the p38 MAPK/JNK/ERK signaling pathway in cardiac tissue following 5-FU treatment. Further in vivo and in vitro experiments confirmed that TMP treatment reduced 5-FU-induced PANoptosis in cardiomyocytes and inhibited the activation of p38 MAPK/JNK/ERK signaling pathway. The protective effects of TMP on PANoptosis were reversed by pathway activators. In conclusion, TMP alleviates 5-FU-induced cardiac injury and reduces cardiomyocyte PANoptosis via suppressing the p38 MAPK/JNK/ERK signaling pathway. ...