Xin-Ji-Er-Kang modulates NRF2 to inhibit ferroptosis and attenuate doxorubicin-induced myocardial injury

  • Phytomedicine. 2025 Sep 25:148:157302. doi: 10.1016/j.phymed.2025.157302.
Si-Min Yang  1 ,  Zhang-le Hu  2 ,  Hui-Yu Jia  3 ,  Pang-Bo Yang  4 ,  Zhi-Wei Xu  5 ,  Cong Ma  5 ,  Sheng-Yong Luo  6 ,  Wei Chen  7 ,  Shan Gao  8
Affiliations
  • 1. The Fourth Affiliated Hospital of Anhui Medical University, Chaohu, Anhui 238000, China; Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 2. Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
  • 3. Anhui Medical College (Anhui Academy of Medical Sciences), Hefei 230061, China.
  • 4. Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 5. Department of Cardiology, Anhui No .2 Provincial People ' s Hospital, Hefei 230041 Anhui, China.
  • 6. Anhui Medical College (Anhui Academy of Medical Sciences), Hefei 230061, China. Electronic address: [email protected].
  • 7. Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 200433, China. Electronic address: [email protected].
  • 8. The Fourth Affiliated Hospital of Anhui Medical University, Chaohu, Anhui 238000, China; Department of Pharmacology, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
PMID: 41056858 DOI: 10.1016/j.phymed.2025.157302
Abstract

Background: Xin-Ji-Er-Kang (XJEK), a traditional Chinese medicine formulation, has shown protective effects in various murine models of Cardiovascular Disease. However, its potential mechanisms in mitigating drug-induced cardiotoxicity, particularly its role in regulating Ferroptosis, remain unclear.

Aim of the study: This study aimed to evaluate the cardioprotective effects of XJEK against doxorubicin (DOX)-induced myocardial injury and to elucidate its potential mechanisms.

Materials and methods: The protective effects of XJEK were assessed using in vivo and in vitro models of DOX-induced cardiotoxicity (DIC). Cardiac function, related biomarkers, mitochondrial function, and indicators of Ferroptosis were evaluated. To clarify the mechanism, NRF2 expression was silenced using small interfering RNA (siRNA).

Results: XJEK significantly alleviated DIC both in vivo and in vitro by restoring mitochondrial function, reducing lipid peroxidation, lowering Reactive Oxygen Species (ROS) production, and decreasing iron accumulation and ferroptosis-related protein expression. Mechanistically, XJEK exerted these protective effects by inhibiting Ferroptosis through activation of the NRF2 pathway.

Conclusion: XJEK effectively attenuates DOX-induced cardiotoxicity by suppressing Ferroptosis via NRF2 activation. These findings suggest that NRF2-mediated anti-ferroptosis signalling contributes to the cardioprotective effects of XJEK, highlighting its therapeutic potential for managing drug-induced myocardial injury.

Keywords
Cardiotoxicity; Ferroptosis; Mitochondrial; NRF2; Xin-Ji-Er-Kang.
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