1 Introduction
1.1 Discovery and Member Overview
Microphthalmia/transcription factor E (MiT/TFE) and the Upstream stimulating factors (USFs) subfamily both belong to the basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor superfamily. Their discovery originated from research on bHLH-LZ protein structures; although they belong to the same superfamily, they exhibit significant differences in member composition and structural characteristics.
MiT/TFE was initially named the MiT (Microphthalmia-TFE) subfamily, a designation closely linked to its core member, the Microphthalmia-associated transcription factor (MITF). MITF was first identified in mice and named for the "microphthalmia" phenotype resulting from its mutation.
[1]This phenotype is closely associated with defects in eye and pigment cell development, establishing MITF's status as a key regulator of the pigment cell lineage.
[2]With ongoing research, other family members such as Transcription Factor E3 (TFE3), Transcription Factor EB (TFEB), and Transcription Factor EC (TFEC) were successively identified and classified into the same subfamily based on structural and functional similarities. Among these, TFE3 was first recognized and named during studies on the regulation of the μE3 site of the human immunoglobulin heavy chain enhancer (IgH enhancer).
[3-4]TFEB and TFEC were named based on their sequence homology with TFE3 and their positioning within the gene family.
[5-6].
Studies confirm that the four members of the MiT/TFE family share a highly conserved bHLH-LZ domain (
Figure 1), capable of forming only homo- or heterodimers within the family, without cross-interaction with other bHLH-LZ family members; this characteristic establishes their classification as an independent subfamily
[1,7]. This family is highly conserved evolutionarily; core members MITF, TFEB, TFE3, and TFEC are stably present in vertebrates, and functional homologs also exist in lower organisms (such as HLH-30 in nematodes and Mitf in fruit flies)
[8-9]. The gene localization and isoform characteristics of human MiT/TFE family members exhibit distinct specificity: the MITF gene is located at 3p14.1 and has more than 10 alternative splicing isoforms, with different isoforms being specifically expressed in different cells such as melanocytes and monocytes
[10-11]; TFEB (6p12.1), TFE3 (Xp11.23), and TFEC (7q33) have relatively fewer isoforms. Notably, due to the natural absence of a transcriptional activation domain, TFEC is the sole transcriptional repressor in the family; its function primarily involves competitively binding DNA or forming heterodimers with activator members, thereby antagonizing the transcriptional activity of other members
[7].
Unlike the discovery path of the MiT/TFE family, research on the USF subfamily began with explorations related to the adenovirus major late (AdML) promoter. The Sawadogo team
[12-13]identified a nuclear protein capable of binding to the "GGCCACGTGACC" sequence upstream of the promoter and named it "Upstream Stimulatory Factor (USF)." In 1990, Gregor et al.
[14]confirmed that USF belongs to the c-Myc-related DNA-binding protein family by isolating the full-length cDNA encoding the human USF protein; its structure contains an HLH motif and LZ repeat sequences located at the C-terminus, enabling DNA binding in dimeric form. Subsequently, Henrion et al.
[15]further distinguished USF1 and USF2 as two independent and highly homologous gene members through mouse genomic clone analysis.
Studies have found that USF1 and USF2 not only share the bHLH-LZ domain, but also possess a unique "USF-specific region (USR)" at their N-termini (
Figure 1), a structural feature that distinguishes them from other bHLH-LZ family members and serves as the key basis for their classification as an independent subfamily
[16-18]. This family exhibits extremely high cross-species conservation; the amino acid sequences of its core members, USF1 (1q22-23) and USF2 (19q13.1), show over 99% homology among humans, mice, and rats
[15,19-21]. Unlike the tissue-specific expression of the MiT/TFE family, the USFs subfamily lacks tissue-specific isoforms; its members are widely expressed in various tissues and organs of the body, participating in the regulation of basic physiological processes
[19,22].
1.2 Overview of Physiological Functions and Pathological Significance
Based on their unique structural features, the MiT/TFE and USFs subfamilies play distinct regulatory roles in cellular physiological processes. Abnormalities in the functions of both can trigger a series of pathological changes, making them important driving factors in disease onset and progression.
The MiT/TFE subfamily serves as a key regulatory hub for cellular metabolism and stress response, primarily functioning through the autophagy-lysosome pathway. Among them, activating members such as MITF, TFEB, and TFE3 can bind to the Coordinated Lysosomal Expression and Regulation (CLEAR) elements in target gene promoters, upregulating the expression of hundreds of downstream genes, regulating autophagosome formation, fusion with lysosomes, and substrate degradation. Their target genes include lysosomal hydrolases (e.g., CTSA, HEXA) and autophagy-related proteins (e.g., LC3B, P62). This regulatory mechanism is highly conserved evolutionarily and represents a critical pathway for maintaining cellular homeostasis.
