ATNFAIP8--dependent survival axis protects cardiomyocytes from anthracycline-induced cardiotoxicity

Abstract

Anthracycline-induced cardiotoxicity limits the therapeutic efficacy of cancer treatment and is characterized by mitochondrial dysfunction, oxidative stress, inflammatory activation, and cardiomyocyte apoptosis. The cardiomyocyte-intrinsic survival mechanisms that counteract these stress pathways remain incompletely defined. Doxorubicin-induced cardiotoxicity was modeled using human induced pluripotent stem cell–derived cardiomyocytes and a murine model of anthracycline injury. Cardiomyocyte viability, mitochondrial structure and bioenergetics, oxidative stress, inflammatory signaling, and contractile function were assessed using high-content imaging, ultrastructural analysis, metabolic flux measurements, and functional assays. Transcriptomic profiling was performed to identify candidate survival regulators, followed by molecular, genetic, and functional validation in vitro and in vivo. Doxorubicin induced dose-dependent cardiomyocyte injury marked by reduced cell survival, increased apoptosis, mitochondrial ultrastructural disruption, impaired oxidative phosphorylation, excessive reactive oxygen species generation, and increased tumor necrosis factor–α secretion. In vivo, doxorubicin exposure resulted in reduced survival and progressive systolic and diastolic dysfunction accompanied by myocardial architectural disorganization and cardiomyocyte loss. Transcriptomic analysis identified TNFAIP8 as a doxorubicin-responsive gene whose expression was reduced in injured cardiomyocytes and myocardium. Loss of TNFAIP8 was sufficient to impair cardiomyocyte viability and phenocopied key features of doxorubicin-induced injury. Conversely, preservation of TNFAIP8 expression was associated with attenuation of oxidative stress–driven inflammatory signaling, reduced FGFR1 activation, and suppression of caspase-3–dependent apoptosis, accompanied by improved cardiomyocyte survival and contractile performance. Doxorubicin-induced cardiotoxicity is driven by oxidative stress–associated inflammatory signaling that converges on destabilization of the cardiomyocyte survival factor TNFAIP8, thereby lowering the apoptotic threshold. Maintenance of TNFAIP8 defines a cardiomyocyte-intrinsic survival axis that preserves mitochondrial integrity, limits apoptotic activation, and protects cardiac structure and function under anthracycline stress.