<p>Sorafenib, an established multi-kinase inhibitor, is a cornerstone of treatment for advanced hepatocellular carcinoma (HCC). This study explores the efficacy of combining sorafenib with cilostazol, a phosphodiesterase-3 inhibitor with emerging anticancer properties, using the HepG2 cell line. We assessed the effects on cell proliferation, apoptosis, and the expression levels of key regulatory proteins and genes, including VEGF, SMAD4, Bcl-2, TGF-β, Bax, and caspase-3. The combination treatment resulted in a significant reduction in the IC₅₀ of sorafenib. Colony formation assays demonstrated that both cilostazol and sorafenib individually inhibited HepG2 cell growth, with combination therapy leading to a further decrease in colony numbers compared to individual treatments. Enhanced apoptosis was observed with the combination, as evidenced by increased Bax and caspase-3 levels and decreased Bcl-2 expression. Additionally, the combination therapy exhibited potent anti-angiogenic effects, significantly reducing VEGF and TGF-β levels. These findings suggest a synergistic interaction between sorafenib and cilostazol, offering promising insights for optimizing therapeutic strategies in HCC management.</p>