Hepatocellular carcinoma (HCC) is a common cause of cancer death worldwide and ranks among the top ten most prevalent cancers [1]. Since early-stage HCC is asymptomatic, diagnosis can only be made through certain early biomarkers in patients, such as serum alpha-fetoprotein (AFP), glypican-3 (GPC3), and tumor-associated antigens (TAAs) [2]. Consequently, most patients cannot be diagnosed and treated at an early stage; moreover, HCC has a poor prognosis with high mortality rates [1]. For patients with early- and intermediate-stage HCC, surgical therapies such as liver resection and liver transplantation show good efficacy [3]. However, surgical treatment requires consideration of factors such as tumor stage and patient physical condition, making it unsuitable for some patients. Currently, systemic treatments including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), external beam radiotherapy, oncolytic viruses, and some adjuvant clinical surgical therapies have become new research strategies for treating HCC [4], but the outcomes remain unsatisfactory. Systemic drug therapy has also become an important approach in current HCC treatment, with many targeted drugs already approved for clinical use in HCC patients, such as sorafenib, regorafenib, and lenvatinib, providing new therapeutic directions for HCC patients [5]. However, due to the heterogeneity of HCC and the emergence of acquired resistance after long-term medication, the clinical benefits of these drugs remain limited [6]. There is an urgent need to explore the key mechanisms involved in the occurrence and development of HCC and to conduct drug interventions targeting these key targets to provide new strategies for clinical patients with HCC. Recent studies have shown that the occurrence and development of tumors are not solely related to the increased expression of pathogenic genes; post-translational modifications of proteins also play an important role [7]. Among these, ubiquitination and deubiquitination modifications, as significant post-translational modifications, are associated with the lifecycle of proteins. An increasing number of studies indicate that during the occurrence and development of HCC, the ubiquitination levels of pathogenic proteins are abnormally decreased, suggesting that researching the deubiquitination mechanisms and developing related drugs may provide new avenues for the treatment of HCC [8]. In this article, we summarize the pathogenic mechanisms of the ubiquitin modification system and deubiquitinating enzymes (DUBs) in HCC, as well as potential small molecule interventions.