HDCA suppresses exosomal lncRNA MSTRG171708 release to inhibit Treg-mediated immunometabolism in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) exhibits poor patient outcomes due to its propensity for metastasis, yet the mechanisms linking metabolic dysregulation and immune evasion remain unclear. This study reveals that reduced hyodeoxycholic acid (HDCA) levels, coupled with elevated tumor-derived extracellular vesicles (EVs) carrying the long non-coding RNA MSTRG171708, correlate with aggressive HCC progression and enhanced lung metastasis. Mechanistically, MSTRG171708-enriched EVs are internalized by regulatory T (Treg) cells, stabilizing the HIF-1α/PKM2/PHD3 axis and triggering a metabolic shift toward glycolysis, thereby augmenting Treg migratory capacity and fostering an immunosuppressive microenvironment conducive to metastasis. Furthermore, HDCA suppresses EVs release by transcriptionally downregulating RAB27 and SNAP23, key mediators of exosome biogenesis, and effectively curtails metastatic burden in vivo. Clinically, high MSTRG171708 levels in HCC patients are associated with decreased HDCA levels and increased Treg infiltration. These findings establish HDCA-mediated regulation of EVs trafficking as a critical link between epigenetic modulation and immunometabolic reprogramming, proposing HDCA restoration as a novel therapeutic strategy to impede HCC metastasis.