Mechanism of endoplasmic reticulum stress: Insights for potential therapeutic benefits in burns

Burns are injuries to the skin and deep tissues caused by thermal effects, which can trigger inflammation, necrosis, and systemic pathological reactions, often leading to life-threatening complications such as shock, infection, and multi-organ failure. Endoplasmic reticulum stress (ERS) is a key driving factor for tissue damage after burns. Burns are proposed to induce ERS through multiple mechanisms, including protein denaturation, inflammatory cytokine storms, and metabolic disturbances, Under stress conditions, cells can activate three key sensors, IRE1, PERK, and ATF6, to fully activate the main signaling pathway of unfolded protein response (UPR). In severe burns, sustained ERS promotes cell death via CHOP-mediated apoptosis, programmed necrosis, and ferroptosis (activated by the PERK-eIF2α-ATF4 pathway), exacerbating tissue injury. The progressive elevation of endoplasmic reticulum stress markers such as GRP78 and CHOP during burn course has been proven to be an important biological indicator for evaluating the degree of secondary organ damage. Consequently, therapeutic interventions such as propranolol (to counteract catecholamine effects) and 4-PBA (to stabilize protein folding) are under investigation as potential approaches for improving burn outcomes. This review systematically examines the pathological mechanisms of burn-induced ERS, associated modes of cell death, clinical manifestations of organ dysfunction, potential drug therapies, and other burn-related stress responses.