SULT1E1 suppresses hepatocellular carcinoma progression via activation of the TGF-β/SMAD signaling pathway and cell cycle arrest

BACKGROUND: Sulfotransferase family 1E member 1 (SULT1E1) is a key estrogen-metabolizing enzyme whose dysregulation has been implicated in several hormone-related malignancies. However, its expression pattern, biological function, and clinical significance in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: SULT1E1 expression was analyzed in HCC tissues and cell lines using public datasets (TCGA and GEO) and a retrospective cohort of 85 HCC patients. Gain-of-function experiments were performed to evaluate the effects of SULT1E1 on HCC cell proliferation, migration, stem-like properties, and cell cycle progression in vitro. Transcriptomic profiling, pathway enrichment analyses, and pharmacological inhibition were used to explore underlying mechanisms. Subcutaneous and orthotopic xenograft mouse models were employed to assess the in vivo effects of SULT1E1. RESULTS: SULT1E1 expression was significantly downregulated in HCC tissues and cell lines and was associated with poor prognosis. Overexpression of SULT1E1 suppressed HCC cell proliferation, migration, colony formation, and tumorsphere formation, while inducing G1 phase cell cycle arrest. Transcriptomic and enrichment analyses indicated that SULT1E1 is involved in the regulation of cell cycle–related pathways and activation of the TGF-β/SMAD signaling pathway. Mechanistically, SULT1E1 overexpression increased SMAD2/3 phosphorylation, and pharmacological inhibition of TGF-β signaling partially reversed its tumor-suppressive effects. In vivo, SULT1E1 overexpression significantly inhibited tumor growth in HCC xenograft models. CONCLUSIONS: SULT1E1 functions as a tumor suppressor in hepatocellular carcinoma by restraining cell proliferation, migration, and stem-like properties, at least in part through activation of the TGF-β/SMAD signaling pathway and induction of cell cycle arrest. These findings suggest that SULT1E1 may serve as a potential prognostic biomarker and therapeutic target in HCC. TRIAL REGISTRATION: Not applicable.