Epigenetic mechanisms exert control over gene expression at both the transcriptional and post-transcriptional levels, including DNA methylation, RNA methylation, RNA interference, and histone modifications (18–20). Ubiquitin-mediated degradation and the reverse process of deubiquitination regulate histones as part of the epigenetic machinery. Epigenetic mechanisms play an active role in reshaping the cellular transcriptome, thereby governing gene expression, cell differentiation, and development (20).

Innate and adaptive immune reactions are related to epigenetic modification (21). Remarkably, epigenetic regulation is a crucial player in the onset and development of inflammatory response (22). Numerous studies have highlighted the roles of USPs in various inflammatory diseases by modifying epigenetics. USPs play crucial roles in epigenetic mechanisms by regulating certain post-translationally modified epigenetic factors, such as NF-κB and p53, thereby influencing inflammation (23, 24). For example, USP9X can interact with Bcl10 of the Carma1-Bcl10-Malt1 (CBM) complex and remove the TCR-induced ubiquitin chain from Bcl10, thus promoting NF-κB activation induced by TCR signaling pathway, and then actively affecting the cytokine production, T cell proliferation and differentiation (24). Additionally, USPs can interfere with the stability of proteins involved in epigenetic mechanisms, such as histone deacetylases, regulating the termination of DNA repair and the reorganization of chromatin structure (25). USP11 can interfere with the chromatin remodeling NuRD complex, and coordinate with NuRD-associated histone deacetylation to regulate the DNA repair process and genomic stability (25). Overall, USPs play crucial roles in regulating the inflammatory response by removing Ub from targeted protein complexes and affecting the stability of epigenetic factors, thereby regulating inflammation-related gene expression and the transmission of epigenetic information.

Periodontitis, a chronic inflammatory disease, is characterized by the inflammation of the pocket wall, the resorption of alveolar bone, the formation of periodontal pocket, and the separation between gingiva and tooth, as well as the loss of tooth (26). Moreover, periodontitis is the primary cause of tooth loss in adults, and it leads to periodontal tissue damage and is associated with a variety of systemic complications, such as diabetes, obesity, cardiovascular disease, and so on (27–29). Numerous studies have stated periodontitis is mainly caused by the imbalance of the oral microbiota and host resistance (30), associated with environment factors, host factors and genetic factors (31). As one of the epigenetic modifications, USPs are key regulators of the inflammation responses in periodontitis (32).

Recent studies have shed light on the contrasting roles of USP5 and CYLD in periodontitis, offering potential avenues for therapeutic interventions ( Table 1 ). It has been reported that USP5 is upregulated in the gingival crevicular fluid and gingival tissues of patients with periodontitis, showing a positive correlation with proinflammatory factors through the STAT3 signaling pathway, which exacerbates the inflammatory response in chronic periodontitis (33). Furthermore, CYLD has been reported to ameliorate alveolar bone loss in mouse models of periodontitis by regulating the number and activity of osteoclasts, as well as the genes related to osteogenesis and osteoclastogenesis in alveolar bones (34, 35). CYLD can also modulate the NF-κB signaling pathway, which plays a crucial role in the inflammatory response and osteoclast mediation in periodontitis (34).

Pneumonia is a prevalent respiratory system inflammatory disease, which can be caused by a variety of pathogens. The clinical symptoms include cough, phlegm production, chest pain, fever, as well as severe complications such as acute lung injury (ALI) and pulmonary fibrosis (36, 37). However, there is still a lack of accurate treatment to cure pneumonia, necessitating the exploration of better therapeutic targets. Recently, it has been reported the key roles of USPs in pneumonia, which may provide novel insights that could have clinical implications for the management of the disease ( Table 2 ).

Several studies have reported that USP11 and USP14 contribute to the aggravation of inflammation in LPS-induced pneumonia (39–41). USP11 exacerbates pneumonia by deubiquitinating and stabilizing LPA1, a proinflammatory factor, enhancing LPA1-mediated proinflammatory effects (39). Knockdown or pharmaceutical inhibition of USP11 alleviates the lung damage induced by LPS in mice (39). Furthermore, USP14 plays a proinflammatory role in pneumonia (40, 41). The overexpression of USP14 in mouse models leads to the degradation of I-κB, increasing the release of factors such as TNF-α and IL-8 in lung epithelial cells (41). Besides, PARP-1 is an important binding enzyme of pneumonia signaling pathway (42). In human lung epithelial cells, it has been demonstrated that USP14 aggravates the inflammatory response by interacting with PARP-1 and increasing its expression (40). Furthermore, USP14 upregulates the expression of pro-apoptotic proteins while downregulating the anti-apoptotic protein (40). This leads to increased apoptosis of lung epithelial cells and inhibition of cell growth, which can contribute to severe complications in pneumonia (40).