[8,23-24].
In addition, members of the MiT/TFE family each possess tissue-specific functions: MITF governs melanocyte differentiation, activates pigment synthesis genes, and simultaneously regulates mast cell and osteoclast development
[25-27]; TFEB is responsible for maintaining metabolic homeostasis, promoting mitochondrial biogenesis and fatty acid oxidation, and mediating organ responses to nutritional stress
[28-29]; TFE3 combines immune and metabolic regulation, participating in antibody production, allergic reactions, and glucose metabolism control
[30-33]; TFEC, as an inhibitory member, maintains familial regulatory balance by competitively binding or forming heterodimers to antagonize activating members
[34-35].
Unlike the stress response functions of the MiT/TFE family, the USF subfamily enhances transcriptional efficiency through general transcriptional regulation and DNA looping, serving as a key hub for transcription initiation control and multi-system physiological homeostasis. USF1 and USF2 form homodimers or heterodimers that bind to E-box elements (CANNTG) and recruit transcriptional co-factors and histone-modifying enzymes, constructing a scaffold for RNA polymerase II binding to the promoter.
[36-39]Meanwhile, dimers of this family can further assemble into tetramers via the LZ-Ext domain, binding to two E-box sites to mediate DNA looping, thereby bringing promoters and enhancers closer together and significantly enhancing the transcriptional efficiency of target genes.
[40]Studies have shown that the USF subfamily plays a critical role in various physiological processes such as metabolism
[41-43], development
[37,44], stress response
[45-46], cell cycle
[47-48], and many other physiological processes.
The MiT/TFE and USF subfamilies play important roles in physiological and pathological processes. Their functional abnormalities are closely associated with various diseases, including cancer, metabolic disorders, and immune dysregulation, holding significant value for clinical research. Members of these two subfamilies influence cell fate and disease progression by regulating processes such as autophagy, lysosome biogenesis, metabolic balance, and immune responses, thereby providing potential targets for the treatment of related diseases.
In the field of cancer, dysregulation of the MiT/TFE and USF subfamilies is closely associated with the occurrence and development of various tumors. For example, mutations in MITF are closely linked to the development of melanoma, renal cancer, and sarcoma, while abnormal activation of TFE3 and TFEB in certain cancers
[49]. Studies indicate that approximately 20% of melanomas exhibit MITF gene amplification
[50-51]; TFE3/TFEB gene fusions (such as ASPL-TFE3 and MALAT1-TFEB) can drive the occurrence of renal cell carcinoma (tRCC) and alveolar soft part sarcoma (ASPS), with mechanisms involving enhanced autophagy and promoted metabolic reprogramming to adapt to harsh microenvironments
[52-56]. Regarding the USF family, high expression of USF2 is associated with breast cancer tumor growth
[57]and pancreatic cancer tumor cell survival
[58]; in chronic lymphocytic leukemia (CLL), knocking down USF2 can significantly inhibit disease progression
[59]. Furthermore, knocking down USF1 can inhibit MDA-MB-231 cell proliferation and reduce breast cancer tumor volume, whereas high expression of USF1 promotes tumor progression in hepatocellular carcinoma as well as cell proliferation, migration, and invasion in lung adenocarcinoma
[60-61].
In terms of metabolic diseases, members of both subfamilies have been confirmed to participate in regulating glucose and lipid metabolism; their functional abnormalities may lead to metabolic disorders such as insulin resistance and obesity. For example, functional abnormalities of MITF in macrophages can exacerbate chronic inflammation, thereby promoting the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
[62]. USF1 mutations are closely associated with familial combined hyperlipidemia (FCHL), which can lead to abnormal expression of hepatic lipid metabolism genes (such as APOC3), triggering hypercholesterolemia and hypertriglyceridemia.
[63-64]. USF2 participates in regulating the expression of apolipoprotein A5 (APOA5) and synergistically activates the APOA5 promoter with the thyroid hormone receptor beta (TRβ), affecting triglyceride metabolism; its functional abnormalities are associated with thyroid dysfunction and hypertriglyceridemia.
[65].
