The Toll-like receptor (TLR) family comprises of more than ten members, among which TLR2 and TLR4 have been most extensively investigated. Members of the TLR family are expressed by a wide range of immune cell types, including dendritic cells (DCs), macrophages, B cells and other innate and adaptive immune cells. TLRs recognize extracellular and endosomal PAMPs, initiating signaling through Toll/IL-1 receptor (TIR) domain-containing adaptor proteins (79). These receptors activate two primary adaptor-dependent signaling cascades: the myeloid differentiation gene response 88 (MyD88)-dependent pathway, utilized by all TLRs except TLR3, and the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway, employed by TLR3 and, through the TRIF-related adaptor molecule (TRAM), by TLR4 (80) (Figure 3). TRIM proteins regulate both the MyD88 and TRIF-dependent signaling branches at many stages, ranging from receptor-proximal adaptor molecules to downstream kinases and transcriptional regulators. They exert TLR signaling outputs through both ubiquitin-dependent and ubiquitin-independent mechanisms, either potentiate or suppress immune activation. These signaling cascades ultimately govern the expression of inflammatory cytokines, chemokines, and type I interferons (IFNs). Understanding the regulatory involvement of TRIM proteins in these pathways is therefore crucial for clarifying the molecular mechanisms that link TLR signaling to trained immunity and immune homeostasis. TLR ligands have been shown to induce long-term functional reprogramming of innate immune cells through metabolic and epigenetic mechanism (81).

The three main members of the RIG-I-like receptor (RLR) family are laboratory of genetics and physiology 2 (LGP2), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) (96). Except for LGP2, RLRs have two N-terminal caspase recruitment domains (CARDs), a C-terminal regulatory domain (RD) and a central DExD/H-box helicase domain. RLRs identify viral RNA molecules by their unique DExD/H-box RNA helicase, thereby triggering antiviral immune responses. Upon recognition and binding of PAMPs, RIG-I and MDA5 change their conformation, exposing their CARD domains and allowing them to engage with the mitochondrial antiviral signaling protein (MAVS). This interaction subsequently triggers downstream activation of the NF-κB and IFN pathway of signaling (97, 98). Although LGP2 lacks CARD domains necessary for direct signaling, it is a positive regulator of antiviral responses mediated by RIG-I and MDA5. LPG2 enhances the sensitivity of RIG-I and MDA5 to viral infection by facilitating viral RNA recognition through its ATPase domain. Both RIG-I and MDA5 are extremely regulated by post-translational changes, ensuring their rapid activation upon viral detection while preventing excessive immune responses (99, 100).

Recent studies have established that TRIM proteins are essential in modulating RLR-dependent antiviral signaling. TRIM25, one of the most well-characterized E3 ubiquitin ligases in this context, promotes RIG-I oligomerization and its interaction with MAVS, leading to efficient downstream signal transduction (50). The ubiquitin-specific peptidase 15 (USP15) enhances TRIM25 stability by inhibiting its K48-associated ubiquitination, thus positively modulating the TRIM25-RIG-I signaling axis (51). Structural analyses of TRIM25 have identified a potential binding pocket within its SPRY domain that mediates interaction with RIG-I. This discovery suggests that small-molecule compounds targeting this domain could serve as therapeutic agents to inhibit aberrant RIG-I activation in autoimmune or hypersensitivity disorders (101).

Other TRIM proteins also contribute to the regulation of RLR signaling. TRIM35 acts as a positive regulator by catalyzing K63-dependent polyubiquitination of TRAF3, which leads to the formation of the TRAF3-MAVS-TBK1 signaling complex and facilitates activation of IRF3/7 (102). Similarly, TRIM14, a mitochondria-associated adaptor, recruits the IKKγ/NEMO adaptor to MAVS, thereby enhancing RIG-I-dependent activation of IRF3 and NF-κB pathways (36). In addition, several other TRIM family members, including TRIM4 (27), TRIM65 (69), TRIM31 (59), TRIM13 (103), and TRIM44 (65), have been reported to regulate RLR signaling through direct ubiquitination of RLRs or MAVS. Depending on the cellular context and target lysine residues, these TRIMs can catalyze activating (K63-linked) or inhibitory (K48-linked) ubiquitin chains. Some also control MAVS turnover or aggregate clearance, influencing the duration and magnitude of interferon responses (see Table 1). Dysregulated TRIM-RLR interactions can modify host susceptibility to RNA viruses and lead to chronic interferonopathies when negative feedback mechanisms fail. Given that RLR signaling is central to antiviral defense, TRIM proteins that potentiate this pathway represent promising candidates for antiviral enhancement, whereas those that suppress it may serve as potential therapeutic targets in interferon-mediated autoimmune diseases.

