Sex-specific differences of amlexanox in a mouse model for atherosclerosis and MASLD

In the liver, treatment produced marked sex‑specific effects: male mice exhibited substantial improvement in steatosis, whereas female mice showed worsened lipid accumulation. These outcomes were reflected in pronounced sex‑dependent differences in serum and hepatic lipid and metabolite profiles, indicating regulation of fatty acid and bile-acid metabolism predominantly in males. Protein analyses in liver and adipose tissue further supported opposing metabolic and inflammatory responses between sexes after amlexanox treatment.

Collectively, our findings indicate that therapeutic IKKε inhibition with amlexanox does not prevent progression of advanced atherosclerosis in this model but effectively ameliorates MASLD in male mice. In contrast, female mice experience aggravated hepatic lipid deposition. These results underscore the importance of incorporating sex‑specific analyses in metabolic and cardiovascular research and highlight the need to evaluate therapeutic strategies such as amlexanox in both sexes.