In contrast, some USPs show the anti-inflammatory role in pneumonia. USP38 has been shown to alleviate the inflammatory response in lung and bleomycin-induced pulmonary fibrosis in mouse models (37). This effect is achieved through deubiquitinating the IL-33 receptor and negatively regulating the IL-33-triggered signaling pathway and autophagic degradation (37).

In the early stages of infection, Klebsiella can evade the host defense immunity system by causing a lack of inflammatory response (43). CYLD is known to suppress the NF-κB signaling pathway during the initial inflammatory response triggered by Escherichia coli, Klebsiella, and Streptococcus pneumoniae, which ultimately exacerbates subsequent lung infections (43–45). Notably, CYLD deficiency offers protection against Streptococcus pneumoniae pneumolysin (PLY)-induced ALI, bacterial translocation, and lethality (36). Furthermore, CYLD contributes to the worsening of ALI by suppressing the expression of plasminogen activator inhibitor 1 (PAI-1), a recognized biomarker of tissue injury that plays a crucial role in tissue repair (36, 46). However, it’s important to note that after infection with Streptococcus pneumoniae, CYLD serves as a critical negative regulator for injury-induced fibrotic response by inhibiting TGF-β signaling pathway (36, 47).

Pathogens can also impact host deubiquitinating enzymes to contribute to disease progression. For example, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a secretory chloride channel, which plays an important role in mucociliary clearance by human airway epithelial cells and the innate immune response in the lung (38). Pseudomonas aeruginosa secretes the bacterial toxin Cif, which inhibits USP10, leading to decrease USP10-mediated deubiquitination of CFTR and increase CFTR degradation in lysosomes, causing the weaker mucociliary clearance and the harder removal of pathogens to cure pneumonia (38).

Furthermore, there are some drug discoveries about USP and pneumonia, such as QingFeiPaiDu decoction and wogonoside. Mechanically, it decreases the expression of USP14 to reduce the phosphorylation of LPS-stimulated transcription factor 2(ATF2), an important regulator of cytokines, to play an anti-inflammatory role (48).

Atherosclerosis, an inflammatory disease primarily situated within arterial walls, arises due to the aberrant accumulation of low-density lipids (LDL) and lipid proteins (49–51). This process involves the participation of diverse cell types, including smooth muscle cells (SMCs), macrophages, neutrophil granulocytes, endothelial cells (ECs), and other leukocytes (49–51). Existing research has demonstrated the pivotal roles of NLRP3 inflammasome, IL-1β, and TNF in atherosclerosis (49, 51). Consequently, there is an imperative to identify more precise upstream or downstream targets to facilitate a more accurate therapeutic approach for atherosclerosis (49, 51).

Recent investigations have significantly highlighted the substantial involvement of USPs in atherosclerosis progression. Studies indicate that USP9X, USP10, USP14, USP17, USP20, and USP36 play regulatory roles in the atherosclerotic process ( Table 3 ). Macrophages intake an excess of lipids, leading to the proliferation of macrophages and secrete inflammatory factors, which causes the formation of foam cells, thus aggravating atherosclerosis (49, 52, 54). This process hinges on receptor activity, including CD36, SR-A, and SR-B1 (57).

Notably, USP9X has been identified as a suppressor of macrophage lipid intake, exhibiting lower expression levels in atherosclerosis compared to normal cells. Mechanically, USP9X removes polyubiquitin chains from SR-A63, thus inhibiting lipid intake by macrophages, impeding foam cell formation, and reducing the ensuing inflammatory response (52). Furthermore, USP9X, alongside USP14 and USP36, contributes to the regulation of ECs (53, 54, 60). Respectively, in atherosclerosis patients, USP14 is observed to be downregulated in ECs, and it inhibits the inflammatory response in ECs (54). This downregulation hampers the activity of NF-κB and the degradation of its associated regulatory factors, which are stimulated by oxidized LDL (ox-LDL) (54). On the other hand, USP36 contributes to atherosclerosis progression through the exosomal microRNA-197-3p signaling pathway (60). Furthermore, both USP14 and USP36 play roles in the proliferation and mobilization of human aortic smooth muscle cells (HASMCs) (55, 56). Additionally, USP14 and USP10 can increase the formation of foam cells via removing Ub from CD36, thereby stabilizing the CD36 protein and promoting the uptake of ox-LDL (57, 61). To briefly sum up, USP14 has shown effects on ECs, SMCs and foam cells in the development of atherosclerosis (54, 55, 61). Moreover, USP20 alleviates inflammation in SMCs in TNF and IL-1β-induced atherosclerosis by deubiquitinating RIPK1, a vital factor of inflammation and cell death (58, 59).

