As one of the most critical post-translational modifications, ubiquitination involves the transfer of ubiquitin onto a substrate protein, forming an isopeptide bond, in turn resulting in the alteration of the stability and/or activity of the substrate (Liu F., 2024; Lacoursiere et al., 2022; Dikic and Schulman, 2023). This process is catalyzed by the collaboration of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. Among them, E3 ubiquitin ligases are of crucial importance, as they determine the specificity and extent of ubiquitination of substrate proteins (Zhang, 2025). Conversely, deubiquitination modification is to break the isopeptide bond between ubiquitin and the substrate protein, and deubiquitination enzymes (DUBs) playing a pivotal catalytic role in this cascade reaction (Lim et al., 2013).

There are mainly nine classes of DUBs, including ubiquitin-specific proteases (USPs), ovarian tumor domain proteases (OTUs), ubiquitin C-terminal hydrolases (UCHs), Machado-Joseph domain (or Josephin domain)-containing proteins (MJDs), JAMM/MPN domain metalloproteases (JAMMs), Zinc finger with UFM1-specific peptidase domain protein (ZUFSP/ZUP1), MIU-containing novel DUB family (MINDY), monocyte chemotactic protein-induced protein (MCPIP) and permuted papain fold peptidase of dsDNA viruses and eukaryotes (PPPDE) (Ge, 2022; Ren, 2023). Among these DUBs, the USPs family contains the largest number of members and has been the most extensively studied (Cruz et al., 2021). Enzymes of the USP family can recognize their substrate proteins and deubiquitinate them, maintaining substrate stability, thereby counteracting the effects of E3 ligases on specific cellular substrates. This property has a direct impact on diseases, including cancer (Dewson et al., 2023). The intracellular localization of USPs varies, such as the nucleolus, Golgi body, and endoplasmic reticulum, which helping USPs deubiquitination modification of substrate proteins with different subcellular localization (Clague et al., 2019). Numerous evidences suggest that ubiquitin-specific peptidase 36 (USP36) plays a crucial role in regulating various physiological and pathological processes, including ribosome biosynthesis, ribotoxic stress response, DNA replication stress, hypoxia adaptation, oxidative stress, and selective autophagy (Fang, 2023; Ren et al., 2019; Bhattacharya et al., 2020; Meng et al., 2019). Thus the present article comprehensively reviewed the regulatory functions of USP36 in these pathophysiological processes and the underlying molecular mechanisms.

DNA replication stress refers to the slowdown or stalling of the progression of replication forks during DNA synthesis, posing a threat to the replication stability of genome (Da Costa, 2023; Berti et al., 2020). DNA replication damage and replication fork stalling can trigger DNA replication stress during DNA replication (Saxena and Zou, 2022). Cells respond to DNA replication stress through various mechanisms, including the reversal of replication forks, the uncoupling of replication forks, and the restart of stalled replication forks (Gaillard et al., 2015). Studies have demonstrated that USP36 is crucial for the effective restart of replication forks (Yan et al., 2020). USP36 is localized in the nucleolus under normal conditions, maintaining the integrity of nucleolar functions. However, when cells experience DNA replication stress, USP36 migrates from the nucleolus to the nucleoplasm and colocalizes with the DNA damage-tolerant polymerase PrimPol at stalled replication forks through its N-terminal USP domain (Yan et al., 2020; Diaz-Talavera, 2022). Yan et al. found that there is a positive correlation between the expression levels of USP36 and PrimPol in ovarian cancer, and USP36 can increase the protein stability of PrimPol through deubiquitination modification, thereby counteracting DNA replication stress (Yan et al., 2020). While knockdown of USP36 significantly increases the sensitivity of ovarian cancer cells to the DNA replication stress inducer hydroxyurea, while restoring PrimPol expression can reverse this phenomenon (Yan et al., 2020). Taken together, these findings suggest that USP36 stabilizes PrimPol through deubiquitination, thus playing a role in counteracting DNA replication stress (Figure 2A) (Yan et al., 2020). High DNA replication stress in cancer cells may lead to genomic instability, and targeting replication stress can help identify new cancer susceptibility loci (Wen, 2025; Da Cos and ta, 2023). Therefore, targeted inhibition of USP36 to block PrimPol-mediated replication fork restart, combined with the use of DNA replication stress pathway inhibitors, may enhance the chemosensitivity of ovarian cancer cells, providing a novel approach for ovarian cancer treatment. Meanwhile, the development of highly selective small-molecule inhibitors targeting USP36 will offer a more specific tool for the precise regulation of DNA replication stress and overcoming tumor chemoresistance.

The activation of gene transcription mediated by HIF is a crucial mechanism for cells to maintain their survival and function under hypoxic conditions (Yuan, 2024; Batie, 2022). However, USP36 has been reported to be involved in regulating hypoxia adaptation independent of HIF in cervical cancer (Filippopoulou et al., 2020; Chachami et al., 2019; Filippopoulou, 2024). Under normoxic conditions, USP36 and EXOSC10 are co-localized in the nucleolus, where USP36 can function as an E3 SUMO ligase to mediate the SUMOylation of EXOSC10 (Filippopoulou, 2024). However, under hypoxic conditions, EXOSC10 dissociates from USP36 and migrates from the nucleolus to the nucleoplasm along with its deSUMOylation. The deSUMOylation of EXOSC10 upregulates the expression levels of hypoxia-responsive genes (such as PTGS2,CA9, etc.) (Filippopoulou, 2024) (Figure 2B). These findings suggest that USP36 plays a significant regulatory role in hypoxia adaptation.

