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Int J Biol Sci 2026; 22(8):4194-4224. doi:10.7150/ijbs.130460 This issue Cite

Review

Ubiquitin-Modifying Enzymes as Cell-Fate Regulators in Intestinal Inflammation

Chenchen Qian^1,2, Fangmin Ning¹, Yong Xu¹, Jingjing Shao¹, Binglu Shi¹, Chenjian Zhou² , Yi Wang¹

1. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
2. Pharmacy Department, Wenzhou Central Hospital, Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.

✉ Corresponding authors: Yi Wang, PhD, Professor, E-mail: yi.wang1122edu.cn; Chenjian Zhou, Email: zhouchenjianedu.cn

Received 2025-12-23; Accepted 2026-3-18; Published 2026-4-8

Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Intestinal homeostasis relies on the intricate balance of cell fate decisions within the intestinal epithelium and immune compartments. Ubiquitin-modifying enzymes (UMEs), including E2 conjugating enzymes, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs), have emerged as pivotal molecular regulators of these processes by orchestrating post-translational modifications that dictate protein stability, activity, and localization. In this review, we systematically summarize the essential roles of UMEs in modulating diverse cell-fate outcomes and their subsequent effects on intestinal barrier integrity and immune responses. Furthermore, we discuss the pathogenic dysregulation of specific UMEs in IBD and highlight their potential as diagnostic biomarkers and therapeutic targets. Finally, we explore emerging strategies, including small-molecule inhibitors and PROTAC technology, for targeting UMEs in clinical applications. By integrating current advances, this review provides novel insights into the ubiquitin-mediated regulation of intestinal cell fate and offers new perspectives for the management of IBD and the prevention of colitis-associated cancer (CAC).

Keywords: cell fate, inflammatory bowel disease, ubiquitin-modifying enzymes, post-translational modifications

Introduction

Inflammatory bowel disease (IBD), together with other forms of chronic colitis, represents a spectrum of persistent inflammatory disorders of the gastrointestinal tract, primarily including ulcerative colitis (UC) and Crohn's disease (CD) [1, 2]. Its global incidence and prevalence have increased steadily, imposing a substantial healthcare burden [3]. The pathogenesis of chronic colitis, including IBD, involves multiple interconnected mechanisms, including disruption of the intestinal epithelial barrier, endoplasmic reticulum (ER) stress, immune dysregulation, and intestinal microbiota dysbiosis [4, 5]. Although agents targeting TNF-α and related pathways have been used in IBD treatment, their efficacy remains limited, with high recurrence rates and significant adverse effects [6]. Therefore, identifying novel molecular mechanisms and therapeutic targets remains a major priority. Moreover, emerging evidence indicates that dysregulated cell fate programs represent a key pathological convergence point linking chronic intestinal inflammation and disease progression, including IBD and colitis-associated cancer (CAC) [7].

In this disease context, “cell fate” does not refer solely to transient changes in signaling activity but also encompasses irreversible or long-lasting biological outcomes that determine tissue integrity and immune equilibrium [8]. These regulatory programs operate at both cellular and tissue levels. At the cellular level, they control epithelial cell survival or programmed cell death (including apoptosis, necroptosis, pyroptosis, and ferroptosis), intestinal stem cell renewal and differentiation, polarization and functional reprogramming of innate immune cells, and lineage commitment of adaptive immune cells [9-15]. At the tissue level, these processes collectively shape pathological outcomes, including chronic inflammation, fibrotic remodeling, dysplasia, and CAC [16, 17]. Collectively, cell fate regulation represents the terminal decision layer through which upstream inflammatory signals are translated into concrete cellular behaviors and disease-relevant pathological outcomes. Here, we emphasize that stress-adaptive responses, such as the unfolded protein response (UPR) and autophagy, are increasingly recognized as fate-modulating programs that influence cellular trajectories, rather than independent terminal fate endpoints.

Consistent with this framework, accumulating evidence indicates that ubiquitin-modifying enzymes (UMEs) act as key molecular switches linking inflammatory signaling networks to fate-determining programs. By controlling the stability, localization, and activity of core regulators involved in cell death, stress adaptation, differentiation, and immune activation, UMEs actively bias cellular trajectories toward survival versus death, repair versus injury, and immune tolerance versus chronic inflammation. Accordingly, ubiquitination and deubiquitination emerge as upstream determinants of cell fate decisions in the inflamed intestinal microenvironment.

Ubiquitin-modifying enzymes (UMEs), composed of ubiquitination enzymes (E1, E2, and E3 ligases) and deubiquitinating enzymes (DUBs), represent a central post-translational regulatory system governing protein homeostasis and signaling, thereby controlling protein fate and downstream cellular decisions [18, 19]. Emerging evidence indicates that UMEs play critical roles in IBD pathogenesis by regulating epithelial cell survival and regeneration programs, immune cell activation and differentiation, and stress adaptation responses, thereby shaping epithelial barrier homeostasis and remodeling the inflammatory microenvironment [18-20]. Several UMEs, such as A20, CYLD, OTULIN, and USP13, are aberrantly expressed in intestinal tissues from IBD patients and experimental models, and are closely associated with epithelial injury, immune dysregulation, and disease progression [21-25]. However, systematic insights into the cell-type-specific functions, context-dependent roles, and dynamic regulation of UMEs in distinct IBD subtypes remain limited.

In this review, we systematically summarize recent advances in UME-mediated regulation of cell fate during intestinal inflammation. By integrating evidence across distinct cell types and signaling contexts, we highlight how these molecular switches orchestrate the transition between survival and death, repair and injury, and immune tolerance and chronic inflammation, thereby providing a conceptual framework for therapeutic targeting.

Hierarchical regulation of UMEs in intestinal inflammation

System overview, spatial organization, and chain-type specificity

The UME system comprises four enzymatic classes: E1 (activating), E2 (conjugating), E3 (ligating), and DUBs (removing) [26]. This system enables precise regulation of protein stability, subcellular localization, interactions, and functional states, thereby coordinating diverse physiological and pathological processes [19, 27]. During the enzymatic cascade, E1 activates ubiquitin (Ub) in an ATP-dependent manner, E2 transfers ubiquitin to E3, and E3 recognizes specific substrates to catalyze ubiquitin conjugation. Conversely, DUBs remove mono- or polyubiquitin chains from target proteins, ensuring the reversibility and dynamic regulation of ubiquitin signaling (Figure 1A-B).

Ubiquitin can be linked through seven lysine residues (K6, K11, K27, K29, K33, K48, K63) or the N-terminal methionine (M1) to form distinct chain types [28] (Figure 1C). Among them, K48/K11-linked chains mainly mediate proteasomal degradation [29, 30], while K63/M1-linked chains regulate inflammation and immune signaling [31]. In contrast, mono-ubiquitination and atypical linkages such as K6, K27, K29, and K33 are involved in endocytosis, DNA repair, and vesicular trafficking [32]. In IBD, the balance between different chain types and their removal by UMEs is finely tuned to control immune signaling, cell death, autophagy, and epithelial barrier integrity [33]. Disruption of this dynamic equilibrium represents a central molecular mechanism driving chronic intestinal inflammation [33].

