Bibenzyls from Dendrobium huoshanense attenuate alcohol-associated liver disease via AMPK/ATGL, CYP2E1/ALDH2, and gut microbiota modulation.

BACKGROUND

Dendrobium huoshanense, a renowned traditional Chinese medicine, is widely used for liver disease prevention and treatment, exhibiting potential therapeutic effects against alcohol-associated liver disease (ALD). However, its specific active components and mechanisms of action remain unclear.

PURPOSE: This study aimed to isolate bibenzyl compounds from D. huoshanense via structure-guided separation, identify the core active component for ALD treatment, and elucidate its underlying mechanism.

METHODS

Bibenzyl compounds were isolated using preparative HPLC. An in vitro HepG2 cell injury model induced by ethanol/palmitic acid was employed for bioactivity screening. The anti-ALD effects of the active component were comprehensively evaluated in an ALD mouse model and cellular experiments. Integrated multi-omics strategies (liver proteomics, gut microbiota 16S rRNA sequencing) combined with molecular biology techniques (Western blotting, immunofluorescence) were utilized to decipher the core molecular mechanisms.

RESULTS

Five bibenzyl compounds were isolated and identified from D. huoshanense. Among them, 4-hydroxy-3,4',5, α-tetramethoxybibenzyl (HT) exhibited the most potent activity. HT exerted hepatoprotective effects through remodeled gut microbiota by increasing beneficial bacteria and restoring short-chain fatty acid production; activated the AMPK/PPAR-γ/ATGL pathway to promote lipolysis and reduce lipid droplet accumulation; and suppressed oxidative stress by inhibiting CYP2E1 overexpression while enhancing ALDH2 activity, thereby alleviating ethanol-induced oxidative damage.

CONCLUSION

Bibenzyl compounds are the primary active constituents of D. huoshanense for ALD treatment. HT, as the core component, exerts multi-target effects by synergistically modulating the gut-liver axis, lipid metabolism, and oxidative stress pathways, demonstrating significant potential as a novel therapeutic candidate for ALD.