Anticancer activity of sodium propionate in hepatocellular carcinoma cells via downregulation of HDAC2 and HDAC6

Hepatocellular carcinoma (HCC) is an aggressive malignancy driven by epigenetic dysregulation. This study investigates the anticancer potential of sodium propionate (SP) as an epigenetic modulator targeting histone deacetylases (HDACs) using an integrated in silico and in vitro approach. Bioinformatics analyses were conducted using publicly available HCC transcriptomic datasets from GEO database, disease gene database (GeneCards database), and chemical-gene interaction networks (Comparative Toxicogenomic Database) to identify potential therapeutic targets, HDAC2 and HDAC6 as key therapeutic targets in HCC. Computational ADMET screening indicated SP possesses favourable drug-likeness, high oral bioavailability, and low toxicity. Molecular docking and 500-ns molecular dynamics simulations showed stable SP binding to HDAC2, with ligand RMSD of 1.5-2.0 Å, protein RMSD of 3.0-4.5 Å, and active-site RMSF < 1.0 Å, supported by persistent Zn²⁺ coordination and hydrophobic interactions. In vitro evaluations in HepG2 cells revealed distinct dose-dependent cytotoxicity (IC₅₀ = 8.2 mM) and pronounced morphological alterations. Furthermore, SP treatment strongly downregulated the mRNA expression of HDAC2 (0.31-fold, p < 0.001) and HDAC6 (0.60-fold, p < 0.05). This suppression was accompanied by a significant, dose-dependent increase in caspase-3/7 activity, confirming apoptotic induction. These findings suggest SP functions as a dual-action epigenetic modulator in HCC, promoting apoptosis by downregulating HDAC2/6 expression and potentially inhibiting their enzymatic activity. However, biochemical assays, protein-level validation, and in vivo HCC models are necessary to validate this inhibition.