Mitophagy and ER-phagy in doxorubicin-induced cardiotoxicity: mechanisms, crosstalk, and therapeutic implications

Doxorubicin (DOX) is a key chemotherapeutic agent for hematologic malignancies and many solid tumors, but its clinical use is limited by doxorubicin-induced cardiotoxicity (DIC). DIC may present as subclinical myocardial injury, arrhythmias, left ventricular dysfunction, cardiomyopathy, or heart failure. DOX can disrupt organelle function through topoisomerase IIβ (Top2β)-mediated DNA damage and transcriptional stress, oxidative stress, disrupted iron homeostasis, and calcium imbalance. Mitochondrial and endoplasmic/sarcoplasmic reticulum (ER/SR) injury are therefore central pathological features of DIC.

This review summarizes current evidence on mitophagy and ER-phagy in DIC, with emphasis on discrepancies in reported findings across different experimental settings, potential crosstalk mechanisms, and the translational limitations of targeting these pathways for cardioprotection.

Current studies suggest that mitophagy in DIC follows a checkpoint-dependent pattern. Depending on DOX dose, exposure duration, and lysosomal degradative capacity, mitophagy may remove damaged mitochondria, but it may also worsen mitochondrial injury when initiation is insufficient, activation is excessive, or flux is stalled. In contrast, direct evidence for ER-phagy in DIC remains limited. This evidence is mainly derived from CCPG1-mediated protective ER-phagy in chronic fractionated DOX models and FAM134B-associated ER-phagy-related injury signals in acute high-dose injury models. Thus, the functional divergence of ER-phagy in DIC requires confirmation in additional experimental models with rigorous autophagic flux assessment. Mitochondria-associated ER membranes (MAMs) may coordinate mitophagy and ER-phagy by regulating calcium transfer, autophagosome formation, and receptor localization. Overall, current evidence does not support indiscriminate activation or inhibition of mitophagy and ER-phagy. Instead, future interventions may need to preserve flux-complete organelle clearance while avoiding excessive or stalled autophagic signaling. In addition, this framework may help generate research hypotheses that integrate cardioprotection with preservation of antitumor efficacy. However, most evidence comes from cell and animal studies, and further validation in human myocardial tissue and confirmation of cardiac target engagement are still needed.