Lipid metabolism and immune crosstalk in fish gut-liver axis: Insights from SOCS8 knockout and dietary stress models

Metaflammation, a chronic immune response triggered by metabolic dysregulation, poses significant threats to gut-liver homeostasis in aquaculture species. To understand the progression of metaflammation, it is crucial to examine the role of SOCS8 deficiency in socs8^-/- zebrafish, as this species may serve as a disease model for metabolic disorders due to the gradual dysregulation of immunity, metabolism, and the gut microbiota observed in them. This study examines the immune-metabolic crosstalk in grass carp, subjected to soybean meal-induced enteritis, and in socs8^-/- zebrafish under genetic and dietary stress. SOCS8 is a negative regulator of cytokine signaling via the JAK/STAT pathway; its deficiency mirrors the persistent inflammatory and insulin-resistant states commonly seen in carnivorous fish-fed high-soybean diets, making it a valuable model for studying diet-induced metaflammation. Weighted gene co-expression network analysis (WGCNA), differential expression profiling, and immune cell infiltration analysis revealed that grass carp respond to dietary stress with disrupted glucose and lipid metabolism, activating MAPK, NF-κB, and NOD-like receptor pathways associated with metaflammation. In contrast, socs8^-/- zebrafish displayed a metaflammatory state, with upregulation of glucotoxicity and lipotoxicity-related genes such as ppargc1a, prkaa1, mdm2, and srebf1, along with impaired regulatory T cell activity and elevated Th17 polarization. Adaptive immune dysfunction was characterized by a further downregulation of cd74a and s1pr4, suggesting impaired antigen presentation. NicheNet analysis, adapted using zebrafish-human ortholog mapping, identified jam2a and tgfb3 as central ligands mediating immune barrier dysfunction and metabolic inflammation. These ligands were closely associated with macrophage activation, tissue remodeling, and extracellular matrix stress. Consider, these findings collectively elucidate the molecular architecture of metaflammation in both herbivorous and model fish species, emphasizing the role of SOCS8 in regulating immunometabolic balance and providing candidate biomarkers and therapeutic targets for improving gut-liver health in aquaculture.