Sympathetic neuroeffector remodeling and cardiomyocyte ferroptosis in heart failure: A stage- and compartment-specific framework for β-adrenergic/cAMP signaling

Heart failure is characterized by sympathetic remodeling, altered myocardial adrenergic responsiveness, and cardiomyocyte injury, with ferroptosis emerging as a potential contributor to adverse cardiac remodeling. This review proposes a dynamic "sympathetic-ferroptosis continuum" within a "nerve terminal-cardiomyocyte" dual-compartment framework linking cardiac sympathetic dysfunction, β1-adrenergic receptor (β1-AR)/cyclic adenosine monophosphate (cAMP) signaling, and cardiomyocyte ferroptosis susceptibility. Sustained sympathetic drive can coexist with altered norepinephrine (NE) homeostasis at cardiac nerve terminals and myocardial β1-AR desensitization, creating a functional mismatch between sympathetic activity and myocardial signaling responsiveness. At sympathetic nerve terminals, altered β1-AR/cAMP signaling may influence tyrosine hydroxylase-dependent NE synthesis and synapsin 1/RIM1α-associated vesicle mobilization and release, alongside changes in NE transporter-mediated reuptake. In cardiomyocytes, dysregulated compartment-specific cAMP signaling may affect YAP-associated iron homeostasis, LPCAT3-mediated phospholipid remodeling, SLC7A11/GSH/GPX4-dependent antioxidant defenses, and NOX4-related oxidative stress, thereby modifying ferroptosis susceptibility. Together, these pathways provide an integrated mechanistic framework linking neurocardiac signaling imbalance with cardiomyocyte ferroptosis susceptibility. This framework identifies potential targets for preserving adaptive cAMP signaling, improving sympathetic neurotransmitter homeostasis, and limiting ferroptosis-related injury, providing new directions for compartment-specific cardioprotective strategies in heart failure.