Beyond autophagic flux: selective autophagy adaptors and cargo prioritization in cardiac disease.

Cardiovascular disease is the leading cause of death worldwide. Disrupted protein homeostasis contributes significantly to cardiomyocyte dysfunction and loss. While autophagy is recognized as a critical cardioprotective mechanism, most therapeutic strategies have targeted overall autophagic flux, assuming that increasing degradative capacity is inherently beneficial. This approach overlooks a fundamental question: when multiple substrates compete for limited autophagic capacity, what determines which cargo is prioritized? This review focuses on the selective autophagy adaptors (sequestosome 1 [p62/SQSTM1], neighbor of BRCA1 gene 1 [NBR1], Tax1-binding protein 1 [TAX1BP1], optineurin [OPTN], nuclear dot protein 52 kDa [NDP52], and Fab1, YOTB, Vac1, EEA1 domain, and coiled-coil domain containing 1 [FYCO1]) as the molecular machinery governing cargo selectivity. We synthesize evidence demonstrating that adult cardiomyocytes face a unique "triage problem": as post-mitotic cells with a massive proteome and high metabolic demands, they must continuously prioritize which damaged mitochondria, protein aggregates, or sarcomeric components to eliminate. We integrate findings from cardiac studies with mechanistic insights from other cell types to map adaptor function in the heart. We propose that targeting selective autophagy adaptors may offer therapeutic precision beyond global flux modulation, directing autophagic machinery toward the cargo most relevant to individual pathological contexts. Currently, FYCO1 overexpression remains the only adaptor-level intervention validated to rescue cardiac function in vivo, highlighting both proof-of-concept and substantial opportunity for further investigation. Understanding not just how much the heart degrades, but also what it chooses to degrade may open new avenues for treating heart failure and cardiomyopathies.