Bilirubin ameliorates metabolic dysregulation by targeting the HSP90β/SREBPs signaling axis to improve insulin resistance and mitigate ectopic lipid deposition

Aim: Sterol regulatory element-binding proteins (SREBPs) are key transcription factors driving de novo lipid synthesis (DNL) and associated metabolic disorders. This study aims to investigate whether bilirubin, a potential SREBP inhibitor, alleviates lipid accumulation and insulin resistance by targeting the HSP90β/SREBP pathway. Methods: In vitro, HL-7702 cells were treated with bilirubin to assess lipid-lowering effects and SREBP-related gene expression. In vivo, high-fat diet (HFD)-induced obese mice received bilirubin intervention for 6 weeks. Lipid profiles, insulin sensitivity, hepatic SREBP protein levels, and downstream gene expression were analyzed. Mechanistic studies focused on HSP90β activity modulation by bilirubin. Results: Bilirubin significantly reduced lipid accumulation in HL-7702 cells and downregulated SREBPs and their target genes. In HFD-fed mice, bilirubin attenuated obesity, hepatic steatosis, and insulin resistance, accompanied by suppressed SREBP protein levels and expression of target genes. Mechanistically, bilirubin inhibited SREBP activation by targeting HSP90β. Conclusion: Bilirubin ameliorates metabolic syndrome via the HSP90β/SREBP axis, providing a novel therapeutic strategy for lipid metabolism disorders and insulin resistance. These findings highlight bilirubin’s potential as a pharmacological agent against metabolic diseases.