Cyclic GMP-AMP synthase (cGAS), an enzyme that is triggered by double-stranded DNA and acts as a pattern recognition receptor for aberrant or pathogen-derived DNA in the cytoplasm, is the main detector of cytosolic DNA (104). A conformational shift in cGAS upon attachment to double-stranded DNA catalyzes the synthesis of cyclic GMP-AMP (cGAMP), a secondary messenger. cGAMP subsequently interacts with the stimulator of interferon genes (STING) on the endoplasmic reticulum membrane, triggering STING oligomerization and its translocation to the Golgi apparatus. Activated STING provides a platform for the recruitment of kinases TBK1 and IKKi, which phosphorylate the interferon regulatory factors IRF3 and IRF7. Phosphorylated IRF3/7 dimerize and translocate to the nucleus, initiating transcription of IFN-α/β and interferon-stimulated genes (ISGs), thereby establishing an antiviral state. In parallel, STING activation induces NF-κB-dependent transcription, promoting the production of pro-inflammatory cytokines and coordinating a comprehensive innate immune response (105, 106).

TRIM family proteins serve as critical modulators of the cGAS–STING pathway, providing either positive or negative regulation to maintain immune balance. TRIM56 enhances cGAS activity through monoubiquitination, increasing cGAMP production and promoting downstream STING activation. Both TRIM56 and TRIM32 have been reported to promote K63-linked polyubiquitination of STING in response to cytosolic DNA stimulation, facilitating antiviral signaling. However, more recent studies suggest that instead of directly ubiquitinating STING, these TRIMs may generate unanchored polyubiquitin chains that activate NEMO, which, in cooperation with IKKβ and TBK1, drives IRF3 and NF-κB activation (60, 67, 68). Conversely, TRIM30α (58) and TRIM29 (56) mediate K48-dependent ubiquitination of STING, leading to its proteasomal destruction. The negative regulation of STING-dependent signaling in macrophages and DCs during herpes simplex virus type 1 (HSV-1) infection attenuates the antiviral response. TRIM14 stabilizes cGAS by preventing its K48-linked polyubiquitination and recruiting deubiquitinases such as USP14, thereby sustaining type I IFN signaling and enhancing antiviral innate immunity (37). Similarly, TRIM38 also displays context-dependent regulatory role and negatively regulates TLR and RIG-I-like receptor pathways (61). Under basal conditions, TRIM38 stabilizes these signaling by promoting SUMOylation of cGAS, protecting it from ubiquitination and degradation, which preserves both cGAS and STING function (63) (Table 1). TRIM proteins act as crucial checkpoints in the cGAS-STING pathway. Their dual regulatory roles underscore their significance in innate immune homeostasis and highlight their potential as therapeutic targets in immune-mediated diseases.

These highlight context-dependent regulation as a fundamental property of TRIM proteins. Table 1 also summarizes and highlights the TRIMs context-dependent regulatory role in the immune system. Individual TRIMs can function as signal amplifiers or terminators depending on the receptor engaged, ubiquitin linkage type, cellular compartment and stage of immune activation. This duality enables fine-tuned immune control but also represents a major challenge for therapeutic targeting, as indiscriminate inhibition or activation may disrupt immune homeostasis.

Although TRIM proteins are extensively characterized for their roles in innate immune regulation, they also exert critical and multifaceted functions in adaptive immunity, particularly in the activation of T-cells, their differentiation, and maintaining the state of tolerance. Through ubiquitination-dependent mechanisms, TRIMs regulate essential signaling intermediates, transcriptional regulators, and receptor complexes, establishing a balanced immune activation while preventing autoimmunity. Compared with innate immunity, mechanistic studies of TRIM proteins in adaptive immune cells remain limited, and most available evidence is derived from a small number of well-characterized TRIM family members.

