<p>TATA-binding protein-associated factor 3 (TAF3), a member of the TAF family, plays a crucial role in safeguarding finely balanced transcriptional programs. Previous research identified TAF3 as a critical prognostic marker in hepatocellular carcinoma (HCC). This study aimed to elucidate TAF3’s functional role and mechanistic underpinnings in liver cancer progression. Through the establishment of stable TAF3-knockdown and overexpression cell lines in human HCC cells (HepG2 and MHCC97H), comprehensive functional analyses revealed that TAF3 knockdown significantly inhibited cancer cell proliferation, migration, and invasion, while its overexpression promoted these malignant phenotypes. Clinically, elevated TAF3 expression correlated with aggressive clinicopathological features and poor prognosis in HCC patients. Mechanistic investigations demonstrated that TAF3 transcriptionally activates sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol synthesis, leading to increased intracellular cholesterol accumulation. This cholesterol elevation functionally contributed to oncogenic processes, as exogenous cholesterol supplementation reversed the impaired malignancy in TAF3-deficient cells. In <i>vivo</i> validation using a subcutaneous xenograft mouse model confirmed that TAF3 knockdown suppressed tumor growth, an effect effectively counteracted by high-cholesterol dietary intervention. Collectively, these findings establish that TAF3 promotes liver cancer progression through transcriptional activation of SREBP2 and subsequent enhancement of cholesterol biosynthesis. The study identifies a novel TAF3/SREBP2/cholesterol axis as a promising therapeutic target in TAF3-overexpressing hepatocellular carcinomas, providing mechanistic insights into the interplay between transcriptional regulation and metabolic reprogramming in cancer progression.</p>