From mechanisms to targeted therapy: Deubiquitinases shed light on liver diseases

The ubiquitin-proteasome system (UPS) serves as the primary pathway for intracellular protein degradation. Deubiquitinases (DUBs), which remove ubiquitin chains from substrate proteins, play a critical role in modulating protein stability, activity, and subcellular localization. DUBs are categorized into six major families: USPs, OTUs, JAMMs, MJDs, UCHs, and MINDYs. And, they are essential regulators of both physiological and pathological processes through finely regulating the stability of key signaling proteins.

This review thoroughly outlines the mechanisms of DUBs in four major liver diseases:

In metabolic dysfunction-associated steatotic liver disease (MASLD), DUBs such as USP1 and USP2 promote disease progression by regulating lipid accumulation, inflammatory responses, and related pathways, while USP4 and USP7 exhibit protective roles by reducing lipid accumulation and enhancing insulin signaling, among other mechanisms.

In liver fibrosis, DUBs like USP1 and USP4 exacerbate fibrosis by facilitating the activation of hepatic stellate cells and extracellular matrix deposition. In contrast, USP18 and CYLD play inhibitory roles. Notably, USP9X exhibits opposite effects depending on the cell type.

In viral hepatitis, DUBs exert their effects by regulating viral replication, immune responses, and additional molecular mechanisms. For example, USP18 and USP15 promote the progression of hepatitis B or C. Although OTUD7B inhibits hepatitis C virus replication, its mechanism remains unclear.

In hepatocellular carcinoma (HCC), many DUBs are abnormally expressed. This review details their roles in processes such as proliferation, metastasis, programmed cell death, aerobic glycolysis, immune evasion, and drug resistance, highlighting their potential as critical therapeutic targets.

With advancements in DUB-targeting technologies, such as CRISPR activation screening, chemical proteomics, and targeted protein degradation strategies like PROTACs, DUBTACs, and MembTACs, it is now possible to interfere with traditionally “undruggable” targets and improve the selectivity and druggability of DUBs inhibitors. The review also summarizes the progress of DUB inhibitors in treating liver diseases, emphasizing their potential in combination therapies to enhance chemotherapy sensitivity or reverse resistance to targeted therapies. However, challenges remain in clinical translation due to issues such as limited selectivity and potential organ toxicity. Future work should focus on improving specificity, developing targeted delivery systems, and exploring synergistic mechanisms with existing therapies.

The article concludes that DUBs exhibit complex and diverse regulatory functions in liver diseases. Some DUBs may have dual roles, both promoting and inhibiting disease, while others show opposing effects in different diseases or cell types. This underscores the importance of cell specificity, disease stage, and substrate competition in determining DUB function, suggesting the need for stage-specific and context-dependent intervention. Additionally, since liver diseases often progress and transform (e.g., HCC commonly arises from MASLD or viral hepatitis), many DUBs play pivotal roles across disease types, and their inhibitors show broad-spectrum therapeutic potential, offering new avenues for liver disease treatment.

In summary, DUBs are involved in the pathophysiological processes of various liver diseases. This review facilitates a deeper understanding of the underlying pathogenesis of these liver conditions and provides a theoretical foundation and potential strategies for the development of targeted therapies for liver diseases.

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