Several TRIM family members act as E3 ubiquitin ligases that conjugate distinct ubiquitin chain linkages. K63-linked chains promote signaling complex formation and K48-linked chains mediate proteasomal degradation at early steps of T-cell receptor (TCR) signaling. Certain TRIMs stabilize TCR complexes by interacting with the TCR ζ-chain, enhancing receptor surface expression and calcium mobilization, thereby enhancing T-cell activation (107). Upon TCR engagement, kinases such as Lck (Src-family) and ZAP-70 (Syk-family) are activated, triggering downstream pathways including PI3K–Akt, MAPK, NF-κB, and AP-1, which collectively promote IL-2 transcription, T-cell proliferation, and survival (107–109). TRIM proteins also play key roles in T-cell lineage differentiation, influencing the balance between effector subsets such as Th2 cells and regulatory T cells (Tregs). Certain TRIMs promote Th2 differentiation associated with allergic inflammation, whereas others negatively regulate Th2-driven immune responses (110). Conversely, specific TRIMs can suppress Treg differentiation in CD4⁺ T cells, thereby predisposing to autoimmune disease development (111). Beyond activation and differentiation, TRIMs modulate peripheral T-cell tolerance by regulating activation thresholds, managing effector functions, and preventing intense proliferation (112).

TRIM27 acts as a negative modulator of TCR signaling by mediating ubiquitin-dependent degradation of proximal signaling molecules and limiting PI3K/Ca²⁺ flux, thereby suppressing CD4⁺ T-cell proliferation and cytokine release (113). TRIM21 (also known as Ro52) is a well-studied TRIM that is involved in innate as well as adaptive immunity, and functions as a modulator of the IL-23/Th17 axis negatively (114). TRIM21 has a role in T-cell activation since the overexpression of TRIM21 in Jurkat cells increases IL-2 synthesis after CD28 stimulation, while TRIM21 knockdown in Jurkat cells show decreased IL-2 induction (115). TRIM21 deficiency in mice results in excessive proliferation of T-cells and increased secretion of inflammatory cytokines such as IL-6 and IL-17, summarizing features of systemic lupus erythematosus through the IL-23-Th17 pathways (116). Mechanistically, TRIM21 may influence the IRF4/IRF5 axis, thereby promoting differentiation of antibody-secreting plasma cells (117).

TRIM30α negatively regulates T-cell signaling by promoting lysosomal degradation of TAK1-binding protein 2 (TAB2) and TAB3, leading to inhibition of the TAK1–NF-κB axis and reduced T-cell activation (57). In mice, TRIM30 deficiency alters CD4/CD8 T-cell ratios, enhances T-cell proliferation in some settings, but can diminish IL-2 production by downstream NF-κB, suggesting a context-dependent role in maintaining homeostatic activation thresholds (118). In contrast, TRIM28 functions as a positive modulator of CD8⁺ T-cell activation through epigenetic mechanisms. It orchestrates chromatin remodeling and three-dimensional chromatin looping at crucial activation-associated genes, such as Ifng, Gzmb, Tbx21, and IL2, thereby promoting transcriptional activation during cytotoxic responses (119). TRIM28 also regulates T helper 17 (Th17) and Treg differentiation, influencing the balance between immune tolerance and autoimmunity (120). In human T cells, TRIM28 interacts with Foxp3 through the TRIM28–FIK–Foxp3 complex, which is essential for the suppressive function of Tregs. Disruption of this complex revokes Treg suppressive capacity and leads to dysregulated Foxp3 target gene expression, a mechanism implicated in autoimmune pathogenesis (121).

In signal transducer and activator of transcription 1 (STAT1) signaling, TRIM24 acts as a negative regulator. It interacts with nuclear receptors, including retinoic acid and estrogen receptors, along with chromatin-associated factors, thereby inhibiting STAT1-mediated transcriptional activity (122). TRIM24 expression is elevated in Th2 cells, where it contributes to allergic asthma pathogenesis by dampening IL-1-induced gene expression and mitigating IL-1β-driven bronchial inflammation (123). Furthermore, TRIM32 deficiency enhances Th2 cell differentiation and cytokine production, exacerbating atopic dermatitis, suggesting that TRIM32 functions as a negative regulator of Th2-mediated allergic responses (124).