The intestinal immune system primarily comprises intestinal epithelial cells, innate immune cells, and adaptive immune cells (Figure 2A). Within this organized cellular landscape, UMEs display distinct cell type-specific distributions and functional roles (Figure 2B-D), forming a multilayered regulatory architecture that coordinates epithelial barrier homeostasis and immune responses. This spatial and functional stratification provides a structural basis for the fine-tuned regulation of ubiquitin signaling during intestinal inflammation.

Hierarchical regulation of cell fate by E2 ubiquitin-conjugating enzymes

E2 ubiquitin-conjugating enzymes constitute the core module of the ubiquitination cascade, determining ubiquitin chain elongation modes, linkage specificity, and substrate fate [34]. Beyond their enzymatic activity, accumulating evidence indicates that E2 enzymes also modulate substrate stability and signaling complex assembly, thereby regulating the amplitude and duration of inflammatory and stress-responsive pathways [35-38]. In intestinal inflammation, E2-mediated regulation primarily tunes the amplitude of inflammatory signaling and the cellular activation thresholds, thereby influencing epithelial stress tolerance, antigen presentation, and immune polarization. Within the hierarchical cellular-to-tissue regulatory framework defined above (Tables 1-2), E2 functions can be systematically mapped onto epithelial, innate immune, adaptive immune, and tissue outcome layers, highlighting their coordinated contributions to inflammatory progression and tissue remodeling (Figure 2B, Figure 3, Table 3).

 Figure 1 

Roles of UMEs in IBD. (A) The ubiquitination cascade involves E1-mediated ubiquitin activation, E2-mediated transfer, and E3-catalyzed substrate modification, while DUBs remove ubiquitin and maintain signaling balance. (B) IBD susceptibility genes encode multiple UMEs, underscoring their critical roles in disease pathogenesis. (C) Distinct ubiquitin linkages (mono-, multi-mono-, and poly-ubiquitin chains such as K48, K63, and M1) confer specific cellular outcomes including degradation and signaling regulation. Created in BioRender. Qian, C. (2026) https://BioRender.com/u85g4fh.

 Figure 2 

Cell fate-layered landscape of UME functions in intestinal inflammation. (A) Schematic overview of major cellular compartments involved in intestinal inflammation, including intestinal epithelial cells, innate immune cells, and adaptive immune cells across the epithelial barrier and lamina propria. (B) Summary of reported functions of E2 ubiquitin-conjugating enzymes across epithelial, innate immune, and adaptive immune compartments. (C) Classification of E3 ubiquitin ligases according to their reported protective or pathogenic roles in regulating epithelial and immune cell fate decisions. (D) Classification of DUBs based on their functional impact on inflammatory and stress-responsive pathways across distinct cellular compartments. Protective roles refer to functions that promote epithelial barrier integrity, immune homeostasis, resolution of inflammation, or tumor-suppressive outcomes, whereas pathogenic roles indicate activities that amplify inflammatory signaling, impair barrier function, or facilitate chronic inflammation and colitis-associated tumorigenesis. UMEs marked with asterisks (*) exhibit context-dependent or bidirectional effects depending on cell type, inflammatory stimulus, or disease stage. “Not yet studied” indicates the absence of direct experimental evidence in the corresponding cellular compartment rather than confirmed lack of function. Created in BioRender. Qian, C. (2026) https://BioRender.com/9xtir6c.

 Figure 3 

Cell fate-layered organization of E2 ubiquitin-conjugating enzyme functions in intestinal inflammation. Schematic illustrates the hierarchical organization of E2 enzyme-mediated regulation across interconnected cellular fate layers and downstream tissue-level outcomes during intestinal inflammation. Cellular fate layers include epithelial fate, innate immune fate, and adaptive immune fate, whereas tissue-level outcomes represent the integrated pathological consequences arising from the cumulative effects of these cellular programs. Representative biological processes regulated at each layer are indicated, including epithelial cell death and barrier restitution, macrophage polarization and inflammasome activation, T cell differentiation and immune exhaustion, as well as tissue-scale outcomes such as chronic inflammation and colitis-associated cancer (CAC) progression. Created in BioRender. Qian, C. (2026) https://BioRender.com/d0r43h0.

In intestinal inflammation, available evidence suggests that E2-mediated regulation primarily modulates the intensity of inflammatory signaling and the cellular activation thresholds. Gene expression analyses revealed that E2 enzymes, including UBE2A, UBE2D2, and UBE2L6, are differentially expressed in intestinal macrophages under inflammatory conditions in the gut [39]. UBE2W attenuates DSS-induced colitis by limiting NF-κB-driven inflammatory amplification and epithelial barrier damage [40]. UBC9 exhibits cell type-specific effects: in CD4⁺ T cells, reduced UBC9 enhances pathogenic Th17 responses [41]; in IECs, UBC9 downregulation exacerbates NF-κB-dependent inflammation and colitis susceptibility [42]; whereas in DCs, UBC9-mediated SUMOylation of RBPJ promotes T-cell activation and Th1/Th17 polarization, with DC-specific Ubc9 deletion alleviating experimental colitis [43]. Collectively, these findings suggest that E2 enzymes act as critical regulators of intestinal immune homeostasis, influencing epithelial barrier integrity and immune cell polarization (Figure 3, Table 3). Notably, compared with the extensive characterization of E3 ligases and DUBs, current knowledge of E2 enzymes in intestinal inflammation remains limited and largely confined to a small subset of family members. Thus, E2-mediated regulation should be viewed as an emerging regulatory layer, with substantial gaps remaining in mechanistic and disease-level understanding.

Hierarchical regulation of cell fate by E3 ligases

E3 ubiquitin ligases function as molecular switches that govern the stability and activity of key regulatory proteins during inflammation.

Unlike E2 enzymes that primarily tune activation thresholds, E3 ligases control signal directionality and strength, thereby shaping distinct cellular programs. In intestinal inflammation, they coordinate stress responses, survival, and cell death across multiple signaling axes, forming a multilayered regulatory framework that links molecular events to tissue-level outcomes (Figure 2C, Figure 4A, Table 4). Structurally, the E3 ligases discussed encompass major classes, including RING, HECT, RBR, and non-classical types [44].

Hierarchical regulation of E3-mediated cell fate

As illustrated in Figure 2C, E3 ligases are distributed across epithelial, innate, and adaptive immune compartments, forming an integrated regulatory network that coordinates barrier repair, immune activation, and inflammatory resolution in intestinal inflammation [19, 45] (Figure 2C, Table 4).

The colonic epithelium is composed of multiple specialized intestinal epithelial cell populations, including colonocytes, goblet cells, enteroendocrine cells, and stem cells (Figure 2A). Within IECs, representative E3 ligases such as HACE1, NEDD4L, and RNF186 regulate stress-adaptive responses and barrier-associated fate programs, thereby controlling epithelial survival, regeneration, and injury susceptibility [46-49]. In innate immune cells, E3 ligases, including TRIM26, TRIM31, and Pellino1/3, modulate inflammasome activation and the amplitude of inflammatory signaling, shaping the magnitude and persistence of mucosal immune responses [50-53]. In adaptive immune cells, representative E3 ligases, including ITCH, RNF5, TRAF5, TRIM21, and UHRF1, cooperatively sustain mucosal immune homeostasis by regulating Th1/Th17 differentiation, limiting pro-inflammatory signaling, and stabilizing Treg function, thereby preventing colitis exacerbation and preserving epithelial barrier integrity [54-58]. Together, E3 ligases form a hierarchical, cross-compartment regulatory network that links epithelial repair, innate inflammatory amplitude, and adaptive immune tolerance, thereby coordinating inflammation resolution and tissue protection in intestinal inflammation.

