Multi-omics analysis reveals the mechanism of Cistanche deserticola against alcoholic liver disease via bile salt hydrolase and SCD1

Ethnopharmacological relevance

Cistanche deserticola Y. C. Ma, revered as “desert ginseng” in traditional Chinese medicine, has been historically prescribed for treating five strains and seven injuries, and nourishing the five zang organs. While the total glycosides from C. deserticola (GCs) demonstrate hepatoprotective potential against acute alcoholic liver disease (ALD), their efficacy in chronic ALD and mechanism remain unexplored.

Aim of the study

This study aimed to investigate the protective effects of GCs against chronic ALD and to elucidate its molecular mechanisms by multi-omics approach.

Materials and methods

A chronic ALD mouse model evaluated the therapeutic effects of GCs, with systematic assessment of hepatic pathological features including liver index, liver functions, and oxidative stress, etc. Integrated multi-omics strategies (plasma-targeted metabolomics, bile acid-specific profiling, hepatic transcriptomics) were employed to delineate metabolic reprogramming and identify critical signaling pathways. The BSH inhibitor caffeic acid phenethyl ester (CAPE) was used as a pharmacological tool for the mechanistic investigation of GCs. The molecular mechanism was validated by qRT-PCR, Western blot, and small interfering RNA (siRNA)-mediated gene silencing methods.

Results

GCs treatment significantly attenuated ALD pathologies. Plasma-targeted metabolomics and bile acid profiling demonstrated GCs-mediated remodeling of bile acid homeostasis and lipid metabolic networks. Mechanistically, GCs potently inhibited BSH activity, which was validated the pivotal role in ALD pathogenesis by CAPE. Transcriptomic and molecular analyses revealed that GCs subsequently reduced SCD1, and activated AMPK/mTOR signaling, thereby coordinately regulating lipid catabolism, and inflammatory cascades.

Conclusion

These findings highlight the protective effects of GCs against chronic ALD through inhibition of BSH activity to dictate bile acid metabolism, thereby alleviating cholestasis, which subsequently regulate SCD1/AMPK/mTOR signaling pathway.