TRIM proteins function predominantly as E3 ubiquitin ligases or scaffold adaptors, modulating B-cell responses at multiple levels. They influence B-cell receptor (BCR) and TLR signaling intermediates through K63 or K48-linked ubiquitination, either enhancing or terminating downstream signaling. Additionally, TRIMs recruit deubiquitinases or autophagy receptors to stabilize or remove signaling complexes and regulate chromatin accessibility and transcription factor activity, establishing long-term functional programs in B cells (73). Through these mechanisms, TRIM proteins exert broad control over adaptive immunity, modification B-cell activation, antigen processing, nucleic acid sensing, and transcriptional programs that dictate activation thresholds, class-switch recombination, and immune tolerance. Beyond direct B-cell effects, TRIMs also modulate T-cell functions and differentiation, contributing to the overall regulation of immune homeostasis, as discussed in the previous section.

Abnormal B-cell differentiation or apoptosis can lead to autoimmune disorders. For example, in a recent study, Trim21 deletion enhances B-cell proliferation and production of antibodies, primarily due to defects in B-cell rather than effects caused by T cells or DCs. TRIM21 is also a known autoantigen that binds anti-SS-A antibodies, commonly identified in the sera of individuals with autoimmune disorders (46, 117). TRIM proteins further regulate B-cell function via the noncanonical NF-κB pathway. TRIM55 mediates the ubiquitination of p100, facilitating its processing into the transcription factor p52. In mice with B-cell specific loss of Trim55, germinal center development and antibody synthesis were markedly reduced, suggesting TRIM55 is a possible therapeutic target in autoimmune disorders (125).

TRIM33 is another key regulator that governs the homeostasis and function of multiple immune cell types, including DCs, which serve as sentinels of the immune system (126). It is found in Trim33^fl/fl Cre-ER^T2 mice that TRIM33 deletion impaired DCs differentiation from hematopoietic progenitors across developmental stages. This deficiency also downregulated essential genes such as Irf8 and Bcl2l11 for DCs differentiation, maintenance and survival. TRIM33 thereby highlights its role as a critical regulator of both innate and adaptive immunity (127). Available evidence from mechanistic studies in adaptive immunity is limited but indicates that TRIM proteins regulate B-cell biology, shape humoral immunity, maintain immune tolerance, and influence autoimmune disease susceptibility.

A classic autoimmune disease, systemic lupus erythematosus (SLE) is characterized by the generation of autoantibodies, dysregulated type I IFN signaling, and multi-organ involvement. A hallmark of SLE is the presence of elevated autoantibodies against TRIM21 (Ro52), which can impair its E3 ligase activity. Another characteristic is the disruption of the negative mediation of type I IFN signaling, and alters the differentiation of B-cell. This contributes to a self-amplifying inflammatory loop that exacerbates disease activity (128). TRIM21 mediates ubiquitination and proteasomal degradation of critical substrates, including STING, thereby restricting type I IFN production. In Trim21 deficient mice, lupus-like pathology emerges, characterized by expansion of Th17 cells and elevated anti-double-stranded DNA antibodies (129).

Furthermore, TRIM5 has been associated with SLE pathogenesis. In peripheral blood mononuclear cells (PBMCs) from individuals with SLE, it is strongly expressed and correlates with the expression of antiviral genes. Elevated TRIM5 levels are associated with reduced naive CD4⁺ T cells and an increased proportion of M2 macrophages, which modulate immune responses in SLE. TRIM5 can inadvertently activate innate pathways of NF-κB and type I IFN production, thereby amplifying inflammatory responses and contributing to disease progression (130). Inhibition of IFN has become a new treatment for SLE patients and these observations position TRIM21 and TRIM5 as potential therapeutic targets to restore immune homeostasis and limit tissue damage in SLE.

Sjögren’s syndrome (SS) is an autoimmune disease that mostly affects exocrine glands, especially the salivary and lacrimal glands. It causes lymphocytic infiltration and glandular dysfunction. TRIM21/Ro52 and corresponding autoantibodies (anti-TRIM21/Ro52) are well-recognized autoantigens in SS and other autoimmune diseases, including SLE (131). Detection of anti-TRIM21 antibodies is a key diagnostic marker for SS.

