The clinical stakes are enormous. Up to a quarter of patients treated with doxorubicin develop cardiac injury during or after therapy, ranging from silent myocardial damage to full-blown congestive heart failure. The risk climbs steeply with cumulative dose: at 400 mg/m² the incidence of heart failure hovers around 5 percent, but it jumps to roughly 26 percent at 550 mg/m² and a staggering 48 percent at 700 mg/m². Dexrazoxane remains the only FDA-approved cardioprotective agent, yet concerns about whether it might blunt doxorubicin’s anticancer power have limited its use. Beta-blockers and other supportive measures help some patients, but none directly address the fundamental breakdown in cellular housekeeping that Tian and colleagues identify as central to the disease.

To understand why the heart is so vulnerable, one must appreciate its cellular architecture. Cardiomyocytes are packed with mitochondria — the power plants that fuel continuous contraction — and with the sarcoplasmic reticulum, a specialized endoplasmic reticulum that stores and releases the calcium ions triggering each heartbeat. Doxorubicin attacks both. It intercalates into DNA and traps topoisomerase IIβ in lethal cleavage complexes, generating persistent double-strand breaks. Simultaneously, it disrupts iron metabolism and drives redox cycling, flooding cells with reactive oxygen species. The mitochondria swell, their cristae collapse, and their DNA mutates. The ER loses its ability to fold proteins properly and to buffer calcium. These twin injuries converge on the same problem: the cell’s recycling systems must somehow keep pace with escalating damage.

Mitophagy is the cell’s way of selectively devouring broken mitochondria. When a mitochondrion loses its membrane potential, a protein called PINK1 accumulates on its outer surface and recruits Parkin, which tags the organelle with ubiquitin chains that autophagy receptors like p62 and optineurin recognize. Alternatively, receptor proteins such as BNIP3, NIX, and FUNDC1 can bind LC3 directly on forming autophagosomes, bypassing the ubiquitin step entirely. Either route ends with the damaged mitochondrion sealed inside an autophagosome, fused with a lysosome, and digested. But here is where the review delivers its most provocative insight: doxorubicin does not simply switch mitophagy on or off. Instead, it disrupts the process at multiple checkpoints — damage sensing, cargo labeling, autophagosome formation, and lysosomal degradation — and the outcome depends entirely on which checkpoint fails first.

The authors marshal evidence from dozens of preclinical studies to build this checkpoint-dependent framework. In some models, low doses of doxorubicin trigger a compensatory mitophagy response that genuinely protects the heart by clearing damaged mitochondria before they accumulate. In others, the drug drives excessive mitochondrial fragmentation through the fission protein DRP1, creating a feed-forward loop in which Parkin recruitment accelerates fission, which in turn generates more fragments for mitophagy to consume — eventually depleting the cell’s mitochondrial reserve faster than it can be replaced. Still other studies reveal a third failure mode: cytosolic p53, elevated by doxorubicin, binds Parkin and prevents it from reaching mitochondria, starving the pathway at its very first step. And in models where flux has been directly measured, autophagosomes pile up because the final fusion with lysosomes never happens, leaving damaged organelles stranded inside cellular garbage bags that never get emptied.

What makes this framework so powerful is that it explains decades of apparently contradictory findings. Studies reporting that doxorubicin

The apparent contradictions in the literature become even more tractable when one considers how experimental design shapes what investigators observe. The review emphasizes that discrepancies among studies reporting protective organelle clearance, insufficient autophagy initiation, or stalled degradation may reflect differences in doxorubicin dose, exposure duration, and exposure pattern, as well as the choice of experimental model and whether autophagic flux was actually measured rather than inferred. A single time point showing abundant autophagosomes, for instance, could indicate either vigorous recycling or a jammed disposal system; only dynamic flux assays can distinguish between these possibilities. Many earlier studies relied on static markers such as LC3-II abundance or puncta formation, which cannot by themselves reveal whether cargo ultimately reaches the lysosome. This methodological blind spot may account for a substantial fraction of the conflicting conclusions that have accumulated over the years, and it underscores the review’s call for standardized flux assessment in future work.

ER-phagy, the selective degradation of endoplasmic reticulum through autophagy, receives comparatively less experimental attention in the doxorubicin setting, and the authors are careful to frame the available evidence cautiously. Receptor proteins such as FAM134B, RTN3, ATL3, and TEX264 can each recognize stressed or damaged ER fragments and deliver them to autophagosomes, but the specific contributions of these receptors in cardiomyocytes exposed to anthracyclines remain incompletely mapped. Existing studies differ in the doxorubicin regimens employed, the receptor pathways interrogated, and the rigor of flux measurement, making direct comparison difficult. The review therefore proposes functional divergence of ER-phagy as an interpretive framework rather than a settled conclusion: in some contexts ER-phagy may relieve stress by clearing misfolded protein aggregates and damaged reticular membranes, while in others it may strip the cell of calcium-handling capacity at the sarcoplasmic reticulum, worsening contractile dysfunction. Disentangling these possibilities will require receptor-specific tools and longitudinal designs that current literature largely lacks.