Furthermore, the role of the MiT/TFE subfamily in immune regulation and neurodegenerative diseases, as well as the role of the USFs subfamily in growth and development, has also attracted significant attention. In autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), abnormal expression of MITF and TFEB may lead to excessive activation of immune cells, promoting the release of inflammatory factors
[62,66-69]. In models of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, TFEB overexpression can enhance lysosomal degradation capacity, reduce toxic protein aggregation, and delay disease progression
[49,70-72]. In the field of development, homozygous mutations in USF2 combined with heterozygous or homozygous mutations in USF1 lead to embryonic lethality in mice
[73]; abnormal expression of USF1 is associated with progressive decline in sperm function and testicular atrophy
[74-75].
In summary, the MiT/TFE and USF subfamilies exhibit multiple physiological and pathological functions in cancer, metabolic diseases, and immune regulation, with their dysregulation closely linked to the mechanisms underlying various diseases. Although both belong to the bHLH-LZ superfamily, they have evolved distinct functional specialization patterns, and their potential as therapeutic targets is garnering increasing attention. Therefore, deeply elucidating the structure and function of the MiT/TFE and USF subfamilies, and clarifying their roles in disease initiation and progression, is of critical importance for developing novel therapeutic strategies. In this article, we will review the structures and spatial conformations of the MiT/TFE and USF subfamilies and discuss their potential as targets for cancer therapy.
2 Structure and Function
MiT/TFE and the USF subfamily both belong to the bHLH-LZ transcription factor superfamily. Their core functional domains are highly conserved, but they have evolved differentiated functional characteristics based on their unique structural modifications. As
Figure 2shows, the core functional domains of both consist of three functionally distinct modules arranged in order: first, the Basic region, which is rich in conserved basic amino acid residues (such as Arg and Lys) and can recognize and bind to E-box DNA (consensus sequence CANNTG); second, the HLH domain (Helix-loop-helix), composed of two α-helices (H1, H2) and a flexible loop connecting them, providing initial structural support for and mediating protein dimerization; third, the LZ domain (Leucine zipper), formed by hydrophobic amino acid residues, represented by leucine, arranged in a "heptad repeat" pattern. Notably, the LZ domain is not only the core domain for protein dimerization or multimerization, but its unique structural features also serve as a key marker distinguishing this subfamily from other bHLH-LZ families (such as the MYC/MAX subfamily).
[40,49,76].
2.1 Structure and Spatial Conformation of MiT/TFE Family Proteins
The MiT/TFE subfamily consists of four core members: MITF, TFEB, TFE3, and TFEC. The composition of their domains and the core features of their spatial conformations can be summarized as "the synergistic integration of a conserved functional core and a highly dynamic dimerization interface," which serves as the structural basis for achieving specific functional regulation. Compared with other bHLH-LZ family members, the hallmark structural feature of the MiT/TFE subfamily is the presence of three consecutive amino acid insertions in the LZ region, such as MITF's
264AKE
266site, TFEB's
295SRE
297, etc. (
Figure 2). This insertion directly disrupts the continuity of the typical "heptad repeat" motif of the bHLH-LZ family, resulting in a helical periodic "off-registered" conformation in the LZ region, which becomes the most significant structural feature distinguishing the MiT/TFE subfamily from other homologous families
[49,77]. Furthermore, surrounding the "three-amino acid" insertion, the MiT/TFE proteins exhibit significant differences in spatial conformation, dimerization specificity, and DNA-binding ability, which will be elaborated in detail below.
The sequence conservation of the core domain of the MiT/TFE subfamily exhibits distinct regional differentiation: the basic region responsible for DNA binding and the HLH region mediating subunit polymerization share over 60% sequence homology, ensuring that family members share the core functional framework of "dimerization-targeted DNA binding"; whereas the sequence conservation of the LZ region is significantly reduced, with homology below 40%
[5,78]. This difference in conservation provides a key structural basis for dimer selectivity among MiT/TFE members, enabling them to form only homodimers (e.g., MITF-MITF, TFEB-TFEB) or heterodimers (e.g., TFEB-TFE3, MITF-TFEC) within the family.
As the sole transcriptional repressor within the MiT/TFE subfamily, TFEC's functional specialization also stems from structural differences in its LZ region. The LZ domain of TFEC lacks key residues associated with transcriptional activation and cannot fold into a stable transcriptionally active conformation. It exerts its repressive function primarily through two mechanisms: first, by competitively binding to E-box elements in the promoter regions of target genes, thereby occupying the DNA binding sites of activating members (such as TFEB and MITF); and second, by forming heterodimers with activating members to disrupt their active conformations, consequently blocking transcriptional activation.
