Curcumin attenuates di(2-ethylhexyl) phthalate-induced hepatic injury in chicks via oxidative stress, glycolysis, and PANoptosis-related signaling.

Curcumin is a natural polyphenol with hepatoprotective potential, whereas di(2-ethylhexyl) phthalate (DEHP) is a widely used environmental plasticizer that poses a threat to poultry liver health. This study investigated the protective effects of curcumin against DEHP-induced hepatic injury in chickens and examined the involvement of reactive oxygen species (ROS)-dependent hypoxia-inducible factor 1 alpha (HIF-1α)-mediated glycolysis and PANoptosis-related molecular responses. In vitro, Curcumin attenuated DEHP-induced mitochondrial ROS overproduction, restored ATP generation and mitochondrial membrane potential, improved calcium homeostasis, and alleviated mitochondrial dysfunction and endoplasmic reticulum stress. Curcumin also suppressed DEHP-induced HIF-1α, HK2, PKM, and LDH expression, whereas ROS activation weakened these effects. Glycolysis inhibition further reduced apoptosis-, necroptosis-, and pyroptosis-related molecular markers, highlighting a regulatory role of the ROS-HIF-1α-glycolysis axis. In vivo, DEHP exposure decreased body weight while increasing the liver index and serum activities of alanine aminotransferase and aspartate aminotransferase. It also induced pronounced hepatic histological and ultrastructural damage, accompanied by oxidative stress, inflammatory responses, mitochondrial dysfunction, glycolytic activation, and PANoptosis-related molecular responses. Curcumin supplementation substantially ameliorated these pathological changes by restoring antioxidant capacity, preserving mitochondrial function and metabolic homeostasis, suppressing the expression of inflammatory cytokines, and attenuating programmed cell death-related molecular markers. Furthermore, network pharmacology, molecular docking, molecular dynamics simulation, and cellular thermal shift assay consistently identified HIF-1α as a potential molecular target underlying the hepatoprotective effects of curcumin. Collectively, these findings demonstrate that curcumin effectively protects against DEHP-induced hepatic injury in chickens, at least in part, by suppressing ROS accumulation, inhibiting HIF-1α-mediated glycolytic disorder, and consequently attenuating downstream PANoptosis-related molecular responses.