USP49 regulates lipid metabolism in hepatocellular carcinoma by stabilizing RACK1 to promote tumor proliferation and migration.

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While ubiquitin-specific peptidase 49 (USP49) has been implicated in various cancers, its role in HCC is unclear. Here, we found that USP49 is upregulated in HCC tissues and associated with poor prognosis. Functional assays demonstrated that USP49 promotes HCC proliferation and migration both in vitro and in vivo. Mechanistically, USP49 directly interacts with and deubiquitinates RACK1, thereby stabilizing it. This stabilization leads to RACK1-driven transcriptional activation of key fatty acid metabolic enzymes, enhancing triglyceride synthesis and fueling tumor growth through metabolic reprogramming. Collectively, our study identifies the USP49/RACK1 axis as a critical driver of HCC progression and nominates USP49 as a promising therapeutic target.