AbstractS-palmitoylation is a reversible protein lipidation that controls the subcellular localization and function of targeted proteins, including oncogenes such as N-RAS. The depalmitoylation enzyme family ABHD17s can remove the S-palmitoylation from N-RAS to facilitate cancer development. We previously showed that ABHD17C has oncogenic roles in hepatocellular carcinoma (HCC) cells, and its mRNA stability is controlled by miR-145-5p. However, it is still unclear whether ABHD17C is regulated at the post-translational level. In the present study, we identified multiple ubiquitin-specific proteases (USPs) that can stabilize ABHD17C by inhibiting the ubiquitin-proteasome-mediated degradation. Among them, USP35 is the most potent stabilizer of ABHD17C. We found a positive correlation between the elevated expression levels of USP35 and ABHD17C, together with their association with increased PI3K/AKT pathway activity in HCCs. USP35 knockdown caused decreased ABHD17C protein level, impaired PI3K/AKT pathway, reduced proliferation, cell cycle arrest, increased apoptosis, and mitigated migration and invasion. USP35 can interact with and stabilize ABHD17C by inhibiting its ubiquitination. Overexpression of ABHD17C can rescue the defects caused by USP35 knockdown in HCC cells. In support of these in vitro observations, xenograft assay data also showed that USP35 deficiency repressed HCC development in vivo, characterized by reduced proliferation and disrupted PI3K/AKT signaling. Together, these findings demonstrate that USP35 may promote HCC development by stabilization of ABHD17C and activation of the PI3K/AKT pathway.