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

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.

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

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.

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.

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.