Dendrobium polysaccharides ameliorate alcohol-induced liver injury by inhibiting the pathogenic ER stress-sphingolipid axis.

Abstract

BACKGROUND: Alcohol-associated liver disease (ALD) is a major global health burden with incompletely understood molecular mechanisms. Endoplasmic reticulum stress (ERS) and sphingolipid dysregulation contribute to ALD, but their mechanistic link remains unclear. PURPOSE: This study aimed to elucidate how Dendrobium polysaccharides (DPs) protect against ALD through modulation of the ERS-sphingolipid axis. METHODS: A Gao-binge mouse model of ALD was established. Polysaccharides from Dendrobium loddigesii Rolfe (DLP) and Dendrobium officinale Kimura et Migo (DOP) were administered. Integrated liver transcriptomics, metabolomics, and lipidomics were conducted, with validation by qRT-PCR and Western blot. Hepatocyte assays were performed to assess oxidative stress and inflammation. RESULTS: DPs markedly alleviated alcohol-induced hepatic and intestinal injury, evidenced by improved biochemical markers, histology, and reduced oxidative stress. Unbiased multi-omics analysis subsequently identified a pathogenic "ERS-sphingolipid axis" as the core responsive mechanism, where alcohol-induced ERS drives the accumulation of toxic ceramides. Targeted validation confirmed that DLP, which exhibited superior efficacy to DOP, potently suppressed key ERS sensors (PERK, IRE1α, ATF6), thereby normalizing ceramide levels and restoring sphingolipid homeostasis. CONCLUSION: Dendrobium polysaccharides protect against ALD by disrupting the ERS-sphingolipid axis, alleviating lipotoxicity and inflammation. This study identifies the axis as a central pathogenic hub and provides mechanistic insight into Dendrobium polysaccharides as promising candidates for therapeutic development for for ALD.