Hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths, is often linked to dysregulated cell cycle proteins. This study focuses on the role of WISP1 in modulating Cyclin D1, a key cell cycle regulator, in HCC. The study used HCCLM3 and Hep3B cells to assess the expression of Cyclin D1 and cell proliferation following the treatment of WISP1. This was achieved through Western blot, qRT-PCR, and EdU assays. Additionally, animal studies were conducted to evaluate the effects of WISP1 treatment on Cyclin D1 expression and cell proliferation. Overexpression of WISP1 in HCC cells led to a marked decrease in Cyclin D1 protein levels and reduced cell proliferation. WISP1 influences Cyclin D1 through post-translational modifications, particularly ubiquitination and proteasomal degradation. The findings revealed that WISP1's modulation of Cyclin D1 plays a critical role in inhibiting HCC cell growth, highlighting a potential therapeutic target for HCC treatment.