Erythropoietin modulates hepatic inflammation, glucose homeostasis, and soluble epoxide hydrolase and epoxides in high‐fat diet‐induced obese mice

Obesity-related liver disease remains a critical global health challenge, underscoring the need to elucidate the molecular mechanisms underlying hepatic inflammation and metabolic dysfunction, and to identify novel therapeutic targets. This study aimed to determine whether erythropoietin (EPO) modulates soluble epoxide hydrolase (sEH) and lipid mediator pathways to ameliorate hepatic inflammation and metabolic dysfunction in high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed HFD with or without EPO treatment, and metabolic phenotyping, including glucose tolerance testing and homeostasis model assessment of insulin resistance, was performed. Hepatic histology and quantitative real-time polymerase chain reaction were conducted, together with flow cytometry to assess macrophage polarization, western blotting for sEH, and targeted liquid chromatography-tandem mass spectrometry profiling of cytochrome P450 epoxygenase-derived epoxides. EPO treatment improved glucose metabolism, reduced hepatic steatosis, lowered Ccr2, Mcp1, and Tnfα expression, promoted a shift of hepatic macrophages toward an M2 (anti-inflammatory) phenotype, downregulated hepatic sEH protein levels, and increased both hepatic and plasma concentrations of epoxygenase-derived epoxides. These findings indicate that EPO suppresses hepatic sEH and favors pro-resolving lipid mediator signaling, suggesting a potential therapeutic avenue for obesity-related hepatic inflammation.