Epigenetic Silencing of <scp>SFRP5</scp> Promotes Hepatocellular Carcinoma Progression and Metastasis via Wnt/β‐Catenin Signaling

Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor prognosis, frequent metastasis, and therapy resistance. Epithelial-mesenchymal transition (EMT) and aberrant Wnt/β-catenin signaling are key drivers of HCC progression. Secreted frizzled-related protein 5 (SFRP5), a Wnt/β-catenin signaling antagonist, has been implicated in various cancers, but its role in HCC remains unclear. This study explores the regulatory interactions between SFRP5, EMT, and Wnt/β-catenin signaling in HCC. Bioinformatics analysis, patient-derived tissue samples, and in vitro experiments revealed significant downregulation of SFRP5 due to promoter hypermethylation. Methylation-specific PCR confirmed extensive SFRP5 methylation, while treatment with 5-Aza-2'-deoxycytidinerestored SFRP5 expression, suppressing Wnt/β-catenin signaling and EMT. Functional assays demonstrated that SFRP5 overexpression inhibited HCC cell proliferation, migration, and colony formation while promoting apoptosis. Western blot and immunofluorescence confirmed that SFRP5 restoration suppressed β-catenin and its targets (MYC, Cyclin D1, Survivin), increased E-cadherin, and decreased mesenchymal markers (Vimentin, Fibronectin, Twist). In vivo xenograft models showed that SFRP5 overexpression reduced tumor growth and EMT marker expression. These findings highlight SFRP5 as a tumor suppressor in HCC, where epigenetic silencing promotes tumor progression via Wnt/β-catenin signaling activation. Targeting SFRP5 methylation may provide a novel therapeutic strategy for HCC.