Ion channels and GPCRs as pharmacological regulators of ferroptosis and pyroptosis in metabolic diseases

Metabolic diseases, including type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, and atherosclerotic cardiovascular disorders, are increasingly recognized as conditions driven not only by metabolic imbalance but also by dysregulated cell death pathways. Beyond apoptosis, ferroptosis and pyroptosis have emerged as pivotal non-apoptotic cell death pathways linking metabolic stress, oxidative injury, and chronic inflammation. Ferroptosis is characterized by iron-dependent lipid peroxidation, while pyroptosis is mediated by inflammasome activation and gasdermin-dependent membrane pore formation, both of which contribute to progressive tissue dysfunction in metabolic organs. Growing evidence highlights ion channels and G protein-coupled receptors (GPCRs) as critical upstream regulators of these processes. Ion channels governing Ca²⁺, K⁺, and Fe²⁺ fluxes modulate redox balance, mitochondrial integrity, and inflammasome activation, thereby shaping cellular susceptibility to ferroptosis and pyroptosis. In parallel, GPCRs integrate hormonal, lipid, and microbial-derived signals to influence antioxidant defenses, iron homeostasis, and inflammatory signaling cascades. This review provides a comprehensive synthesis of current knowledge on the roles of ion channels and GPCRs as pharmacological regulators of ferroptosis and pyroptosis in metabolic diseases. This article discusses mechanistic insights, pathway cross-talk, and emerging therapeutic strategies, including repurposed drugs, small-molecule inhibitors, and nutraceuticals targeting these surface receptors. By framing metabolic diseases as disorders of regulated cell death signaling, this review underscores ion channels and GPCRs as promising, druggable targets for next-generation interventions aimed at halting metabolic inflammation and tissue injury.