Under cold stress, the processes of autophagy, apoptosis and energy metabolism are pivotal for sustaining energy and tissue balance. However, the molecular regulatory mechanisms and interactions underlying these processes are still largely unknown. In this study, the molecular mechanisms underlying the regulation of energy homeostasis and tissue homeostasis of Cranoglanis bouderius (13 +/- 0.5 g) under cold stress conditions were investigated using histological, metabolomic, and transcriptomic approaches after programmed cooling (25(degrees) C, 20(degrees) C, and 15(degrees) C). Results revealed an uptick in the serum antioxidant activity of C. bouderius during cold stress, contrasted with a decrease in cholesterol levels. Histological assessments revealed extensive damage, marked by evident apoptotic signals, in the gills, liver, and muscles. Transmission electron microscopy and mitochondrial membrane potential analysis also indicated that cold stress induced mitochondrial damage in the liver of C. bouderius, resulting in decreased mitochondrial membrane potential and increased mitochondrial fusion and autophagy. The integrated analysis of metabolomics and transcriptomics suggests that under cold stress, energy homeostasis is primarily regulated by the coordinated action of the AMPK and PPAR signaling pathways, with potential modulation by metabolites like epinephrine. The obstruction of biosynthetic processes is primarily associated with the inhibition of signaling pathways such as PI3K/AKT/mTOR and protein processing in the endoplasmic reticulum. Sustained activation of AMPK alleviates the PI3K/AKT/mTOR-mediated inhibition of autophagy and apoptosis, potentially underpinning the transition from autophagy-mediated apoptosis suppression to apoptosis promotion during cold stress. In summary, these findings elucidate the consequences arising from the altered interactions within the AMPK/PPAR/PI3K/AKT/mTOR pathway under cold stress conditions and offer a theoretical basis for enhancing the ability of fish species to cope with cold stress.