Epithelial cell fate: balancing survival and death to maintain barrier homeostasis

Within an inflammatory microenvironment, intestinal epithelial cells continuously navigate a dynamic balance between survival and death, with E3 ligases acting as central regulators of this decision-making network [59]. TNF-α can trigger epithelial apoptosis; however, UHRF1, HACE1, cIAP1, and RNF5 promote pro-survival programs by catalyzing ubiquitination at key signaling hubs (e.g., RIPK1 and TRAF2), thereby strengthening NF-κB-dependent survival signaling and shifting cell fate toward anti-apoptotic pathways [46, 56, 60, 61]. In contrast, a subset of E3 ligases directly modulates stress-associated death programs: Hrd1 protects the epithelium by alleviating ER stress and limiting inflammatory amplification [62], whereas RNF183 enhances stress-linked apoptotic signaling and exacerbates mucosal injury [63]. Beyond canonical apoptosis control, E3 ligases further shape epithelial fate through multiple adaptive stress-response pathways. In ferroptosis regulation, NEDD4L induces epithelial ferroptosis by suppressing the SLC3A2-GPX4 axis, thereby restricting aberrant proliferation and impeding the transition from inflammation to colorectal cancer [47]. In autophagy control, Parkin promotes autophagy-lysosome-dependent degradation of VDR, dampening vitamin D signaling and compromising barrier homeostasis [64]. Conversely, MARCH8, RNF8, and RNF128 support epithelial stability by driving selective autophagy to eliminate inflammation-associated substrates, thereby restraining inflammatory spread [65-67]. E3 ligases also exert bidirectional control over oxidative stress adaptation. RINCK and RNF31 suppress NRF2-mediated antioxidant programs, increase ROS accumulation, and aggravate epithelial injury [68, 69]. In contrast, Hakai and TRIM59 enhance NRF2-dependent antioxidant and metabolic homeostatic responses to buffer oxidative stress, maintain barrier function, and limit persistent inflammation [70, 71]. In parallel, MARCH3, TRIM21, and TRIM27 target inflammatory receptors and key nodes in innate immune signaling, whereas TRIM34 in goblet cells suppresses feed-forward inflammatory cascades, thereby sustaining the epithelial-immune interface [72-75]. Collectively, the epithelial E3 ligase network integrates apoptosis, autophagy, ferroptosis, and oxidative stress pathways to form a central regulatory hub for epithelial fate decisions under inflammatory stress, thereby shaping barrier homeostasis and influencing disease trajectories.

Innate immune cell fate: inflammasome-driven pyroptosis and functional polarization

During intestinal inflammation, innate immune cells undergo both programmed pyroptosis and functional polarization, and E3 ligases serve as key determinants of these fate transitions. TRIM31 restrains inflammasome activation and pyroptosis by promoting ubiquitination and degradation of NLRP3 [51]. In contrast, RNF31 enhances NLRP3 inflammasome activity via ubiquitin-dependent mechanisms, amplifying inflammatory output and exacerbating tissue damage [76]. In macrophage polarization, Pellino1 drives pathological polarization by augmenting STAT3-dependent inflammatory signaling [52], whereas TRIM33 promotes inflammation resolution by supporting monocyte differentiation and facilitating the M1-to-M2 transition [77]. Moreover, c-Cbl, MARCH3, TRAF2, TRAF3, and UHRF1 collectively restrain excessive cytokine production by tuning signaling thresholds at inflammatory receptors and regulating the NF-κB/IRF transcriptional axis, thereby maintaining mucosal innate immune homeostasis [60, 72, 78, 79]. Conversely, Pellino3, RNF40, TRAF4, TRAF6, TRIM14, and TRIM26 act as signal amplifiers that increase TLR/NOD pathway output [50, 53, 80-82], whereas cIAP1/2, RNF99, RNF138, TRIM27, and TRIM58 impose negative feedback to limit inflammatory signaling strength [83-87]. In summary, these opposing modules define the magnitude of innate immune responses and thereby influence the persistence of intestinal inflammation and the risk of malignant progression. Overall, E3 ligases fine-tune innate immune fate by bidirectionally regulating inflammasome activity, polarization circuits, and receptor-centered inflammatory signaling networks.

Adaptive immune cell fate: lineage specification and immune tolerance

In the adaptive immune compartment, E3 ligases govern T-cell lineage specification and immune tolerance by controlling the stability of transcription factors and the intensity of upstream signaling. ITCH suppresses Th17 differentiation by ubiquitinating and promoting the degradation of RORγt, while also contributing to the Treg program [54, 55]. Loss of ITCH results in excessive Th17 expansion, impaired barrier repair, and immune imbalance, thereby driving spontaneous colitis and increasing cancer risk [54, 55]. UHRF1 exerts cell-type-dependent effects in intestinal inflammation. It limits Treg differentiation by maintaining DNA methylation, and its loss attenuates colitis in T cell transfer models [88]. In contrast, UHRF1 restrains TNF-α expression in macrophages via promoter methylation, and its deficiency aggravates DSS-induced colitis [60]. In addition, RNF5, TRAF5, and TRIM21 cooperatively restrain pathogenic Th1/Th17 effector programs and limit excessive adaptive immune activation; deficiency in these regulators exacerbates CD4⁺ T-cell-driven colitis phenotypes [56-58].

Tissue-level regulation of disease outcomes: from inflammatory homeostasis to a cancer-permissive state

At the tissue level, E3 ligases coordinate epithelial homeostasis with innate and adaptive immune responses, thereby critically influencing whether inflamed colonic tissue resolves back to homeostasis or progresses into chronic inflammation. This tissue-scale decision subsequently shapes the long-term risk of CAC. Several E3 ligases, including MARCH3, RNF128, RNF138, and TRIM21, inhibit the colitis-to-cancer transition by suppressing IL-6-STAT3 signaling, constraining aberrant epithelial proliferation, and/or dampening NF-κB activity [72, 73, 85, 89]. In contrast, TRIM27 promotes this process [74]. Clinical observations further support this directional regulation, with the former group frequently downregulated in IBD or CRC tissues [72, 73, 85, 89], whereas TRIM27 is markedly upregulated in CRC specimens, consistent with their opposing functions along the inflammation-tumor fate axis [74].

It should be noted that most of the regulatory mechanisms summarized in this section are derived from inflammation-driven experimental systems, including chemically induced models such as azoxymethane/dextran sulfate sodium (AOM/DSS) and genetically engineered models of chronic colitis [47, 90]. These models primarily recapitulate key pathological features of CAC, including persistent inflammatory stress, epithelial barrier disruption, immune microenvironment remodeling, and inflammation-dependent tumor initiation and progression. In contrast, sporadic colorectal cancer is predominantly driven by oncogenic mutations and develops within a distinct etiological and microenvironmental context. Therefore, while certain ubiquitin-dependent regulatory pathways may be shared, caution should be exercised when extrapolating inflammation-centered mechanisms directly to mutation-driven sporadic CRC.