Under physiological conditions, TRIM21 inhibits type I IFN signaling by ubiquitin-mediated degradation of IRF3/5. In SS patients, PBMC analyses reveal elevated TRIM21 transcript levels, coupled with persistently high IRF3 and IRF5 protein expression. TRIM21/Ro52 transcription is upregulated by IRF1/2 and suppressed by IRF4/8, consistent with its overexpression in SS. Autoantibodies against TRIM21 impair its ability to degrade IRFs, resulting in dysregulated IFN production and elevated pro-inflammatory cytokines, subsequently high TRIM21/Ro52 expression (132, 133). In vitro studies demonstrate that anti-TRIM21 antibodies can sterically hinder the interaction between TRIM21 and its E2 ubiquitin-conjugating enzyme, hence preventing normal autoubiquitination and degradation of substrates (128). This dysregulation amplifies autoimmunity in SS and highlights it as a potential therapeutic target by either restoring TRIM21 function or alleviating the effects of anti-TRIM21 antibodies.

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is defined by chronic relapsing intestinal inflammation, impaired epithelial barrier function, dysregulated immune responses, and genetic predisposition. TRIM proteins contribute to both susceptibility and progression of IBD through their modulation of immunological signaling and maintenance of gut homeostasis.

One prominent TRIM member associated with the susceptibility of IBD is TRIM20, which is encoded by the MEFV gene (134). TRIM21 suppresses pro-inflammatory cytokines in the gut and inhibits differentiation of CD4⁺ T cells into Th1 and Th17 inflammatory subsets (135). TRIM22 has been identified as a signaling modulator of nucleotide-binding oligomerization domain containing 2 (NOD2), essential for microbial recognition and inflammatory responses. Variants in the SPRY domain of TRIM22 impair its K63-linked ubiquitination of NOD2, consequently weakening NOD2-dependent muramyl dipeptide (MDP) signaling and promoting Crohn’s disease-associated inflammation (136).

TRIM27 increases gut inflammation by promoting the STAT3 and JAK1 interaction, leading to the activation of STAT3 and the amplification of pro-inflammatory signaling in the colon. Knockout studies in mice demonstrate resistance to dextran sulfate sodium (DSS)-induced colitis, supporting the pro-inflammatory role of TRIM27 protein (137). TRIM27 also stabilizes β-catenin, thereby activating Wnt/β-catenin signaling to promote the self-renewal of intestinal stem cells. Knockout of Trim27 impairs organoid formation, a process that can be restored by reintroducing either TRIM27 or β-catenin. This underscores the therapeutic potential of addressing the TRIM27/Wnt/β-catenin pathway in IBD (138). TRIM31 regulates intestinal inflammation by promoting ubiquitination and proteasomal degradation of NLRP3, a critical component of the inflammasome that facilitates IL-1β secretion. By attenuating inflammasome activity, TRIM31 protects against excessive intestinal inflammation (139). Dysregulated TRIM activity in the gut compromises barrier integrity, alters T-cell differentiation, and disrupts the balance between pro-inflammatory and regulatory T-cell subsets, which further drives the inflammatory cascade associated with IBD.

Familial Mediterranean fever (FMF) is an autoinflammatory condition marked by repeated episodes of fever, serositis, and systemic inflammation. This disorder is primarily caused by changes in the MEFV gene, which makes the TRIM20 (pyrin). These mutations disrupt TRIM20-mediated ubiquitination and the regulated degradation of inflammatory mediators, resulting in persistent activation of inflammatory-related pathways and increased release of IL-1β, a central hallmark of FMF pathogenesis (140). The sustained IL-1β signaling drives systemic inflammatory responses and, in some cases, contributes to intestinal inflammation resembling IBD.

Psoriasis is a persistent inflammatory dermatological condition marked by keratinocyte proliferation, aberrant immune activation, and the formation of scaly skin plaques. Multiple TRIM proteins play essential roles in modulating inflammatory responses within keratinocytes.

