7,8-Dihydroxyflavone attenuates cisplatin-induced cardiomyocyte apoptosis and mitochondrial dysfunction via the p53/Nrf2 pathway

  • Toxicol Appl Pharmacol. 2025 Sep 22:505:117578. doi: 10.1016/j.taap.2025.117578.
Zhen Tian  1 ,  Ting-Ting Tan  1 ,  Yu-Wei Hu  1 ,  Jia-Tong Yao  1 ,  Xiao-Ting Kang  1 ,  Jin-Yu Zhou  2 ,  Dong-Xu Jia  1 ,  Qing-Liu Li  2 ,  Ru-Jin Liang  2 ,  Li-Mei Zhao  3 ,  Hua Zhu  4 ,  Jing Zhao  5 ,  Peng-Zhou Hang  6
Affiliations
  • 1. Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou 225001, China; Yangzhou Key Laboratory of Clinical Pharmacy and Drug Research, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; College of Pharmacy, Dalian Medical University, Dalian 116044, China.
  • 2. Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou 225001, China; Yangzhou Key Laboratory of Clinical Pharmacy and Drug Research, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China.
  • 3. Department of Pathology and Pathophysiology, Suzhou Medical College of Soochow University, Suzhou 215123, China.
  • 4. Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou 225001, China; Yangzhou Key Laboratory of Clinical Pharmacy and Drug Research, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China. Electronic address: [email protected].
  • 5. Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou 225001, China; Yangzhou Key Laboratory of Clinical Pharmacy and Drug Research, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China. Electronic address: [email protected].
  • 6. Department of Pharmacy, Northern Jiangsu People's Hospital, Yangzhou 225001, China; Yangzhou Key Laboratory of Clinical Pharmacy and Drug Research, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China. Electronic address: [email protected].
PMID: 40992637 DOI: 10.1016/j.taap.2025.117578
Abstract

Cisplatin (CDDP), while effective as a chemotherapeutic agent, poses significant cardiovascular risks that constrain its clinical utility. This study investigated the cardioprotective effects of 7,8-dihydroxyflavone (7,8-DHF) against CDDP-induced toxicity and explored the underlying molecular mechanisms in cardiomyocytes. CDDP exposure produced dose-dependent cytotoxic effects, characterized by reduced cell viability and elevated Lactate Dehydrogenase (LDH) release. Co-treatment with 7,8-DHF markedly attenuated CDDP-induced cellular damage by preventing cell death, minimizing LDH leakage, and preserving mitochondrial membrane potential (MMP). The compound also suppressed cardiomyocyte Apoptosis, evidenced by fewer TUNEL-positive cells and restoration of the Bcl-2/Bax ratio. 7,8-DHF decreased mitochondrial Reactive Oxygen Species (ROS) accumulation and enhanced cellular antioxidant defenses by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) signaling. Additionally, 7,8-DHF treatment decreased both 53BP1 foci formation and p53 protein expression. The specificity of these protective mechanisms was confirmed using pharmacological agents: Nutlin-3a (p53 activator) and Brusatol (Nrf2 inhibitor), both reversed the cardioprotective effects of 7,8-DHF, establishing the critical role of p53/Nrf2 pathway modulation. In summary, these findings demonstrate that 7,8-DHF protects against CDDP-induced cardiotoxicity by preserving mitochondrial function and preventing Apoptosis through targeted inhibition of the p53 signaling and activation of Nrf2-mediated antioxidant responses in cardiomyocytes. Our study provides preliminary evidence for the potential of 7,8-DHF in mitigating CDDP-associated cardiac injury.

Keywords
7,8-Dihydroxyflavone; Cardiotoxicity; Cisplatin; Mitochondria; Nrf2; p53.
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