Ferulic acid attenuates hepatic steatosis and modulates PTGS2, PPARG, and FADS2 expression: an integrated network pharmacology, molecular dynamics, and experimental study

Ferulic acid (FA), a principal phenolic constituent of Angelica sinensis, attenuates hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Here, we employed an integrated approach combining network pharmacology, transcriptomics, molecular dynamics (MD), single-cell RNA-seq (scRNA-seq) pseudobulk analysis, and in vitro validation in a PA/OA-induced HepG2 model. External validation revealed consistent upregulation of FADS2 across cohorts, whereas PTGS2 exhibited cohort-dependent directionality. Single-cell pseudobulk analysis suggested a hepatocyte-intrinsic trend for FADS2 and PPARG, although donor-level significance was not reached (p = 0.29 and p = 0.10, respectively). Molecular docking predicted favorable binding of FA to FADS2 (−8.539 kcal/mol), PTGS2 (−7.146 kcal/mol), and PPARG (−5.882 kcal/mol). In vitro , FA dose-dependently reduced lipid accumulation (Oil Red O and TC/TG) without cytotoxicity (confirmed by CCK-8). qPCR revealed that FA suppressed lipogenic genes (SREBP-1c, FASN, ACC1) and the desaturase SCD, while restoring the expression of the fatty acid oxidation marker CPT1A and the hepatocyte-intrinsic desaturase FADS2. Western blot confirmed FA suppressed PTGS2 and PPARG protein expression. The coordinated suppression of lipogenesis and restoration of FADS2 expression is consistent with a ‘lipid remodeling’ hypothesis—FA may shift lipid flux toward less toxic, highly desaturated species—which warrants dedicated mechanistic validation. We identify FADS2 as a novel transcriptional signature of FA, with PTGS2 and PPARG as supported candidate targets.