Increased expression of TRIM21 has been noted in psoriatic epidermal cells, and its suppression in human keratinocytes significantly reduces the synthesis of inflammatory cytokines and chemokines (141). The E2 ubiquitin-conjugating enzyme UBE2L3 regulates TRIM21 activity, and its overexpression decreases STAT3 pathway activation and IL-1β levels. In a mouse model of psoriasis induced by imiquimod (IMQ), reduced UBE2L3 expression was associated with caspase-1 activation in the epidermis. Overexpression of UBE2L3, in turn improved psoriasis-like lesions and reduced levels of both pro-IL-1β and mature IL-1β (142). Similarly, silencing of TRIM21 decreased the release of TNF-α, IL-6, and IL-1β in cells stimulated by LPS (143). Furthermore, TRIM33 is markedly upregulated in psoriatic lesions and acts as a positive modulator of inflammation in keratinocytes. TRIM33 promotes the ubiquitination of Annexin A2 (Anxa2), hence promoting its interaction with NF-κB subunits p50 and p65, which enhances transcription of downstream pro-inflammatory genes such as IL-6, IL-1β, and NLRP3 (144). The elevated epidermal expression of TRIM33 in psoriasis underscores its contribution to disease pathology, emphasizing the therapeutic potential of targeting TRIM-mediated signaling pathways to mitigate psoriatic inflammation.

Type 1 diabetes (T1D) is an autoimmune disorder in which the immune system destroys pancreatic β-cells. Both genetic and functional evidence suggest that TRIM27 mutations correlate with increased susceptibility to T1D. TRIM27 exerts a protective role in pancreatic tissue by suppressing TNF-α-induced β-cell death. In Trim27-deficient mice, exposure to streptozotocin (STZ) induces severe diabetes, reflecting enhanced β-cell apoptosis. Mechanistically, TRIM27 regulates the deubiquitination of receptor-interacting protein 1 (RIP1), preventing caspase-3 activation and β-cell apoptosis (Table 2). Loss of TRIM27 leads to decreased β-cell mass and an increase of cytokines such as IFN-γ and IL-1β (153). TRIM72 is known as Mitsugumin 53 (MG53), functions as an E3 ligase that modulates insulin signaling and membrane repair in β-cells. Dysregulation of TRIM72 leads to insulin resistance and β-cell dysfunction through ubiquitin-mediated degradation of the insulin receptor and insulin receptor substrate-1 (IRS-1), thereby disrupting glucose and lipid metabolism (154, 155). Further functions of the TRIM72 protein in insulin signaling and its potential as a therapeutic target in human insulin resistance and type 1 diabetes require more research.

It is a chronic inflammatory disorder of the central nervous system (CNS) characterized by demyelination, neuroinflammation, and persistent neurological impairment (156). In an experimental autoimmune encephalomyelitis (EAE) model, TRIM21 was found to interact with pyruvate kinase M2 (PKM2), facilitating its nuclear translocation and promoting phosphorylation of STAT3 and NF-κB, as well as interaction with c-Myc. This process enhances astrocyte glycolysis and proliferation, contributing to neuroinflammation in multiple sclerosis (MS) (150). Targeting the TRIM2-PKM2 axis may provide a promising therapeutic approach for MS. Additionally, mutations in TRIM32 have been associated with neuronal damage and demyelination, as reported in a clinical case by Marchuk et al. (2021) (151). Human endogenous retroviruses (HERVs) have been implicated in the pathogenesis of MS by triggering immune and inflammatory responses and disrupting neuronal signaling (157, 158). TRIM proteins such as TRIM5α and TRIM22 regulate antiviral immunity by recognizing retroviral capsids and shaping immune responses to HERVs. Aberrant activation of these pathways can lead to sustained type I IFN and NF-κB signaling and promote the activation of autoreactive T and B cells. This process linking antiviral immune dysregulation drives loss of self-tolerance and contributes to demyelination and neurodegeneration. Aberrant regulation of these TRIM proteins may contribute to immune activation and disease progression in MS (158).

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that primarily affects synovial joints, leading to persistent inflammation, synovial hyperplasia, and cartilage destruction. Fibroblast-like synoviocytes (FLS) play a crucial role in the pathogenesis of RA by promoting the production of TNF-α and IL-1β, thereby propagating inflammation (159).

