When defence mechanisms fail: Multi-omics evidence of antioxidant system collapse in Thymallus grubii liver under...

Increasing global temperatures pose a severe threat to the survival of cold-water fish species. As a significant cold-water fish in China, the Amur grayling (Thymallus grubii) primarily inhabits mountain streams, favouring clear and cold waters, rendering it particularly vulnerable to the impacts of global warming. Therefore, intensive research into the effects of acute high-temperature stress on the liver of T. grubii is of significant importance. Our study systematically elucidates the mechanism by which acute heat stress affects the liver of T. grubii through integrated analysis of hepatic transcriptomics and metabolomics. The results indicate that high-temperature stress induces severe damage to the liver, manifesting as hepatocyte vacuolation, nuclear damage, and tissue congestion. Multi-omics analysis revealed that high-temperature stress induces metabolic reprogramming in the liver while suppressing amino acid and energy metabolism. Furthermore, high-temperature stress significantly alters the antioxidant defence mechanisms, maintenance of protein homeostasis, and regulation of energy metabolism within the organism. In response to high-temperature stress, the organism promotes emergency energy supply through enhanced glycolysis and the pentose phosphate pathway, whilst also boosting NADPH synthesis to assist in maintaining antioxidant levels. However, organisms allocate limited energy and resources to core defence mechanisms and emergency energy supply during oxidative stress responses, thereby suppressing certain synthetic (de novo glutathione synthesis) and detoxification functions. Moreover, high-temperature stress promotes the expression of ferroptosis initiator ACSL4 while simultaneously suppressing the Xc-/GSH/GPX4 antioxidant defence axis, thereby reducing cellular resistance to ferroptosis. In summary, acute hyperthermic stress significantly reduces cellular resistance to ferroptosis by disrupting lipid metabolism and suppressing the antioxidant defence axis. This finding provides crucial theoretical support for understanding the metabolic regulatory mechanisms in aquatic organisms under extreme conditions.