From Proteostasis Collapse to Endothelial Failure: Mechanistic Pathways Linking Heat Stress, Regulated Cell Death, and Coagulopathy

This review proposes an integrative mechanistic model that brings together apoptosis, pyroptosis, ferroptosis, necroptosis, and necrosis within the broader context of heat-induced proteostasis disruption. Rather than depicting a strictly sequential or fully validated causal pathway, the model provides a conceptual framework through which interactions among cellular stress responses, endothelial dysfunction, heatstroke-induced coagulopathy (HIC), and multiple organ dysfunction syndrome (MODS) may be understood. Under extreme heat stress, widespread protein unfolding and chaperone saturation activate the unfolded protein response, disrupt endoplasmic (ER) calcium homeostasis, and couple through Ca2+-mediated injury to mitochondrial dysfunction and oxidative stress. These processes are reciprocally amplifying: reactive oxygen species (ROS) from failing mitochondria deepen proteostatic damage and potentiate necroptotic and ferroptotic signaling, while inflammation-driven immune activation further increases ROS production, closing a self-reinforcing cycle. The resulting engagement of multiple RCD pathways, apoptosis, pyroptosis, ferroptosis, and necroptosis, each with qualitatively distinct DAMP signatures, promotes inflammasome activation and a cytokine storm that destabilizes the endothelial glycocalyx, impairs barrier integrity, and triggers a pro-coagulant shift underlying HIC. We further examine biomarker candidates reflecting these mechanisms, evaluate emerging therapeutic strategies, ranging from HSP modulation and antioxidant therapy to endothelial-protective agents, mitophagy regulators, and nanomedicine, and outline the future role of multi-omics, machine learning, and regenerative approaches. By bringing together molecular, cellular, vascular, and systemic processes into a single cohesive model, this review proposes a conceptual foundation to guide diagnostic refinement, therapeutic innovation, and forensic interpretation in severe heat-related injury.