Ammonium tetrathiomolybdate ameliorates heat stroke-induced murine liver injury by activating the Nrf2/HO-1 signaling pathway and inhibiting oxidative stress.

Abstract

Amid accelerating global climate change, heat stroke has emerged as a critical public health challenge worldwide. This condition can lead to circulatory failure, disseminated intravascular coagulation (DIC), multi-organ dysfunction, and even death. Liver injury, a common complication of heat stroke, serves as a direct contributor to mortality, yet effective therapeutic agents remain lacking. In this study, we investigated the protective effects of ammonium tetrathiomolybdate (ATTM), a small-molecule inorganic molybdenum-sulfur compound, against heat stroke-induced acute liver injury and elucidated its underlying mechanisms. ATTM pretreatment significantly alleviated heat stroke-induced acute liver injury, reduced hepatocyte apoptosis and systemic inflammatory responses, and improved survival rates in heat stroke-challenged mice. Liver RNA-seq data underscored the critical role of oxidative stress in the pathogenesis of heatstroke. ATTM significantly ameliorated mitochondrial damage and ROS generation, findings corroborated by both in vivo and in vitro experiments. Subsequent investigation into the mechanism underlying ATTM's suppression of oxidative stress revealed that it activates the Nrf2/HO-1 antioxidant pathway. This activation alleviates heat stress-induced mitochondrial damage and ROS production, thereby conferring therapeutic benefits. These findings establish ATTM as a highly promising therapeutic candidate for heat stroke.