The TRIM38-NLRP6 axis (nucleotide oligomerization domain-like receptor family pyrin domain containing 6) has been found to negatively affect the canonical NF-κB pathway in RA-FLS through an inflammasome-independent mechanism. TRIM38 interacts with NLRP6 and TAB2/3, inducing their lysosome-dependent degradation. This inhibits NF-κB activation and decreases cytokine production in FLS (146). A recent study has also linked ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, to the pathogenesis of RA. Inducing ferroptosis in RA-FLS can alleviate disease progression (160).TRIM16 expression is downregulated in RA, while its overexpression suppresses disease severity in mouse models. TRIM16 promotes the ubiquitination and degradation of the transcription factor Snail family zinc finger 1 (Snai1), which normally inhibits ferroptosis. The TRIM16-Snai1 axis enhances ferroptosis and exerts anti-inflammatory effects by counteracting TNF-α, identifying a novel immunoregulatory mechanism and therapeutic target to control prognosis in RA (161).

Additionally, TRIM3 has been shown to suppress FLS proliferation and reduce inflammatory cytokine secretion via the p38 MAPK signaling pathway. Low TRIM3 expression is observed in RA synovial tissue relative to healthy controls, while its overexpression increases p53 and p21expression, leading to cell cycle arrest and decreased production of TNF-α and IL-6 (147). TRIM33 is also downregulated in RA synovial fibroblasts (RASFs). KLF9 is a transcription factor related to proliferation, apoptosis and is widely involved in B and T-cell differentiation. The transcription factor KLF9 positively modulates the expression of TRIM33, which in turn suppresses TNF-α-induced proliferation of RASF and the release of inflammatory cytokines such as IL-1β, IL-6, IL-8. Activation of the KLF9-TRIM33 axis thus restrains abnormal fibroblast proliferation and inflammatory responses, highlighting its potential as a therapeutic target that can intervene and reverse RA progression (149).

TRIM proteins contain diverse functional domains that enable them to regulate multiple cellular processes, with the RING domain serving as a key determinant of E3 ubiquitin ligase activity. Although ubiquitination represents a central mechanism of action, several TRIM family members also exert ubiquitin-independent functions (15). Effective therapeutic targeting cannot rely solely on direct inhibition of catalytic activity. Instead, successful modulation of TRIM proteins requires a detailed understanding of their multi-domain architecture and adapter-like properties to achieve selective and context-appropriate intervention. These features highlight the need for alternative therapeutic strategies that extend beyond catalytic inhibition, including targeted protein degradation and domain-selective modulation.

Therapeutic modulation of TRIM proteins can be broadly divided into direct and indirect approaches. Direct strategies aim to alter the catalytic or scaffolding functions of TRIM by targeting its RING-type E3 ubiquitin ligase domain or substrate-binding (PRY/SPRY) domains (162, 163). The shallow and extended protein-protein interaction (PPI) interfaces of TRIMs complicate conventional small-molecule inhibition. Recent structure-guided designs and fragment-based screening methods have begun to identify druggable allosteric sites. Complementary indirect strategies exploit the broader ubiquitin-proteasome and deubiquitinase networks that regulate TRIM turnover or substrate fate. Inhibitors of deubiquitinases and E2-E3 interface modulators can fine-tune TRIM activity without directly blocking the ligase function (Figure 4) (164, 165).

Proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs) are being developed to selectively degrade or stabilize pathogenic TRIM variants. These approaches offer a precision strategy for autoimmune and interferon-driven diseases (166–168). Parallel research efforts also focus on targeting downstream pathways influenced by TRIM proteins, such as cGAS-STING, NF-κB, or TBK1-IRF3. Small-molecule agonists or antagonists may restore balance in dysregulated immune signaling (169, 170). Although no therapeutic drugs currently exist that directly target TRIM proteins at the experimental or clinical stage, their extensive involvement in immunological regulation makes them promising candidates for future drug development. These emerging pharmacological frameworks enable pathway-specific modulation of immune responses and position TRIM proteins as tractable nodes within the ubiquitin landscape, despite historical challenges in targeting E3 ligases.

TRIM proteins are increasingly recognized as diagnostic and prognostic biomarkers across autoimmune-related diseases. Among them, anti-Ro52/TRIM21 autoantibodies are well-established serological markers in systemic autoimmune disorders such as SLE and Sjögren’s syndrome. Their expression levels are correlated with disease severity, IFN signatures, and distinct clinical phenotypes (171, 172). The structural domains of TRIM proteins, such as the C-terminal substrate-binding domains (PRY/SPRY, PHD-BRD, NHL), are essential for their molecular interactions or functions and may be exploited for diagnostic targeting (166, 173, 174).