A further layer of complexity arises from the physical intimacy of the two organelles. Mitochondria-associated ER membranes, or MAMs, are contact sites where the ER and mitochondria lie within tens of nanometers of each other, tethered by protein complexes that coordinate calcium transfer, mitochondrial dynamics, and stress signaling. In healthy cardiomyocytes, these junctions allow efficient shuttling of calcium ions from the sarcoplasmic reticulum into mitochondria to match energy production with contractile demand. Doxorubicin disrupts this architecture, and the review argues that MAM dysfunction may serve as the mechanistic hinge connecting mitochondrial injury, ER stress, and selective autophagy imbalance. Receptors involved in mitophagy and ER-phagy localize at or near these contact sites, and autophagosome formation itself can be coordinated there. If MAM integrity deteriorates, calcium mishandling, energetic failure, and defective organelle quality control may reinforce one another, producing a vicious cycle that no single-pathway intervention is likely to break.

When mitochondrial clearance fails, the consequences extend beyond energy depletion. Damaged mitochondria that persist within cardiomyocytes can leak mitochondrial DNA into the cytosol and release mitochondrial reactive oxygen species, both of which activate inflammatory signaling through the cGAS-STING pathway and the NLRP3 inflammasome. This places mitophagy at the interface between organelle quality control and innate immunity, suggesting that failed clearance may convert a purely metabolic injury into a sterile inflammatory process that accelerates myocardial damage. Such a mechanism could help explain why cardiac injury after doxorubicin sometimes progresses long after the drug has been cleared from the body, and why late-onset cardiotoxicity, with a reported mean latency of approximately seven years, remains so difficult to predict or prevent.

The temporal dimension of doxorubicin-induced cardiotoxicity adds another consideration for translational efforts. Acute injury occurring within hours to days of exposure is often at least partly reversible and involves vacuolar change, interstitial edema, and inflammatory infiltration. Early-onset chronic disease emerges within a year and represents the most common clinically relevant pattern, evolving from subclinical dysfunction toward overt heart failure. Late-onset disease can surface years or even decades later, with restrictive cardiomyopathy appearing relatively more frequently and reflecting progressive fibrosis and myofibrillar disorganization following cardiomyocyte death. Because the dominant injury mechanisms and the state of the autophagy machinery likely differ across these phases, a cardioprotective strategy effective during acute exposure may prove useless or even harmful when applied years afterward. Stage-specific targeting of mitophagy and ER-phagy therefore emerges as a central theme of the review.

Subtle structural changes may also serve as early warning signs that current monitoring overlooks. Reductions in left ventricular mass have been observed after doxorubicin exposure in both experimental models and clinical cohorts, and this change can precede any measurable decline in ejection fraction while persisting for at least six months. Such remodeling suggests that functional indices alone capture the injury process late. Combination regimens modify the phenotype further: doxorubicin plus trastuzumab has been associated with reduced cardiac mass and biventricular dysfunction even without severe metabolic abnormalities or very high cumulative anthracycline exposure, and prior anthracycline treatment appears to increase susceptibility to trastuzumab-related cardiotoxicity, possibly through overlapping disruption of mitochondrial quality control.

The review is candid about the limits of the evidence base. Most of what is known about mitophagy and ER-phagy in this setting derives from cell culture and animal studies, and direct evidence from human myocardial tissue is essentially absent. The metformin experience offers a cautionary lesson: in a randomized trial, metformin preserved peripheral mitochondrial respiration to some extent yet failed to demonstrate clear cardiac benefit, implying that biologically plausible interventions may falter when cardiac target engagement is never confirmed. Peripheral surrogate markers, in other words, may not faithfully reflect what is happening inside the myocardium. Any future therapy built on modulating selective autophagy will need pharmacodynamic readouts drawn from cardiac tissue itself, together with careful attention to dose, timing, and the checkpoint at which the pathway has failed. Until such tools exist, the checkpoint framework offered by Tian and colleagues serves less as a treatment manual than as a map of where the search should concentrate.

Subject of Research: Selective autophagy mechanisms in doxorubicin-induced cardiotoxicity

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

Article References: Tian, Y., Chang, A., Guo, Z., Zhou, H., Chang, X., & Wu, J. (2026). Mitophagy and ER-phagy in doxorubicin-induced cardiotoxicity: mechanisms, crosstalk, and therapeutic implications. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.022

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.022

Keywords: doxorubicin, cardiotoxicity, mitophagy, ER-phagy, autophagy, cardio-oncology, heart failure, chemotherapy, doxorubicin-induced, mechanisms, crosstalk, therapeutic