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

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

  • Eur J Pharmacol. 2025 Nov 5:1006:178180. doi: 10.1016/j.ejphar.2025.178180.
Yi Xie 1,  Aling Shen 2,  Huiyun Lin 2,  Huifang Zheng 2,  Guosheng Lin 1,  Youqin Chen 3,  Ying Zhong 1,  Hongshu Liu 1,  Ying Cheng 1,  Meizhu Wu 2,  Lihui Wei 4,  Qingquan Li 5,  Jun Peng 6
Affiliations

Affiliations

  • 1 Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
  • 2 Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
  • 3 Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, OH, 44106, USA.
  • 4 Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: weilihui@fjtcm.edu.cn.
  • 5 Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: 061101040@fuan.edu.cn.
  • 6 Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine in Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China. Electronic address: 2009068@fjtcm.edu.cn.
PMID: 40973012 DOI: 10.1016/j.ejphar.2025.178180
Abstract

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. These findings suggest that TMP is a promising therapeutic candidate for managing chemotherapy-induced cardiotoxicity.

Keywords

5-Fluorouracil; Cardiotoxicity; PANoptosis; Tetramethylpyrazine; p38 MAPK/JNK/ERK signaling pathway.

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