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, encompassing ulcerative colitis (UC) and Crohn’s disease (CD) (62). The etiology and mechanisms underlying IBD are complex, and extensive studies have implicated the involvement of USPs in the disease ( Table 4 ).

Recent studies have highlighted the significant impact of USPs in IBD. USP7, USP47, USP8, and CYLD have been implicated in alleviating IBD. Foxp3 is an essential factor for the development of regulatory T cells (Tregs) (63). USP7 increases the quantity and function of Tregs to maintain self-tolerance and reduce the inflammation of IBD by directly deubiquitinating and enhancing the expression of Foxp3 (63). Cambogin, a potential drug, can enhance the effect of USP7 and holds promise as a future treatment for IBD based on this mechanism (64). Additionally, USP47 is observed to be downregulated in chronic inflammatory mucosal tissue of CD and UC in patients with IBD (69). Knocking down USP47 in mice makes it easier to induce IBD and results in a more severe inflammatory response and tissue damage (69). This occurs by suppressing the NF-κB signaling pathway in intestinal epithelial cells (69). NOD2 is reported to be a strong genetic factor associated with IBD, and USP8 can negatively regulate NOD2-induced IL-8 and IL-6 in bone marrow-derived macrophages to inhibit inflammation in IBD (65). CYLD, another USP, restricts IBD inflammation in the colonic mucosa by inhibiting excessive production of IL-18 through deubiquitinating NLRP6 (70). However, CYLD is significantly downregulated in IBD patients (71). This downregulation leads to severe infection by adherent-invasive Escherichia coli (AIEC), activation of NF-κB, and degradation of IκB-α, thus exacerbating IBD (71).

However, USP16 and USP25 has the contrary impact on IBD. USP16 exhibits increased expression in patients with IBD and contributes to disease inflammation (66, 67). It has demonstrated that USP16 promotes the proliferation and differentiation of T cells, thereby increasing CD4⁺ T cell infiltration and aggravating IBD (66). Furthermore, USP25 significantly regulates proinflammatory cytokines in the colon (68). Knockdown of USP25 leads to hyper-immune responses against bacterial infections, thereby restricting bacterial replication and inflammation (68).

The liver, being the body’s primary detoxifying organ, is susceptible to hepatitis caused by various factors. Hepatitis can be classified into different types, such as viral hepatitis, autoimmune hepatitis, nonalcoholic steatohepatitis (NASH), and others (72, 73). Viral hepatitis has the largest population of hepatitis in the world, including HAV, HBV, HCV, HDV and HEV (73). The development of hepatitis involves complex mechanisms, often characterized by liver inflammation, damage, scarring, and the potential progression to hepatocirrhosis, liver cancer, and even death (73). Recent research has shed light on the involvement of several USPs in the development and progression of hepatitis. These USPs regulate various cellular processes that are crucial to the pathogenesis of hepatitis, including inflammation, immune response, viral replication, and cell death ( Table 5 ). By modulating these processes, USPs contribute to the intricate mechanisms underlying hepatitis.

Sepsis is characterized by the deadly dysfunction of the host’s immune system in response to infections (94). The serious systemic inflammation derives from localized infections or sterile inflammatory diseases (95). Current approaches mainly involve supportive measures such as antibiotics and oxygen therapy, lacking precise targeted therapies (95). Researchers have underscored the complexity of small molecule mechanisms, including molecules like TNF-α, which are being explored as potential targeted therapy (95). However, the more precise targeted molecules are necessary to improve sepsis treatment.

Recently, there have been some studies on the regulation of USPs in the development of sepsis ( Table 6 ). In sepsis, the level of USP9X is upregulated in CD8+ T cells, and this upregulation contributes to the development of sepsis by causing dysfunction in CD8+ T cells (96). This dysfunction can be reversed by WP1130, an inhibitor of USP9X (96). In sepsis, the transcription factor SRY-box 9 (SOX9) is highly expressed in cardiac muscle cells, contributing to cardiac damage (97). USP7 exacerbates the adverse effects of sepsis on the heart by deubiquitinating SOX9 and leading to an upregulation of its expression (97). Moreover, USP10 has been identified as a protective factor for renal tubular epithelial cells against acute kidney injury in LPS-induced sepsis (98).