In parallel, TRIM34, HACE1, ITCH, and NEDD4L restrict the establishment of a pro-tumorigenic premalignant microenvironment by maintaining epithelial stability and/or restraining excessive immune activation [46, 47, 54, 75]. Conversely, Pellino1, Pellino3, and TRIM14 promote chronic inflammatory maintenance and amplify tumor-promoting signaling cascades [52, 53, 82]. Collectively, these antagonistic E3 ligases form a dynamic regulatory network at the tissue scale, orchestrating the balance between inflammatory resolution and cancer-permissive transformation.

Fate “integrators” across cell types and signaling layers: ITCH and RNF186

A subset of E3 ligases exerts coordinated control across multiple cell types and signaling layers, functioning as fate “integrators.” Here, ITCH and RNF186 exemplify this role. ITCH coordinately regulates adaptive immunity, epithelial repair, and fibrotic fate by promoting degradation of RORγt and HIC-5, thereby balancing Th17 differentiation, epithelial homeostasis, and fibroblast activation, ultimately constraining inflammation-associated carcinogenesis and intestinal fibrosis [54, 55, 90]. RNF186 plays bidirectional roles in intestinal inflammation: it can promote ER stress-associated apoptosis via BNip1 ubiquitination [91], yet it also preserves mucosal homeostasis by supporting EPHB2-dependent autophagy, ATF6-UPR signaling, and Occludin-mediated tight-junction proteostasis [48, 49, 92]; loss-of-function variants compromise these protective arms and increase colitis susceptibility [48, 49, 92].

Together, the hierarchical regulation of cell fate by E3 ubiquitin ligases provides a unifying framework linking inflammation to malignant progression. At the cellular level, these ligases dictate epithelial survival versus death, macrophage pyroptosis versus polarization, and T-cell effector versus regulatory differentiation. At the tissue level, these micro-scale fate choices are integrated into macro-scale outcomes, determining whether inflammation resolves or persists (Figure 4A). Dysregulated E3 activity disrupts this equilibrium, driving immunopathology and/or promoting tumorigenesis. Thus, the ubiquitin system not only controls protein turnover but, through cross-scale regulatory networks, ultimately shapes the clinical fate of colonic tissue—healing, chronic inflammation, or malignant transformation.

Hierarchical regulation of cell fate by DUBs

DUBs counterbalance ubiquitin-dependent signaling to fine-tune inflammatory responses in the gut [93, 94]. By removing ubiquitin chains from key regulators, DUBs modulate protein stability, activity, and localization, thereby shaping the behavior of epithelial and immune cells under stress. Rather than merely buffering signals, DUBs construct multilayered regulatory circuits that restore signaling thresholds, resolve inflammation, and preserve cellular equilibrium. In intestinal inflammation, they orchestrate fate decisions across epithelial, innate, and adaptive immune compartments, ultimately impacting whether tissue regains homeostasis or progresses toward chronic inflammation and malignancy. DUBs fall into four major families—USP, OTU, JAMM, and MJD, each defined by distinct catalytic architectures and chain-linkage specificities [94-96] (Figure 2D, Figure 4B, Table 5).

Hierarchical regulation of DUB-mediated cell fate

As shown in Figure 2D and Table 5, DUBs are distributed across intestinal epithelial, innate immune, and adaptive immune compartments, forming a cross-cell type regulatory network that coordinately balances inflammatory responses and tissue repair.

In IECs, OTULIN, USP9X, USP13, USP22, USP25, and USP47 maintain barrier homeostasis and attenuate colitis progression by suppressing NF-κB, STAT3, and inflammation-related signaling pathways [25, 97-101]. In contrast, USP7 enhances oxidative stress and exacerbates inflammatory responses under specific pathological conditions [102], whereas A20 and CYLD exhibit context-dependent dual regulatory roles [103-106]. In innate immune cells, JOSD2, CYLD, A20, OTUD1, and USP38 exert anti-inflammatory effects by limiting inflammatory signal amplification and reducing tissue damage [107-110]. By comparison, BRCC3, OTUD5, OTUD6A, USP16, and USP25 promote immune activation through enhanced cytokine production, thereby modulating the magnitude of inflammatory responses [111-115]. In adaptive immune cells, CYLD, USP7, USP8, USP21, and USP28 regulate T cell activation and the Th17/Treg differentiation balance, maintaining mucosal immune homeostasis and restraining excessive inflammation [109, 116-119]. Conversely, sCYLD promotes inflammatory signaling activation in T cells and enhances pro-inflammatory responses [120]. Collectively, DUBs establish a compartmentalized and reversible deubiquitination regulatory system that cooperates with E3 ligases to coordinately orchestrate inflammation resolution and tissue protection in the intestine.

Epithelial cell fate: balancing apoptosis and stress adaptation to maintain barrier integrity

DUBs preserve epithelial integrity by modulating apoptosis, endoplasmic reticulum (ER) stress, and oxidative responses. OTULIN and USP13 stabilize the epithelial barrier by inhibiting inflammatory signaling (e.g., NF-κB) or alleviating ER stress, thereby limiting TNF-induced or stress-driven epithelial apoptosis [25, 97]. USP25 and USP13 act as anti-stress protectors by either dampening UPR signaling or sustaining STAT3 activation, contributing to epithelial cell survival and tissue repair [25, 100]. In contrast, USP7 suppresses NRF2-dependent antioxidant pathways, resulting in ROS accumulation and increased vulnerability to oxidative injury [102]. These enzymes collectively constitute a DUB network that calibrates epithelial stress responses and determines survival versus death outcomes under inflammatory challenge.

 Figure 4 

Protective and pathogenic roles of UMEs in epithelial-immune cell fate layers and tissue-level outcomes during intestinal inflammation. (A) Summary of E3 ligases and (B) deubiquitinases (DUBs) categorized according to reported protective or pathogenic functions across distinct cell fate layers, including epithelial, innate immune, and adaptive immune fate layers, together with their associated tissue-level outcomes related to colitis-associated cancer (CAC) progression. Venn diagrams illustrate UMEs that act within single compartments or coordinately regulate multiple cellular layers. UMEs shown in overlapping regions indicate shared regulatory roles across epithelial and immune compartments. Tissue-level fate panels summarize enzymes implicated in promoting malignant transition or suppressing inflammation-driven tumorigenesis. UMEs marked with asterisks (*) exhibit context-dependent or bidirectional effects depending on cell type, inflammatory stimulus, or disease stage.

Innate immune cell fate: amplification versus suppression of inflammatory programs

DUBs determine the amplitude and persistence of inflammatory responses in innate immune cells such as macrophages. BRCC3 and OTUD6A enhance inflammasome activation by removing ubiquitin modifications from NLRP3, thereby promoting IL-1β/IL-18 secretion and pyroptosis, which amplifies inflammatory output [111, 113]. USP16 reinforces pro-inflammatory activation by augmenting IKKβ-p105 signaling in macrophages, driving sustained inflammation [114]. In contrast, USP38 suppresses immune overactivation by deubiquitinating H2B and stabilizing KDM5B, which limits NF-κB-dependent IL-6 and IL-23 expression [110]. Taken together, these DUBs form a regulatory module that tunes the polarization state of innate immune cells and dictates inflammatory outcomes.

Adaptive immune cell fate: T cell differentiation, homeostasis, and effector balance

In the adaptive immune system, DUBs regulate the fate of T cell subsets such as Tregs and Th17 cells by modulating activation thresholds and maintaining transcription factor stability. OTUD5 promotes Th17 differentiation and sustains its pro-inflammatory effector functions [112]. In contrast, USP8 stabilizes Tregs by enhancing the Foxo1-IL-7Rα signaling axis [117], and USP21 inhibits Th17 differentiation by constraining AhR activity [118]. These DUBs collectively act within the inflammatory milieu to uphold immune tolerance and prevent dysregulated adaptive immune activation.

