Role of Regulated Cell Death Pathways in Snakebite Envenomation: Mechanisms, Crosstalk, and Therapeutic Opportunities

Snakebite envenomation causes severe tissue damage, often resulting in permanent disability with long-term complications like amputations and organ dysfunction. Current antivenoms, which are antibody-based, have lower tissue penetrability and limited efficacy in minimizing the local effects, highlighting the need for adjunct therapies. Emerging evidence indicates that venom-induced pathology is not restricted to direct cytotoxicity and necrosis; rather, it also involves multiple interconnected Regulated Cell Death (RCD) pathways, but their mechanistic interplay and therapeutic implications remain poorly understood. This review examines how venom toxins induce a cellular stress response characterized by oxidative stress, membrane disruption, and calcium overload, leading to the activation of interconnected regulated cell death (RCD) pathways, including apoptosis, ferroptosis, and pyroptosis, together with autophagy and mitophagy, which primarily function as cellular stress responses that modulate these forms of regulated cell death. We further discuss the crosstalk between these RCD pathways and emerging therapeutic approaches targeting these mechanisms. Understanding these interconnected RCD pathways may facilitate the development of adjunct therapies that complement antivenom, reduce snakebite-induced morbidity, and improve clinical outcomes.