Linderane, a furanosesquiterpene from Lindera aggregata, targets STAT3 to improve metabolic and inflammatory features of MASLD.

ETHNOPHARMACOLOGICAL RELEVANCE: Lindera aggregata (Kosterm.) is a traditional Chinese medicine used for soothing the liver and regulating qi, as documented in classic formulas such as Tiantai Wuyao San and Simo Decoction. However, the active compounds and molecular mechanisms underlying its hepatoprotective effects remain poorly understood.

AIM OF THE STUDY: This study aimed to evaluate the therapeutic potential of linderane (LDR), a furanosesquiterpene from L. aggregata, in metabolic dysfunction-associated steatotic liver disease (MASLD) and to explore its mechanisms, with a focus on STAT3-mediated immunometabolic pathways.

MATERIALS AND

METHODS

MASLD was induced in C57BL/6J mice by feeding a high-fat diet (HFD). LDR was administered orally, and metabolic, inflammatory and histological parameters were assessed. Mechanistic studies were performed in primary hepatocytes and macrophages using Western blotting, RT-qPCR, immunofluorescence, transcriptomics, and cellular thermal shift assays (CETSA).

RESULTS

LDR significantly improved fasting and postprandial glucose levels, enhanced insulin sensitivity, and restored GLUT2/GLUT4 expression. It activated the IRS2/Akt/FoxO1 signaling axis, suppressed gluconeogenic gene expression, and improved hepatic lipid metabolism via modulation of SREBP-1c and PPARα/γ. In macrophages, LDR inhibited M1 polarization and pro-inflammatory cytokine production by suppressing STAT3 phosphorylation, without affecting JAK2 expression. CETSA confirmed a direct interaction between LDR and STAT3 protein.

CONCLUSION

This study demonstrates that STAT3 activation suppresses IRS2-FoxO1 signaling. Linderane targets STAT3 to relieve this suppression while also directly activating the IRS2-FoxO1 axis, thereby ameliorating MASLD. These findings support linderane as a promising natural agent that targets STAT3 and modulates immunometabolic pathways to alleviate MASLD.