Tissue-level outcomes: inflammatory resolution versus tumor-permissive remodeling

At the tissue scale, DUBs integrate epithelial homeostasis, immune responses, and signaling adaptation to shape inflammatory outcomes, determining whether inflamed tissue resolves toward mucosal homeostasis or evolves into a tumor-permissive state. OTUD6A and USP16 promote chronic inflammatory persistence and CAC development by enhancing NLRP3 inflammasome activation or IKKβ-NF-κB signaling [113, 114]. USP25 compromises mucosal antimicrobial defense and epithelial secretory lineage integrity by modulating secretory cell development and the Wnt pathway, thereby facilitating tumorigenesis [115]. In contrast, JOSD2 attenuates tissue inflammatory burden by suppressing macrophage inflammatory pathways [108]; CYLD limits NF-κB and JNK activation [106], USP9X supports epithelial stem/progenitor cell differentiation [98], and USP22 mitigates chronic epithelial injury through transcriptional repression [99]. Collectively, these DUBs define opposing tissue-level outcomes, ranging from stable mucosal homeostasis to inflammation-driven carcinogenic remodeling.

Notably, A20 and CYLD exemplify the context-dependent dual roles of DUBs across distinct cellular environments. Deletion of A20 results in uncontrolled NF-κB activation and systemic inflammation [107, 121]. In contrast, in IECs, A20 exhibits a dose-dependent bifunctional role in TNF signaling [103, 104]. Loss of A20 sensitizes epithelial cells to TNF-induced apoptosis by impairing NF-κB-dependent survival programs [104], whereas excessive A20 expression paradoxically promotes RIPK1-dependent ripoptosome assembly and caspase-8 activation [103]. Mechanistically, both insufficient and excessive A20 activity destabilize TNFR1 signaling homeostasis by altering the balance between membrane-associated complex I and cytosolic death-inducing complex II formation. This threshold-dependent regulatory behavior positions A20 as a rheostat rather than a unidirectional suppressor of inflammation in epithelial compartments. CYLD exhibits similar complexity: in IECs, it promotes necroptosis and epithelial barrier disruption [106], while in immune cells, it exerts anti-inflammatory effects by restricting TRAF-NEMO signaling and NLRP6 inflammasome activation [105, 109]. The short splice variant sCYLD further exacerbates inflammation by inhibiting TGF-β signaling, destabilizing Treg cells, and enhancing Th1/Th17 responses [120].

Collectively, DUBs fine-tune ubiquitination landscapes to orchestrate hierarchical fate decisions within the inflammatory microenvironment. By controlling cell survival, immune balance, and tissue pathology, DUBs serve as critical nodes linking molecular signaling dynamics to disease outcomes, including resolution, chronic inflammation, or tumorigenesis.

From cell fate modulation to pathway control: multi-layered roles of UMEs in inflammatory signaling networks

Following recognition of the layered role of UMEs in shaping cell-fate decisions, accumulating evidence reveals their equally critical function in precisely modulating key molecular nodes within well-defined inflammatory signaling pathways (Figure 5, Tables 3-5). In intestinal inflammation, UMEs dynamically regulate signal transduction complexes, modulate adaptor protein activity, and control the stability of transcription factors across core axes such as TLRs, TNFRs, NOD-like receptors, and STAT signaling, thereby shaping the amplitude, duration, and outcomes of immune responses.

Pattern recognition receptors (PRRs), including TLRs, CLRs, and NOD2, detect microbial and damage-associated molecular patterns and rapidly recruit adaptor proteins such as TRADD, MyD88, IRAKs, and RIP2 to form signaling complexes. These complexes are finely regulated by various E3 ligases (such as Pellino3, ASB3, TRIM62, and cIAP2) and DUBs (including CYLD, USP47, A20, and OTUD1), which together orchestrate signal amplification or termination to balance pro-inflammatory responses with negative feedback control [83, 101, 103, 109, 122-126]. Signals from diverse receptors converge on the TAK1-TAB complex, a key signaling hub whose assembly and activation are modulated by E3 ligases including TRIM26, RNF8, RNF99, and ASB1, thereby allowing graded control over NF-κB and MAPK activation and transcriptional responses [50, 66, 84, 127].

TLR signaling also intersects with STAT3 to influence epithelial-immune crosstalk. Pellino1 promotes STAT3 ubiquitination and nuclear translocation, while USP25 stabilizes STAT3 via deubiquitination, linking inflammatory signaling with epithelial survival [52, 100]. Beyond canonical immune pathways, stress-related signaling is also tightly regulated by the ubiquitin system. Under endoplasmic reticulum stress, RNF186 and USP13 modulate the ubiquitination of GRP78 and ATF6, respectively, adjusting the unfolded protein response and gene expression [25, 92]. In the context of reactive oxygen species (ROS) accumulation, RNF31 and RINCK suppress NRF2 activation, thereby promoting oxidative damage and inflammation [68, 69]. Conversely, TRIM59 enhances KEAP1 degradation, facilitates NRF2 nuclear translocation, and upregulates antioxidant gene expression, mitigating epithelial injury and restraining colitis progression [71]. At the transcriptional level, RNF20, USP22, and USP38 converge on epigenetic regulation to repress inflammatory gene programs [99, 110, 128]. UMEs also govern inflammasome activity: E3 ligases such as RNF31, TRIM31, and MARCH8, along with DUBs like BRCC3, OTUD6A, and CYLD, modulate NLRP3 and NLRP6 ubiquitination, thereby influencing caspase-1 activation, Gasdermin D cleavage, and IL-1β/IL-18 maturation, which shape pyroptotic responses and inflammatory amplification [51, 65, 76, 105, 111, 113]. In adaptive immunity, ITCH suppresses Th17 differentiation by ubiquitinating and degrading RORγt; its deficiency leads to exaggerated NF-κB activity and spontaneous colitis. In parallel, hypoxia represses UBC9 transcription, reducing RORγt SUMOylation and enhancing IL-17 expression, thereby reinforcing Th17-driven pathogenicity [41, 55]. Altogether, UMEs operate across multiple layers of the intestinal inflammatory network, ranging from signalosome assembly to transcriptional control, to define the trajectory of immune activation, tissue injury, and homeostatic resolution, making them pivotal regulators of inflammation and disease fate.

Emerging hotspots and future directions of UME regulation in IBD

Building on the expanding mechanistic understanding of UME function in intestinal inflammation, efforts are now increasingly directed toward developing therapeutic and technological strategies to modulate UME activity in IBD (Figure 6).

Development of small-molecule modulators targeting UMEs

With the increasing recognition of UMEs as pivotal regulators in chronic inflammatory diseases, small-molecule inhibitors targeting DUBs and E3 ligases have become a major research focus. Among them, USP7 and USP14, which regulate NF-κB signaling, inflammatory gene expression, and epithelial barrier homeostasis, have emerged as promising therapeutic targets in IBD.

