Journal of Southern Medical University ›› 2025, Vol. 45 ›› Issue (9): 1946-1958.doi: 10.12122/j.issn.1673-4254.2025.09.14

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Cinnamic acid ameliorates doxorubicin-induced myocardial injury in mice by attenuating cardiomyocyte ferroptosis via inhibiting TLR4

Qi YUN1,2(), Ruoli DU3,4, Yuying HE1,2, Yixin ZHANG5, Jiahui WANG3,4, Hongwei YE3,4, Zhenghong LI1,2, Qin GAO3,4()   

  1. 1.School of Life Sciences, Bengbu Medical University, Bengbu 233030, China
    2.Anhui Engineering Research Center for Neural Regeneration Technology and Medical New Materials, Bengbu Medical University, Bengbu 233030, China
    3.Key Laboratory of Basic and Clinical Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu 233030, China
    4.Department of Physiology, Bengbu Medical University, Bengbu 233030, China
    5.School of Clinical Medicine, Bengbu Medical University, Bengbu 233030, China
  • Received:2025-02-13 Online:2025-09-20 Published:2025-09-28
  • Contact: Qin GAO E-mail:yunqiyq1009@163.com;bbmcgq@126.com

Abstract:

Objective To explore the mechanism of cinnamic acid (CA) for improving doxorubicin-induced myocardial injury (DIC) in mice. Methods Network pharmacology analysis was used to obtain the key targets of CA and DIC. Male C57BL/6J mice were randomized into Sham, DOX, CA (25, 50 and 100 mg/kg)+DOX, and CA+Ferrostatin-1+DOX groups, and their myocardial function and pathology were examined by echocardiography and HE staining. Serum levels of CK-MB, LDH, MDA, IL-6, TNF‑α and myocardial ROS level were detected, and the expression levels of TLR4 and ferroptosis pathway proteins in myocardial tissue were detected by Western blotting. Cultured murine cardiomyocytes (HL-1 cells) with or without transfection with a small interfering RNA targeting TLR4 (si-TLR4) were treated with DOX or Erastin, and the cellular ROS content was measured by DCFH-DA staining; the expression level of GPX4 was detected using immunofluorescence staining. Results Network pharmacology analysis suggested that CA may improve DIC through TLR4 signaling. DOX treatment caused obvious myocardial injury in mice, which showed significantly increased serum levels of CK-MB, LDH, MDA, IL-6, TNF-α and myocardial ROS level with decreased myocardial levels of SLC7A11 and GPX4 proteins and increased levels of TLR4 and PTGS2 proteins. All these changes in the mouse models were significantly alleviated by treatment with CA, and the mice receiving CA or ferrostatin-1 treatment exhibited increased myocardial expressions of SLC7A11 and GPX4 proteins and lowered expressions of TLR4 and PTGS2 proteins. In cultured HL-1 cells, treatment with DOX and Erastin both obviously increased intracellular ROS level and decreased cellular GPX4 expression level, and these changes were strongly attenuated by TLR4 interference. Conclusion CA, as a potent herbal monomer, can effectively alleviate DIC in mice by inhibiting TLR4-mediated ferroptosis.

Key words: cinnamic acid, doxorubicin-induced myocardial injury, ferroptosis, Toll-like receptor 4, network pharmacology