MiR-339-5p promotes hepatic steatosis and inflammation in MASLD by targeting SORT1

OBJECTIVE: This study investigated the clinical significance of serum miR-339-5p in MASLD and explored its molecular mechanisms in hepatic steatosis and inflammation. METHODS: 87 MASLD patients (Np-MASLD, n = 51; MASH-F, n = 36) were enrolled. Serum miR-339-5p was quantified and correlated with clinical indices. In vitro studies used FFA-treated HepG2 cells to assess miR-339-5p and SORT1 effects on lipid accumulation, inflammation. RESULTS: Serum miR-339-5p was significantly elevated in MASLD, correlating positively with disease severity, and served as an independent risk factor for MASH-F progression. In HepG2 cells, miR-339-5p overexpression exacerbated FFA-induced lipid accumulation and IL-6/TNF-α secretion, whereas its inhibition exerted protective effects. SORT1 was validated as a direct target of miR-339-5p and was downregulated in MASLD. miR-339-5p suppressed AMPK phosphorylation and promoted NF-κB activation by targeting SORT1. CONCLUSION: Elevated miR-339-5p promotes hepatocyte lipid accumulation and inflammation in MASLD, potentially by targeting SORT1.