Beyond autoantibodies, altered transcriptional and protein expression of several TRIMs, including TRIM19, TRIM21, TRIM24, TRIM28, and TRIM33, has been associated with disease progression, treatment response, and oncogenic transformation. This demonstrates their effectiveness as molecular classifiers and outcome predictors. The integration of quantitative TRIMs expression assays with high-throughput genomic and proteomic platforms facilitates patient stratification based on immune activation states or TRIMs pathway activity, aiding personalized therapeutic decisions (175–177). Despite their potential, the clinical translation of TRIM proteins as biomarkers remains in its early stages. Large multicenter validation studies are still required to confirm their diagnostic and prognostic significance and to establish standardized assay thresholds for routine clinical use.

Recent advancements in gene and protein-level modulation technologies have opened new therapeutic avenues for targeting TRIM proteins. Gene therapy approaches such as RNA interference (RNAi), antisense oligonucleotides (ASOs), and CRISPR-based regulation offer the potential to silence pathogenic TRIM isoforms or restore deficient TRIM expression in a cell type-specific manner, thereby reestablishing immune homeostasis. In parallel, strategically designed small molecules that modulate TRIM E3 ligase or substrate-binding activities are being complemented by breakthroughs in targeted protein degradation technologies, particularly PROTACs and MGs (178–181). These strategies utilize the cellular ubiquitin system to selectively degrade aberrant TRIMs or their downstream effectors. Proof-of-concept studies, such as TRIM24-directed PROTACs, have shown tumor suppression in preclinical cancer models, validating the feasibility of pharmacologically manipulating TRIM protein stability (182). PROTAC technologies can be designed to engage different E3 ligases, enabling the selective degradation of disease-associated or “undruggable” proteins (183, 184). The integration of gene editing, chemical biology, and proteomics-guided screening is producing a comprehensive therapeutic toolkit for modulating TRIM protein activity in immune-related diseases. Delivery specificity and off-target effects continue to pose substantial translational challenges.

A major translational barrier in targeting TRIM proteins is their high structural conservation, particularly within the RING domain, which complicates selective inhibition and increases the risk of off-target effects across the TRIM family. Many TRIMs share identical catalytic architectures, making it difficult to achieve specificity using conventional small-molecule inhibitors. In addition, TRIM proteins often exhibit stimulus and cell-type-specific dual functions, acting as either pro-positive or anti-negative regulators of immune signaling. This context-dependent functional plasticity raises the risk that indiscriminate inhibition may disrupt immune homeostasis and exacerbate disease.

Despite encouraging progress, various challenges persist in obstructing the translation of TRIM-targeted therapeutics. Many TRIM proteins do not possess clearly defined ligandable sites, and their complex protein-protein interaction interfaces complicate pharmacological targeting. Their opposing functions in distinct cellular contexts further complicate therapeutic intervention, as targeting a TRIM protein may yield opposing outcomes depending on disease stage, tissue, or immune context. Emerging strategies such as PROTACs and MGs offer opportunities to overcome these challenges by enabling domain-specific targeting and conditional degradation of pathogenic TRIM activities while preserving physiological functions.In this context, PROTAC-based strategies may offer a route to enhanced selectivity by exploiting tissue-based E3 ligase recruiters, engaging TRIM-specific ligandable features outside the highly conserved RING domain, and limiting systemic exposure through localized or targeted delivery approaches such as nanoparticle formulations.

Specificity and safety remain major concerns, as systemic modulation of ubiquitin signaling could interfere with proteostasis and trigger unintended immune responses. Pharmacokinetic and delivery issues, including the stability and bioavailability of PROTACs or small-molecule inhibitors, also present key challenges for in vivo applications. Furthermore, species-specific differences in TRIM repertoires and incomplete validation of long-term safety hinder the extrapolation of preclinical findings to humans (22, 185, 186). The lack of selective chemical probes, ligand maps, and validated E3 ligase recruiters further limits experimental precision.

Robust biomarker qualification and patient stratification frameworks are essential for identifying individuals who may benefit from TRIM protein activation versus inhibition strategies. Addressing these gaps through integrated efforts in structural biology, probe development, and translational immunology will be essential to fully realize the therapeutic potential of TRIM proteins in autoimmune and immune-mediated disorders.