Oxidative stress refers to the imbalance of intracellular redox homeostasis, that is, reactive oxygen species are excessively produced, which cannot be offset by the action of antioxidants (Akiyama and Ivanov, 2024). Studies have suggested that USP36 play a role in regulating oxidative stress (Kim et al., 2011) (Figure 2C). USP36 interacts with superoxide dismutase 2 (SOD2) in mitochondria, in turn mediating the deubiquitination modification of SOD2, thereby enhancing the antioxidant capacity of SOD2 (Kim et al., 2011). Further research has demonstrated that the interaction between USP36 and SOD2 is time-dependent and occurs at COP9 signalosome subunit 3 (COPS3) (Kim et al., 2011; Pariano, 2021). The researcher also fund that Anakinra can protect cells from mitochondrial oxidative stress damage by promoting the interaction between SOD2 and USP36-COPS3 (Pariano, 2021). This suggests that targeted regulation of USP36 can enhance SOD2-mediated antioxidant capacity and improve mitochondrial function, providing a potential direction for therapeutic intervention in various diseases, such as Aspergillus fumigatus infection-related pneumonia, mitochondrial dysfunction-associated cardiovascular aging, and age-related neurodegenerative diseases.

Autophagy is a process where cells degrade proteins and organelles for reuse, which is crucial for maintaining intracellular homeostasis (Liu, 2023). Based on the selectivity of substrates, autophagy can be broadly classified into two types: selective autophagy and non-selective autophagy (Liu J., 2024; Glick et al., 2010). For selective autophagy, selective autophagy receptors transport specific substrates (such as damaged organelles, aggregated protein or invading bacteria) to autophagosomes for degradation trough binding with LC3 (Vargas, 2023). While, non-selective autophagy is typically induced by factors like rapamycin, nutrient deprivation, or energy starvation (Liu J., 2024). Growing eidence indicates that USP36 plays a vital role in selective autophagy (Geisler et al., 2019; Wang, 2018; Pickrell and Youle, 2015; Ye, 2023) (Figure 2D). USP36 promotes the phosphorylation of Ser65 of ubiquitin (pSer65-Ub) of PINK1 on the mitochondrial outer membrane by inhibiting the translation of the long isoform of phosphatase and tensin homologue (PTEN-long) (Geisler et al., 2019). The activation of PINK1 promotes the recruitment of Parkin from the cytoplasm to the mitochondria, and then ubiquitinates mitochondrial outer membrane protein and marks damaged mitochondria for autophagic degradation (Geisler et al., 2019; Wang, 2018; Pickrell and Youle, 2015). Furthermore, USP36 can also upregulate the protein expression levels of ATG14L and Beclin-1, thereby promoting Parkin-dependent mitophagy during mitosis (Geisler et al., 2019; Ye, 2023). However, it has been reported that USP36 inhibits the selective autophagy in Drosophila (Taillebourg et al., 2012). Specifically, USP36 reduces the number of LC3-labeled autophagosomes without affecting the activity of the mTOR pathway (Taillebourg et al., 2012). However, the nuclear localization of USP36 limits the research on its mechanisms of direct action on mitophagy, and further exploration of its downstream targets is required. Additionally, further studies are needed to investigate the applicability of USP36 in regulating selective autophagy across different biological models.

This review has comprehensively elaborated the role of USP36 in various pathophysiological processes, including ribosome biosynthesis, ribotoxic stress response, DNA replication stress, hypoxic adaptation, oxidative stress, and autophagy activity. USP36 stabilizes RNA Pol I, DHX33, FANCI, SNAIL1, and H2A through its deubiquitinating activity, thereby promoting the synthesis of precursor rRNA. On the other hand, USP36 plays a key role in the processing and maturation of precursor rRNA through mediating the deubiquitination modification of NPM and FBL or mediating the SUMOylation of EXOSC10, Nop58, Nhp2, and DKC1. USP36 further mediates the cleavage of FUBI-eS30 and the deubiquitination of FANCI, promoting the maturation of the ribosome. Additionally, under conditions of ribosomal toxic stress, USP36 can be transcriptionally activated by HSF1 to counteract this stress. It is noteworthy that USP36 also plays a crucial regulatory role in other cellular processes such as DNA replication stress, hypoxic adaptation, oxidative stress, and selective autophagy (Table 1).

Research has shown that USP36 promotes tumor progression by deubiquitinating a variety of proteins. USP36 promotes the progression of esophageal squamous cell carcinoma (ESCC) through the Hippo/YAP axis; USP36 enhances the invasiveness of glioblastoma by stabilizing SNAIL2, and USP36 accelerates the progression of hepatocellular carcinoma (HCC) through synergistic action with TP53 (Sun, 2022; Li, 2023; Chang, 2023). The proliferation of tumor cells is highly dependent on ribosome biogenesis, and USP36 has been proven to promote ribosome biogenesis through multiple mechanisms. However, how USP36 regulates ribosome biogenesis in tumor cells has not been fully studied. In addition, specific inhibitors have been developed for other deubiquitinases in the USP family (such as USP1 and USP7), but inhibitors targeting USP36 have not been reported yet (Huang, 2023; Guo, 2024). Therefore, in the future, it is still necessary to deeply study the mechanism of action between USP36 and ribosome biogenesis in tumor cells and explore its potential as a new target for tumor therapy. Meanwhile, the development of specific inhibitors for USP36 should be accelerated to provide new strategies for precise tumor diagnosis and treatment.