DNA damage and repair in cardiomyopathy: mechanisms and therapeutic opportunities

Accumulating evidence from human clinical cohorts and animal models indicates that DNA damage plays a pivotal role in the initiation, progression, and severity of cardiomyopathy subtypes. Cardiomyocytes are exposed to continuous mechanical stress due to persistent contractile activity, and this stress is transduced to the nucleus, rendering CMs vulnerable to mechano-transduced DNA damage. CMs are also vulnerable to oxidative stress-induced DNA damage. The DNA damage response (DDR) constitutes a cellular program that integrates lesion sensors, signal transducers, downstream effectors, and repair machineries, thereby governing cell cycle progression and other cell fate decisions. DDR responses have been studied in proliferating cells, whereas adult CMs are withdrawn from the cell cycle, suggesting distinct DDR mechanisms and outcomes may occur in CMs. Although transient DDR activation helps preserve genomic stability in CMs, sustained activation contributes to maladaptive cardiac remodeling, functional decline, and disease progression. Several key DDR components have been identified as potential therapeutic targets, with their inhibition demonstrating cardioprotective effects in various cardiomyopathy models. Moreover, a growing number of novel pathways have emerged as promising avenues for targeting DNA damage and repair signaling in cardiomyopathy. In this review, we discussed molecular mechanisms by which DNA damage and DDR contribute to the onset and progression of cardiomyopathy, and highlight emerging therapeutic strategies aimed at modulating DNA damage and repair pathways to improve cardiac function and clinical outcomes. Understanding how these pathways intersect with cardiomyocyte biology will be essential for translating bench discoveries into durable therapies for patients with cardiomyopathy and heart failure.