Disulfidptosis in heart failure: an emerging mechanism awaiting exploration

Abstract

Heart failure (HF) is a major cardiovascular syndrome with increasing global incidence and mortality rates. Cardiomyocyte injury and ventricular remodeling are central pathological processes driving HF progression. Although several forms of regulated cell death have been implicated in HF, the mechanisms underlying cardiomyocyte injury remain poorly understood. Disulfidptosis, proposed in 2023, is a metabolism-related form of regulated cell death triggered by the depletion of the cellular reducing capacity. Evidence from tumor cell models indicates that under glucose-restricted conditions, cells with high SLC7A11 expression may exhibit insufficient NADPH production due to impaired pentose phosphate pathway (PPP) activity, resulting in disulfide stress, aberrant disulfide cross-linking of filamentous actin (F-actin), cytoskeletal collapse, and cell death. During HF progression, cardiomyocytes commonly undergo glucose metabolic remodeling, redox imbalance, and cytoskeletal abnormalities, which may create a permissive context for disulfidptosis-like injuries. However, direct experimental evidence demonstrating disulfidptosis in cardiomyocytes or the failing myocardium remains limited. Rather than treating transcriptomic associations as evidence of a defined cell-death programme, this review integrates HF-associated metabolic remodelling, impaired redox buffering, and cytoskeletal vulnerability within a testable mechanistic framework. It further defines a staged validation strategy for determining whether disulfidptosis occurs in cardiomyocytes or other myocardial cell populations.