 Figure 5 

Multi-layered regulation of inflammatory signaling networks by UMEs in intestinal inflammation. Schematic overview illustrating how ubiquitin-modifying enzymes (UMEs), including E2 conjugating enzymes, E3 ligases, and DUBs, coordinate the regulation of key inflammatory signaling pathways in intestinal epithelial and immune cells. UMEs modulate receptor-proximal signalosome assembly (TLRs, TNFR, CLRs, and NOD2), downstream kinase cascades (TAK1-TAB, MAPKs, and IKK complexes), transcriptional programs (NF-κB, AP-1, STAT3), stress-responsive pathways (ER stress and oxidative stress signaling), and inflammasome activation (NLRP3/NLRP6). These coordinated regulatory layers collectively shape cell fate outcomes, including inflammatory activation, stress adaptation, programmed cell death, and barrier homeostasis. Blue boxes indicate E3 ligases, red boxes indicate DUBs, and green boxes represent E2 enzymes. Solid arrows denote signaling flow, whereas dashed arrows indicate transcriptional regulation. Created in BioRender. Qian, C. (2026) https://BioRender.com/a9pj9u4.

 Figure 6 

Future perspectives of UMEs in IBD. Schematic summary of emerging research directions and therapeutic strategies targeting ubiquitin-modifying enzymes (UMEs) in inflammatory bowel disease, including small-molecule inhibitors, PROTAC technology, ncRNA-mediated regulation, natural compounds, multi-omics approaches, and clinical translational potential. Created in BioRender. Qian, C. (2026) https://BioRender.com/7t7alxc.

Structural and functional diversity of USP7 small-molecule inhibitors

The therapeutic targeting of USP7 has evolved from early non-specific covalent inhibitors to highly selective allosteric modulators, driven by a deeper understanding of its complex structural dynamics [129, 130]. USP7 transitions between an inactive (apo) state and an active (ubiquitin-bound) state through significant rearrangements of its catalytic triad (Cys223, His464, and Asp481) [129].

Recent studies have identified small molecules that exploit USP7 conformational dynamics to achieve selective inhibition. GNE-6640 and GNE-6776 act as non-covalent inhibitors that bind near the catalytic cleft, induce rearrangement of the switching loop, and prevent ubiquitin engagement, thereby suppressing USP7 activity in cancer models [130]. In contrast, FT671 and FT827 selectively stabilize the apo conformation of USP7, block catalytic triad realignment, and promote MDM2 degradation, leading to restoration of p53 tumor-suppressive signaling [129]. Beyond oncology, USP7 has also emerged as a critical regulator of inflammatory signaling and redox homeostasis. P22077, an early-generation dual inhibitor of USP7 and USP47, exerts anti-inflammatory effects by targeting multiple signaling pathways. Mechanistically, P22077 promotes K48-linked ubiquitination and degradation of TRAF6, thereby attenuating LPS-induced TLR4/NF-κB activation [131]. In addition, USP7 inhibition by P22077 suppresses NLRP3 inflammasome activation by preventing ASC oligomerization and speck formation in a transcription-independent manner [132].

In the specific context of IBD, USP7 plays a deleterious role by modulating the intestinal redox state. Recent evidence highlights that USP7 stabilizes AMBRA1; the accumulated AMBRA1 then antagonizes DUB3-mediated deubiquitination of NRF2, leading to NRF2 degradation and increased oxidative stress in IECs. Consequently, inhibition of USP7 by P5091 or P22077 restores the NRF2-driven antioxidant response and alleviates mucosal inflammation in experimental colitis models [102, 133]. These findings suggest that USP7 inhibitors do not merely suppress inflammation but also act as multifaceted regulators of epithelial barrier integrity and oxidative balance, making them promising candidates for IBD therapy.

Small-molecule inhibitors targeting proteasome-associated USP14

USP14 is a major deubiquitinating enzyme associated with the 19S regulatory particle of the 26S proteasome and plays an essential role in fine-tuning proteasomal protein degradation. Unlike most DUBs, inhibition of USP14 directly interferes with proteasomal substrate processing, making it a potential therapeutic target in diseases characterized by proteostasis imbalance and inflammatory dysregulation.

b-AP15 is a potent small-molecule inhibitor targeting both USP14 and UCHL5. Its inhibition leads to rapid accumulation of high-molecular-weight polyubiquitinated proteins, thereby inducing pronounced proteotoxic stress [134]. In contrast to classical proteasome inhibitors, b-AP15-induced apoptosis is closely associated with enhanced oxidative stress and ROS generation, accompanied by mitochondrial membrane potential loss and structural damage, ultimately driving programmed cell death [135]. Beyond its pro-apoptotic effects in cancer models, b-AP15 also exhibits anti-inflammatory activity. USP14 inhibition attenuates LPS-induced inflammatory responses by suppressing ERK1/2 and JNK signaling and limiting NF-κB nuclear translocation [136]. By simultaneously modulating proteostasis and inflammatory signaling networks, targeting USP14 represents a multifaceted therapeutic strategy for inflammatory disorders.

Other small-molecule inhibitors targeting UMEs

Beyond the USP family, pharmacological modulation of other UMEs, particularly E3 ligases involved in ER stress and epithelial proteostasis, has also been explored. Among these, Hrd1 has attracted attention due to its critical role in regulating unfolded protein response signaling and maintaining epithelial stress tolerance. Experimental inhibition of Hrd1 using LS102 markedly exacerbates colitis severity in murine models, highlighting its protective function in limiting ER stress-driven epithelial injury and inflammatory amplification [62].

Collectively, these studies demonstrate that small-molecule modulation of UMEs can influence intestinal inflammation through multiple mechanisms, including inflammatory signal transduction, redox homeostasis, proteostasis regulation, and epithelial stress adaptation. While USP7 and USP14 inhibitors primarily act by reshaping inflammatory and proteotoxic signaling networks, targeting stress-responsive E3 ligases, such as Hrd1, underscores the importance of preserving epithelial homeostatic capacity. Together, these findings underscore both the therapeutic potential and the inherent complexity of UME-targeted strategies in IBD. Rational drug design will therefore require careful consideration of target selectivity, cell type specificity, and tissue-context dependence to balance anti-inflammatory efficacy with the maintenance of intestinal barrier integrity.

Natural compounds in the regulation of UMEs

Natural products are gaining attention as complementary regulators of UMEs. These bioactive compounds can influence UME expression or activity, thereby modulating intestinal inflammation, oxidative stress, and mitophagy.

For instance, in humanized colitis models, DSS or TNBS challenge significantly downregulated Hrd1 expression while upregulating ER stress markers such as GRP78, PERK, CHOP, and caspase-12. Treatment with ginsenoside Rb1 reversed these changes, suggesting a role in alleviating ER stress by modulating Hrd1 [62]. Similarly, aflatoxin A has been reported to promote the progression of chronic colitis and colorectal cancer by targeting the RINCK signaling pathway [137], underscoring the involvement of UMEs in IBD-associated tumorigenesis. Moreover, the traditional Chinese formula Tongxie Yaofang (TXYF) suppressed tumor formation in a CAC mouse model. TXYF not only inhibited the proliferation of LPS-stimulated epithelial and colorectal cancer cells but also blocked epithelial-mesenchymal transition (EMT) by activating PINK1/Parkin-dependent mitophagy, thereby exerting both anti-inflammatory and antitumor effects [138].

