Background <p>Hepatocellular carcinoma (HCC) is one of the most frequent and deadly tumors worldwide. Despite advances in targeted and immunotherapy, its overall survival rates remain low.TMEM88 has drawn a lot of attention for its roles in various cancers; nevertheless, its exact function and mechanisms in HCC are still unknown.</p> Methods <p>TMEM88 expression was analyzed in 72 HCC tumors vs. adjacent tissues via qPCR/Western blot. Clinical correlations with survival, AFP, and grading were assessed. Functional assays (proliferation, migration, cell cycle) and Wnt/β-catenin signaling (GSK-3β/β-catenin) were evaluated in vitro. Tumor growth was validated in xenografts.</p> Results <p>This study discovered that patients with high TMEM88 expression had significantly improved overall survival and recurrence-free survival, and high expression was associated with lower AFP levels and favorable pathological grading. Furthermore, overexpression of TMEM88 significantly reduced HCC cell proliferation and migration while decreasing the proportion of cells in the S phase of the cell cycle.Western blot analysis revealed that TMEM88 suppresses the Wnt/β-catenin signaling cascade by boosting GSK-3β activity and decreasing β-catenin levels. in vivo tumor xenograft models demonstrated that TMEM88 overexpression substantially inhibited tumor development.</p> Conclusion <p>This study suggests that TMEM88 may exert tumor-suppressive effects in HCC, potentially through modulation of the GSK-3β/β-catenin pathway, and its higher expression appears to be associated with more favorable outcomes. These findings indicate that TMEM88 could serve as a prognostic biomarker and may have therapeutic relevance, although further validation is required before clinical application.</p>