Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.

尽管肝细胞癌 （HCC） 的全身治疗最近取得了进展，但乙型肝炎病毒 （HBV） 诱导的 HCC 患者的预后仍然很差。通过筛选靶向人去泛素酶的 sgRNA 文库，我们发现泛素特异性肽酶 26 （USP26） 缺陷会损害 HBV 阳性 HCC 细胞增殖。具有 Usp26 敲除的基因工程小鼠模型证实 Usp26 驱动 HCC 肿瘤发生。从机制上讲，我们发现 HBV 编码的蛋白质 HBx 与启动子结合并诱导 USP26 的产生，USP26 是一种仅在睾丸中表达的 X 连锁基因。因此，HBx 促进 USP26 与 SIRT1 的结合，通过去泛素化协同稳定 SIRT1，从而促进细胞增殖并阻止细胞凋亡以加速 HCC 肿瘤发生。在 HBV 阳性 HCC 患者中，USP26 被强烈诱导，其水平与 SIRT1 水平和不良预后相关。总的来说，我们的研究强调了 HBV 感染、去泛素酶诱导和 HCC 发展之间的因果关系，确定了可成药靶点 USP26。