Among single compounds, Hyperoside was found to suppress MKRN1 expression, thereby enhancing ubiquitin-mediated degradation of its substrate, PPARγ, ultimately ameliorating DSS-induced colitis in mice [139]. Licorice extract has been shown to activate the Nrf2/PINK1 pathway, promoting mitophagy and reducing inflammatory cytokine production and oxidative stress in UC models [140]. Another study demonstrated that the blueberry anthocyanin malvidin-3-glucoside (MG) upregulated HACE1, restored gut microbial homeostasis, and increased the abundance of beneficial bacteria such as Bifidobacteria, conferring protection in colitis models [141]. Likewise, Qingfei Paidu Decoction (QFPDD) and its bioactive component wogonoside suppressed USP14 expression while promoting ATF2 degradation, resulting in reduced IL-6 and TNF-α production, enhanced IL-10 expression, and alleviation of intestinal inflammation [142]. Furthermore, Chicoric acid was shown to ameliorate DSS-induced colitis by targeting the USP9X/IGF2BP2 axis [143].

Regulation by long non-coding RNAs or microRNAs

In addition to classical regulation at the protein level, increasing evidence indicates that UMEs are also subject to fine-tuned control by non-coding RNA (ncRNA) networks [144]. Specific microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) can modulate the transcription, mRNA stability, or translational efficiency of UME-encoding genes, thereby indirectly influencing downstream signaling functions. Such regulatory layers play important roles in the onset and maintenance of intestinal inflammation [145, 146].

For instance, miR-7 suppresses RNF183 expression and alleviates DSS-induced colitis [147]. Conversely, miR-221/222 enhances NF-κB and STAT3 signaling activity through dual mechanisms: directly stabilizing RelA mRNA and indirectly repressing PDLIM2 (an E3 ligase that promotes the degradation of RelA and STAT3), thereby amplifying proinflammatory signals. Targeting miR-221/222 efficiently disrupts this pathogenic loop and inhibits colorectal cancer cell proliferation [148]. Furthermore, several miRNAs (e.g., miR-125b, miR-181b) and lncRNAs (e.g., NEAT1, MALAT1) have been experimentally validated to regulate key UMEs (such as A20, CYLD, and TRAF6), thereby modulating NF-κB signaling, cell survival, and immune homeostasis [149-153].

Although research on ncRNA-mediated regulation of UMEs in the context of IBD is still in its infancy, these findings highlight ncRNAs as upstream regulators of the UME network. Together, these findings expand our mechanistic understanding of UME regulation. Future studies integrating multi-cellular transcriptome profiling and ncRNA-UME interaction networks may help construct a multi-layered regulatory model, ultimately providing a more comprehensive explanation of UME functions in IBD.

Emerging PROTAC technology for targeting UMEs

In recent years, proteolysis-targeting chimera (PROTAC) technology has attracted considerable attention as a promising strategy for small-molecule drug development due to its ability to induce selective protein degradation [154]. Unlike conventional inhibitors that merely block enzymatic activity, PROTAC recruits an E3 ligase to ubiquitinate the target protein, thereby directing it toward proteasomal degradation. This provides a novel avenue for targeting “undruggable” proteins [155]. Although direct studies on UMEs in the context of IBD are still lacking, the successful application of PROTAC in oncology, autoimmunity, and other disease areas provides a strong theoretical basis for its potential application in IBD.

Of particular note, many UME-regulated proteins are highly stable and thus challenging to inhibit directly (e.g., certain DUBs or catalytically inactive E3 ligases), making them attractive PROTAC targets [156]. Future design strategies may consider developing PROTAC molecules against key IBD-related inflammatory mediators (such as NF-κB subunits, NLRP3, or STAT3). By harnessing E3 ligase-mediated selective degradation, such approaches could achieve precise regulation of inflammatory pathways. Furthermore, combining PROTAC platforms with tissue-specific delivery systems or biomaterial-based organ targeting strategies may further enhance their translational potential and therapeutic efficacy in IBD.

In summary, although PROTAC-based approaches are still in the early stages of research on intestinal inflammation, their mechanistic foundation in ubiquitin signaling highlights the promise of PROTAC as a powerful tool for modulating UMEs. This strategy may open new avenues for therapeutic intervention in IBD pathogenesis.

Multi-omics approaches for dissecting UME regulatory networks

The rapid development of multi-omics technologies has provided new perspectives for elucidating the regulatory roles of UMEs in IBD. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics have revealed cell-type- and tissue-specific expression patterns of UMEs, enabling precise localization of their activity in diseased tissues [157-159]. Integration of proteomic, ubiquitinomic, and transcriptomic data will facilitate the construction of comprehensive molecular regulatory networks of UMEs in intestinal immune inflammation, barrier dysfunction, and cell death. In addition, high-throughput CRISPR/Cas9 functional screens offer the opportunity to systematically identify essential UMEs and define their cell type- or pathway-specific roles. Together, these approaches will accelerate mechanistic dissection and uncover new therapeutic targets in IBD [160-162].

 Figure 7 

Representative UME expression alterations reported in heterogeneous patient cohorts with UC, CD, and CRC. Schematic summary of ubiquitin-modifying enzymes (UMEs) that are differentially expressed in ulcerative colitis (UC), Crohn's disease (CD), and colorectal cancer (CRC) based on reported transcriptomic and tissue-level expression analyses. Blue boxes indicate UMEs that are downregulated, whereas red boxes indicate UMEs that are upregulated in the indicated disease conditions. Enzymes altered in both UC and CD are shown separately from those selectively dysregulated in individual disease subtypes. The CRC-associated panel summarizes UMEs with consistent expression changes during colorectal tumorigenesis. Created in BioRender. Qian, C. (2026) https://BioRender.com/o0txak6.

Clinical translation and diagnostic potential

Current evidence supporting the involvement of UMEs in IBD is primarily derived from heterogeneous human datasets, including bulk transcriptomic profiling, protein-level measurements, peripheral blood biomarker analyses, and genome-wide association studies (GWAS) [163, 164]. As summarized in the “Alteration in patients” category, many UMEs exhibit disease-associated expression changes in tissues from patients with UC, CD, or CRC (Figure 7, Tables 3-5). For example, UBC9, TRIM59, and USP13 are downregulated in patients with UC and CD and exhibit significant correlations with disease activity, indicating that alterations in UME expression may serve as indicators of disease progression or predictors of therapeutic response [25, 42, 71]. However, it should be emphasized that most patient-derived data reflect correlative associations rather than direct causal relationships. In contrast, only a subset of UMEs has been functionally validated in disease-relevant experimental systems, particularly inflammation-driven models such as AOM/DSS-induced CAC or genetically engineered colitis models. Therefore, caution is warranted when inferring mechanistic roles or therapeutic target potential based solely on observational human data. Future studies should prioritize the systematic validation of UMEs as biomarkers and companion diagnostics, alongside mechanistic investigations to establish their direct causal contributions to epithelial dysfunction, immune dysregulation, and inflammatory disease progression. Collectively, integrating multi-layer human datasets with functional validation in inflammation-driven models will be essential for refining the translational relevance of UMEs and prioritizing high-confidence targets for precision intervention in IBD and related inflammatory pathologies.

