Farrerol alleviates obesity and hepatic steatosis by targeting translational regulation to coordinate cellular stress and lipid metabolism.

BACKGROUND

Dysregulation of lipid metabolism is a primary driver of obesity and related metabolic disease. Farrerol is a dihydroflavonoid derived from Rhododendron dauricum L., has known anti-inflammatory and antioxidant properties, but its potential role in regulating lipid metabolism and the underlying mechanisms remains unclear.

PURPOSE: This study aimed to investigate the effect of farrerol on lipid metabolism and explore its potential molecular mechanisms using multi-model systems.

METHODS

The lipid-lowering efficacy of farrerol was initially evaluated in Caenorhabditis elegans (C. elegans) under physiological and citrate-induced high-fat conditions. RNA-seq and RNA interference (RNAi) screening were utilized to identify genes involved in the lipid-regulating effect of farrerol. The lipid-lowering effects and mechanisms were further validated in vitro and in vivo using biochemical assays, untargeted lipidomics, and target-identification approaches including DARTS and CETSA.

RESULTS

In C. elegans, farrerol treatment reduces lipid accumulation induced by citric acid and promoted DAF-16 nucelar translocation. RNA-seq and RNAi screening identified F44E5.4/F44E5.5 and uev-2 as essential upstream regulators for lipid lower effect and DAF-16 activation. In vitro and in vivo, farrerol effectively suppressed hepatic steatosis, modulated hepatic lipid profiles by reducing highly lipotoxic triglycerides, and ameliorated hyperinsulinemia in DIO mice. Mechanistically, target screening revealed that farrerol directly binds to eukaryotic translation initiation factor 4 gamma 1 (eIF4G1). This interaction rescues the expression of the chaperone HSP72, the mammalian ortholog of F44E5.4/5.5, which in turn stabilizes AMPK, thereby inhibiting SREBP1-mediated de novo lipogenesis.

CONCLUSION

Farrerol alleviates lipid accumulation through a conserved eIF4G1/HSP72/AMPK signaling across species. These findings highlight the direct molecular target of farrerol and support its potential as a promising natural therapeutic agent for obesity and hepatic steatosis.