Receptor-interacting protein kinases (RIPK1–RIPK4) in cardiac pathophysiology: Mechanistic signaling, disease contexts, and emerging pharmacological targets

Receptor-interacting protein kinases (RIPKs) are a family of serine/threonine kinases that regulate innate immunity, inflammation, and several modalities of regulated cell death, and are increasingly implicated in cardiovascular disease. Increasing evidence suggests that dysregulated RIPK signaling contributes to cardiomyocyte injury, fibrosis, maladaptive remodeling, mitochondrial dysfunction, and inflammatory amplification in multiple cardiac pathologies. While the roles of RIPK1 and RIPK3 in necroptosis are well recognized, recent studies indicate broader and more complex role in heart disease, including broader non-canonical functions involving mitochondrial regulation, oxidative stress, inflammasome activation, and metabolic remodeling. RIPK2 is emerging as a significant but underrecognized modulator of sterile cardiac inflammation and pathological remodeling. Similarly, RIPK4 has recently been associated with oxidative stress responses and ferroptosis, although direct cardiac evidence remains limited. This review provides an updated overview of RIPK1-RIPK4 signaling within the framework of cardiovascular disease, emphasizing both canonical necroptotic and non-canonical signaling mechanisms. We discuss the involvement of RIPKs in myocardial ischemia/reperfusion injury, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, myocarditis, and doxorubicin-induced cardiotoxicity. We further summarize current and emerging therapeutic strategies targeting RIPKs, including small-molecule inhibitors, natural compounds, and endogenous regulators approaches. Finally, we highlight major knowledge gaps and translational challenges, including isoform-specific functions, temporal dynamics of RIPK activation, safety considerations, and the clinical translation of preclinical findings.