Conclusion, limitations, and future perspectives

By functioning as central regulators of protein homeostasis, UMEs play fundamental roles in controlling cell fate decisions during intestinal inflammation. By coordinating programmed cell death, stress adaptation, and survival signaling across epithelial and immune compartments, UMEs critically shape tissue homeostasis and inflammatory outcomes in IBD. This review has synthesized the current understanding of the expression dynamics and functional properties of E2 enzymes, E3 ligases, and DUBs, highlighting how ubiquitin-dependent mechanisms integrate cell-type-specific signaling networks under inflammatory stress.

Despite substantial progress, major conceptual and technical challenges remain in understanding UME-mediated regulation of intestinal inflammation. Key unresolved questions include the substrate specificity of individual UMEs, the functional selectivity of distinct ubiquitin chain architectures, tissue- and cell-type-dependent heterogeneity, and crosstalk with transcriptional and metabolic programs. In addition, the roles of UMEs in non-epithelial stromal populations, such as fibroblasts and endothelial cells, remain largely unexplored, particularly in the context of inflammation-associated tissue remodeling and disease complications. Limitations of current experimental models should also be considered. DSS- and TNBS-induced colitis models capture specific inflammatory features but do not fully recapitulate the chronic relapsing course, genetic diversity, and clinical heterogeneity of human IBD. DSS models primarily reflect epithelial injury and innate immune activation, whereas TNBS models emphasize hapten-driven, T cell-mediated inflammation. Likewise, AOM/DSS models preferentially represent colitis-associated tumorigenesis rather than sporadic colorectal cancer driven by oncogenic mutations. These limitations underscore the need for cautious translational interpretation and complementary validation across experimental systems.

Importantly, accumulating evidence indicates that UME function is highly stage-dependent along the trajectory of intestinal inflammation. During disease initiation, UMEs mainly shape epithelial barrier integrity, early innate immune activation, and acute epithelial cell death programs. In chronic inflammation, long-term regulation of inflammatory signaling, stress adaptation, and immune cell polarization contributes to disease persistence and tissue remodeling. In contrast, during CAC progression, dysregulation of epithelial survival pathways, genomic stability, and microenvironmental signaling becomes the dominant determinant of malignant progression. As summarized in Figure 4, many E3 ligases and DUBs exhibit context-dependent and bidirectional roles across epithelial, innate immune, adaptive immune, and tissue-level outcome layers. This stage-resolved perspective provides a conceptual framework for reconciling divergent experimental observations and highlights the importance of disease-stage stratification when interpreting UME function. From a translational standpoint, these findings suggest that therapeutic strategies targeting UMEs may require stage-stratified and context-adapted modulation rather than uniform inhibition or activation. For example, transient suppression of pro-inflammatory UMEs may be beneficial during acute inflammation, whereas preservation of epithelial-protective and stress-adaptive UMEs may be critical during chronic disease maintenance and CAC prevention.

Looking forward, integrating multi-omics profiling, spatial transcriptomics, and single-cell technologies will enable systematic mapping of ubiquitin-regulated cell-fate networks within complex inflammatory microenvironments. Combined with emerging chemical biology approaches, including small-molecule modulators and PROTAC-based strategies, these advances will facilitate mechanistic insight into cell death regulation and stress-responsive adaptation. Together, such efforts are anticipated to provide a robust conceptual framework for prioritizing high-confidence therapeutic targets and advancing precision, mechanism-driven interventions for inflammatory diseases.

Abbreviations

AOM: azoxymethane; ASC: apoptosis-associated speck-like protein containing a CARD; ATP: adenosine triphosphate; CAC: colitis-associated cancer; CD: Crohn's disease; CD4⁺: cluster of differentiation 4-positive; CHOP: C/EBP homologous protein; CLRs: C-type lectin receptors; CRC: colorectal cancer; CRISPR: clustered regularly interspaced short palindromic repeats; DCs: dendritic cells; DSS: dextran sulfate sodium; DUBs: deubiquitinating enzymes; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; EMT: epithelial-mesenchymal transition; ER: endoplasmic reticulum; ERK1/2: extracellular signal-regulated kinase 1/2; GRP78: glucose-regulated protein 78; GWAS: genome-wide association studies; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IGF2BP2: insulin-like growth factor 2 mRNA-binding protein 2; IKKβ: inhibitor of nuclear factor kappa-B kinase subunit beta; IL: interleukin; IRAKs: interleukin-1 receptor-associated kinases; IRF: interferon regulatory factor; JAMM: JAB1/MPN/Mov34 metalloenzyme; JNK: c-Jun N-terminal kinase; KDM5B: lysine demethylase 5B; KEAP1: Kelch-like ECH-associated protein 1; lncRNAs: long non-coding RNAs; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; miRNAs: microRNAs; MJD: Machado-Joseph disease; mRNA: messenger RNA; MyD88: myeloid differentiation primary response 88; ncRNA: non-coding RNA; NF-κB: nuclear factor kappa-B; NLRP3: NOD-like receptor family pyrin domain containing 3; NLRP6: NOD-like receptor family pyrin domain containing 6; NOD2: nucleotide-binding oligomerization domain-containing protein 2; NRF2: nuclear factor erythroid 2-related factor 2; OTU: ovarian tumor; PERK: protein kinase RNA-like endoplasmic reticulum kinase; PINK1: PTEN-induced kinase 1; PPARγ: peroxisome proliferator-activated receptor gamma; PROTAC: proteolysis-targeting chimera; PRRs: pattern recognition receptors; RelA: RELA proto-oncogene, NF-κB subunit; RIP2: receptor-interacting serine/threonine kinase 2; RIPK1: receptor-interacting protein kinase 1; ROS: reactive oxygen species; scRNA-seq: single-cell RNA sequencing; STAT3: signal transducer and activator of transcription 3; TAB: TAK1-binding protein; TAK1: transforming growth factor-beta-activated kinase 1; TGF-β: transforming growth factor-beta; Th1: T helper 1; Th17: T helper 17; TLR4: Toll-like receptor 4; TLRs: Toll-like receptors; TNBS: 2,4,6-trinitrobenzene sulfonic acid; TNF-α: tumor necrosis factor-alpha; TNFR1: tumor necrosis factor receptor 1; TNFRs: tumor necrosis factor receptors; Ub: ubiquitin; UBC9: ubiquitin-conjugating enzyme 9; UC: ulcerative colitis; UCHL5: ubiquitin C-terminal hydrolase L5; UMEs: ubiquitin-modifying enzymes; UPR: unfolded protein response; USP: ubiquitin-specific protease; VDR: vitamin D receptor.

Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (82361138563 to Y.W.), the Innovation Team of Hangzhou City (TD2024002 to Y.W.), and Interdisciplinary Research Project of Hangzhou Normal University (2024JCXK06 to Y.W.).

AI usage statement

During the preparation of this manuscript, the author(s) used ChatGPT solely to improve the clarity and fluency of the English writing. After using this tool, the author(s) carefully reviewed and edited the text as needed and take full responsibility for the content of the manuscript.

Contributions

C.Q., F.N., C.Z., and Y.W. conceived and designed the review. C.Q. and Y.X. drafted the manuscript and prepared the tables and figures. C.Q., B.S., Y.X., and Y.W. participated in the literature search. C.Q., F.N., J.S., B.S., C.Z., and Y.X. contributed to the revision of the manuscript. All authors have read and approved the article.

Competing Interests

The authors have declared that no competing interest exists.

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Corresponding authors: Yi Wang, PhD, Professor, E-mail: yi.wang1122edu.cn; Chenjian Zhou, Email: zhouchenjianedu.cn

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