Abstract Body: Introduction: Doxorubicin (DOX) is a potent chemotherapeutic agent effective against various cancers; however, its clinical utility is severely limited by dose-dependent cardiotoxicity. While the precise etiology remains incomplete, mitochondrial oxidative stress and dysfunction are recognized as primary drivers of DOX-induced cardiac injury. Peroxiredoxin III (PrxIII), a mitochondria-specific peroxidase, plays a pivotal role in scavenging hydrogen peroxide (H₂O₂) within the mitochondrial matrix.
Hypothesis: We assessed the hypothesis that PrxIII deficiency exacerbates DOX-induced cardiotoxicity by promoting the accumulation of mitochondrial reactive oxygen species (mtROS), thereby impairing mitochondrial dynamics and disrupting mitophagy flux.
Methods: We utilized PrxIII knockout (KO) mice and wild-type (WT) littermates administered with DOX or saline. Cardiac function was evaluated via echocardiography. To elucidate molecular mechanisms, H9c2 cardiomyocytes were employed. Mitochondrial ROS levels, membrane potential, and mitophagy flux were measured using flow cytometry and immunofluorescence. Protein markers of mitochondrial dynamics (e.g., Drp1, Mfn1/2) and mitophagy (e.g., Parkin, LC3) were analyzed by Western blotting.
Results: DOX administration significantly reduced cardiac function, indicated by decreased Fractional Shortening (FS) and Ejection Fraction (EF) in WT mice; this dysfunction was markedly exacerbated in PrxIII KO mice (EF: 40% ,p<0.01, FS: 20%, p<0.01). Mechanistically, DOX treatment depleted endogenous PrxIII levels in H9c2 cells, which correlated with a 1.7-fold surge in mtROS. PrxIII deficiency led to excessive mitochondrial fission and disrupted mitophagy flux following DOX exposure, resulting in the accumulation of damaged and dysfunctional mitochondria. Conversely, PrxIII overexpression attenuated DOX-induced mtROS generation and preserved mitochondrial integrity.
Conclusion: These findings demonstrate that PrxIII is an essential regulator of mitochondrial quality control in the heart under stress conditions. The depletion of PrxIII exacerbates DOX-induced cardiotoxicity via dysregulated mitochondrial dynamics and oxidative stress. Therefore, targeting PrxIII-mediated mitochondrial antioxidant defense represents a promising therapeutic strategy to prevent chemotherapy-induced heart failure.