Hepatocellular Carcinoma (HCC) is one of the most prevalent forms of malignancies worldwide, with a low overall survival rate and limited treatments. SESTD1 is upregulated in a variety of cancers and may serve as a potential prognostic indicator and therapeutic target. However, the expression pattern and functional relevance of SESTD1 in HCC are still unknown.SESTD1 expression and its prognostic value in HCC were evaluated by parsing multiple databases, including the Cancer Genome Atlas (TCGA), GEO databases, and Kaplan-Meier (KM) plotter. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were conducted to investigate the potential biological functions and regulatory pathways of SESTD1. The relationship between SESTD1 expression and immune-infiltration levels was investigated in the Tumor Immune Estimation Resource (TIMER). RT-qPCR and Western blot analysis of tumor tissues were performed to verify SESTD1expression in HCC. CCK8, colony formation, and transwell assays were used to evaluate the influence of SESTD1 on HCC cell proliferation and migration.The authors identified significantly elevated SESTD1 expression in Hepatocellular Carcinoma (HCC) tissues, which is associated with poor patient prognosis. Functional enrichment analysis revealed that SESTD1 regulates cell proliferation and the cell cycle, and in vitro experiments validated that silencing SESTD1 suppresses HCC cell proliferation and metastasis. Mechanistically, SESTD1 appears to modulate immune cell infiltration within the tumor microenvironment and shows a positive correlation with the expression of immune checkpoint molecules PD-1 and PD-L1.SESTD1 may serve as a diagnostic and prognostic marker, as well as a potential target for immunotherapy in HCC.Copyright © 2025 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.