2. Academic Validation
  3. Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy

Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy

  • Free Radic Biol Med. 2026 Mar 16:246:668-681. doi: 10.1016/j.freeradbiomed.2026.01.040.
Xin Su 1,  Teng Fan 1,  Zeyu Liu 1,  Yuanyuan Huang 1,  Jun Kan 1,  Chuwen Liang 1,  Yuwen Chen 1,  Zhangqi Cao 1,  Shuangli Zhu 1,  Sijia Li 1,  Kai Fu 1,  Can Pan 1,  Fang Wang 1,  Bei Zhang 2,  Liwu Fu 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: [email protected].
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: [email protected].
PMID: 41628696 DOI: 10.1016/j.freeradbiomed.2026.01.040
Abstract

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent cardiotoxicity. Currently, there are no effective strategies to prevent or reverse DOX-mediated myocardial injury, highlighting the urgent need for novel therapeutic approaches.

Objectives: In this study, the cardioprotective effects of crocin, a natural compound derived from Crocus sativus, were investigated in the context of DOX-mediated cardiotoxicity.

Methods: Cardiac function, mitochondrial morphology, ROS production, and ATP content were evaluated in both in vitro and in vivo models of DOX-mediated cardiotoxicity. RNA Sequencing was performed to identify key regulatory pathways affected by crocin. Mitophagy-related mechanisms were investigated through molecular and cellular assays, including immunofluorescence and Western blot analysis of PTEN-induced kinase 1 (PINK1)-associated signaling. PINK1 knockdown and Mitophagy inhibition were performed to assess the impact on the cardioprotective effects of crocin.

Results: Crocin treatment preserved cardiac function and mitigated DOX-mediated myocardial injury in both in vitro and in vivo models, as evidenced by restored left ventricular ejection fraction, reduced mitochondrial ROS accumulation, restoration of ATP production, and improved mitochondrial morphology. Transcriptomic analysis revealed that crocin upregulated PINK1 expression, a key initiator of Mitophagy. Functional assays further confirmed that crocin restored Mitophagy activity suppressed by DOX exposure. The cardioprotective effects of crocin were abolished upon PINK1 knockdown or Mitophagy inhibitor, highlighting the essential role of PINK1-dependent Mitophagy in mediating crocin's effects.

Conclusions: Crocin protects against doxorubicin-induced cardiotoxicity by activating PINK1-mediated Mitophagy and maintaining mitochondrial homeostasis. These findings highlight crocin as a potential therapeutic agent for mitigating DOX-mediated cardiotoxicity.

Keywords

Cardiotoxicity; Crocin; Doxorubicin; Mitophagy; PTEN-induced kinase 1.

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