CBP, responsible for the release of cellular factors during sepsis, undergoes degradation due to ubiquitination (99). USP14 facilitates the release of cell factors in response to LPS during sepsis by deubiquitinating CBP and thereby stabilizing it (99). Recently, it has been proposed that a novel USP14 inhibitor, Neochromine S5, binds to USP14, diminishing its deubiquitination activity and disrupting the interaction between USP14 and TRAF6, which effectively reduces proinflammatory factors, and downregulates NF-κB and STAT1 signaling pathways (104). As a result, Neochromine S5 shows higher efficacy and safety in alleviating sepsis (104).

Moreover, both USP18 and USP19 have shown potential in mitigating sepsis and enhancing survivability (100, 101). They can curb the production of IL-6, IL-1β, and TNF-α in sepsis by inhibiting the activation of NF-κB through deubiquitination of TAK1 (100, 101). Furthermore, USP39 is downregulated in LPS-induced sepsis and it can decrease the release of proinflammation factors and subsequently sepsis-related inflammation (102). Mechanically, USP39 is recognized as a negative modulator of NF-κB signaling pathway through deubiquitinating and stabilizing IκBα (102). In sepsis, energy consumption changes from C₆H₁₂O₆ to fatty acid oxidation (FAO) (103). USP50 plays a role in aggravating sepsis by stabilizing carnitine palmitoyltransferase 1a (CPT1a) and enhancing FAO (103).

Diabetes is a chronic epidemic disease characterized by the presence of high levels of glucose in the blood, which can cause various complications, including diabetic retinopathy (DR), diabetic nephropathy (DN), diabetic neuropathic pain (DNP), diabetic foot (DF), diabetic cardiomyopathy (DCM), and so on (105–107). It is classified into type 1 diabetes (T1D) and type 2 diabetes (T2D). Recently, there have been numerous studies on USPs in diabetes, shedding light on the intricate roles of USPs in the disease. Further exploration of USPs in diabetes may provide insights into novel treatment strategies for the disease and its associated complications.

Obesity, a significant health issue of the 21st century, is associated with the activation of the innate immune system, expansion of adipose tissue, and various metabolic disturbances (140). It gives rise to numerous long-term complications, including diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD) (141). There are several causes of obesity, such as food intake, adipogenesis and the activation of inflammation (142). In recent years, there has been a growing interest in the roles of USPs in research related to obesity ( Table 10 ). Several USPs, including USP2, USP10, USP14, USP15, USP18, and USP22, have been associated with obesity and related metabolic disorders.

In diet-induced obese mice, it is reported that USP2 can increase the production of hepatic glucose and promote glucose intolerance (143). USP2 is regulated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and influences hepatic glucose metabolism by inducing 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling pathways (143). Furthermore, 3,3’-diindolylmethane, derived from cruciferous vegetables, inhibits adipogenesis in preadipocytes by targeting USP2 activity, thereby inhibiting high-fat diet-induced obesity (144).

NAFLD is caused by mitochondrial dysfunction with persistent imbalance between energy intake and expenditure, and USP10 is a negative regulator of NAFLD (145). However, the protein level of USP10 in liver is decreased in obese and NAFLD patients (146). USP10 inhibits glucose production and adipogenesis in hepatocytes, and its activity modulated by long noncoding RNA myocardial infarct-related transcript 2 (Mirt2) (147). Besides, USP10 improves metabolic dysfunction associated with obesity by regulating liver steatosis, inflammation, and insulin resistance (146, 148, 149). Mechanically, USP10 regulates AMPK phosphorylation and dephosphorylation by removing inhibitory ubiquitin residues (146, 148, 149). Additionally, it inhibits the ubiquitination and degradation of Sirt6 (146, 148, 149).

USP14 can promote hepatic triglyceride accumulation by increasing the stability of fatty acid synthase (FASN), which is the crucial enzyme for hepatic adipogenesis (150). Besides, human intestinal cell differentiation is altered during bariatric surgery, and USP14 can regulate human enterocyte differentiation and influence obesity (155).

USP15 plays a significant role in adipocyte differentiation and the formation of fat droplets. It has been reported that USP15 is closely and functionally related to fatty acid binding protein 4 (FABP4), which is abundant in mature adipocytes (151, 152).

USP18 is downregulated in obese mice, which can improve lipid metabolism and insulin sensitivity (92). In principle, TAK1-dependent signaling is vital for the development of hepatic insulin resistance (153). USP18 can improve insulin sensitivity by deubiquitinating TAK1 and inhibiting TAK1 phosphorylation to downregulate NF-κB signaling pathway and upregulate fat mass and obesity-related protein (FTO) (153, 154).

Furthermore, USP22 reduces hepatic steatosis and obesity by stabilizing Sirt1 protein and regulating Sirt1-dependent mitochondrial respiration (145).