Zedoarondiol regulates steatosis and inflammation in alcoholic liver injury via PTP1B-target mechanisms

Background: Alcohol-associated liver disease (ALD) is a serious global health issue, often accompanied with steatosis and inflammation. Zedoarondiol (ZE), a natural guaiane-type sesquiterpene with antioxidant and anti-inflammatory properties, is promising from Curcuma longa L. for interfering with ALD. However, its definite targets and relevant research in liver health have rarely been reported.

Purpose: To elucidate the efficacy and explore the action mechanisms of ZE against ALD by targeting PTP1B.

Methods: Target fishing and ultra-performance liquid chromatography-mass spectrometry (MS) were performed to recognize peptides captured by ZE from ethanol-induced NCTC1469 cells. MS data were analyzed using Mascot to retrieve the proteins of the matching peptides and score. Molecular docking, molecular dynamics simulation, surface plasmon resonance, microscale thermophoresis, cellular thermal shift assay, and drug-affinity responsive target stability were employed to validate ZE-target interaction and binding strength. Hematoxylin and eosin, Oil red O, and immunohistochemistry staining were performed to evaluate the pathological changes, lipid deposition, and inflammatory infiltration in the liver tissue, respectively. Additional analysis methods, including transmission electron microscopy and western blotting, were used to investigate how ZE aided in treating alcoholic injury.

Results: PTP1B was a vital target protein of ZE in the intervention for ALD. ZE mitigated endoplasmic reticulum stress via the PERK/ATF4/CHOP arm to suppress oxidative stress, ameliorated steatosis by the AMPK/SREBP-1C/PPARα axis, and alleviated inflammation through abating IKKβ/NF-κB phosphorylation.

Conclusion: ZE protected the liver from alcohol-induced injury through targeting PTP1B to regulate steatosis and inflammation, making it a promising active compound for ALD treatment.