Febuxostat Improves MASLD in Male Rats: Roles of XOR Inhibition and Associated JNK/NRF2/HO-1 Pathway Changes

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a peril to public health. Xanthine oxidoreductase (XOR) is implicated in oxidative stress and lipid metabolism, which constitute the pathological basis of MASLD. As a specific XOR inhibitor, febuxostat therefore exhibits considerable potential for mitigating MASLD. However, the efficacy and underlying mechanisms of febuxostat in this context remain to be elucidated. Against this background, the present study aimed to observe the effect of febuxostat on the physiological changes of male MASLD rats and explore the related mechanisms. All rats were assigned to three groups: control, high-fat diet (HF), and high-fat diet with febuxostat (HF + F). After euthanasia, biosamples were immediately harvested to conduct an extensive suite of experiments, encompassing histological examination, assessment of biochemical and oxidative stress markers, serum non-targeted metabolomics, and Western blot analysis. Histological examination showed marked reductions in hepatic lipid accumulation and hepatocellular degeneration in the HF + F group relative to the HF group. Consistently, compared to the HF group, the HF + F group showed significant reductions in the elevated levels of plasma/hepatic lipids, and plasma oxidative stress markers (<i>p</i> < 0.05). Serum metabolomics revealed distinct metabolic profiles among groups, with 51 differential metabolites between HF + F and HF groups, with pathways such as taurine and hypotaurine metabolism and starch and sucrose metabolism being significantly altered (<i>p</i> < 0.05). Western blot analysis showed reduced <i>p</i>-JNK and increased NRF2 and HO-1 expression in the HF + F group (<i>p</i> < 0.05). In summary, we found that inhibiting XOR with febuxostat improved hepatic steatosis, serum metabolic dysregulation and systemic oxidative stress status, and it accompanied by JNK/NRF2/HO-1 pathway key molecule protein alterations in male MASLD rats.