[5,35].
Furthermore, in addition to the core bHLH-LZ domain, the MiT/TFE subfamily provides an additional dimension for functional regulation. The N-terminal regulatory region contains nuclear localization signals (NLS), nuclear export signals (NES), and multiple post-translational modification sites (typically phosphorylation sites S122, S142, and S211 of TFEB), which can dynamically regulate protein nucleocytoplasmic localization and stability through modifications such as phosphorylation and acetylation
[23,79-80]; the C-terminal extension region is unique to MITF, TFEB, and TFE3, where its short unstructured extension sequences interact with co-activators (such as PGC1α) via specific residues, participating in the regulation of transcriptional activation efficiency and expanding the scope of functional regulation of the protein
[11,81].
In terms of spatial conformation, the HLH region of the MiT/TFE subfamily can form a typical four-helix bundle structure through inter-subunit hydrophobic interactions. Helix1 and Helix2 of the two subunits cross-pair, with core hydrophobic residues (such as I224 and L230 in MITF, and I366 and L372 in TFE3) forming a stable hydrophobic core via side-chain stacking, providing structural support for dimer assembly
[82-83]. Influenced by the insertion of three amino acids in the LZ region, its LZ region cannot form a tight parallel coiled-coil conformation, instead exhibiting a "loose and twisted" structural feature. The inherent dynamics of this structure make the LZ region difficult to resolve due to conformational instability, whether in the free state or when bound to DNA. For example, in the complex structures formed by MITF-E-box DNA (PDB: 4ATK) and MITF-M-box DNA (PDB: 4ATI), the LZ region of MITF is completely untraceable; partial conformation of the LZ region can only be resolved with the assistance of the fusion protein Trbp111 (PDB: 7D8T) or in the absence of DNA binding (PDB: 4ATH) (
Figure 3)
[83].
Reported MITF crystal structure data reveal significant conformational heterogeneity in its LZ region: the spatial orientation of the LZ region varies markedly across different crystal forms, with rotation angles exceeding 10°; furthermore, the LZ regions of the two subunits within a single dimer exhibit pronounced asymmetry.
[84]. The LZ regions of family members such as TFEB and TFE3 also possess highly dynamic characteristics; this conformational flexibility directly results in the thermal stability of MiT/TFE dimers being significantly lower than that of other bHLH-LZ family members. Research data indicate that the MITF dimer's
Tm (midpoint temperature of thermal denaturation) value is only 32.3 °C, far lower than the
Tmvalue (~55 °C) of the MAX dimer
[85]. Additionally, the insertion of "three amino acids" in the LZ region creates a steric hindrance effect, further blocking cross-family heterodimerization between MiT/TFE members and non-family bHLH-LZ proteins (such as MYC and MAX), thereby ensuring the specificity of subfamily functional regulation.
[86-89].
After knocking out the 3-amino acid insertion fragment in the LZ region via gene editing, this phenomenon changed significantly, and both the structure and function of MiT/TFE family proteins approached those of the MYC family. The LZ region structure of MITF_Δ3 (PDB: 7EOD) exhibited significant "conservation" characteristics, showing high similarity to the classic bHLH-LZ structure of the MYC family (
Figure 4A). The LZ region without the "3-amino acid" insertion formed a tight parallel coiled-coil conformation; leucine residues restored the "heptad repeat pattern," and stable dimer interfaces were formed between helices through hydrophobic packing, with no obvious kinks or distortions: its conformation was almost identical to the LZ region structure of the MYC-MAX dimer (PDB: 1NKP), and helical symmetry was significantly improved. In contrast, compared to the MYC-MAX dimer (PDB: 1NKP), the LZ region structures of the unedited MITF dimer (PDB: 4ATH), TFEB dimer (PDB: 7Y62), and TFE3 dimer (PDB: 7F09) exhibited obvious distorted deviations (
Figure 4B)
[87].
Meanwhile, after knocking out the insertion fragment, the thermal stability of the dimer is also significantly enhanced, and the thermal denaturation midpoint temperature (
Tm) increases from 32.3 ℃ for MITF to 41.4 ℃ for MITF_Δ3, closer to that of the MAX dimer's
Tm value (~55 ℃). Fluorescence anisotropy experimental data show that the dimerization affinity of MITF_Δ3 (
Kd=1.2 nmol/L) is 24 times that of MITF (
Kd=29.8 nmol/L), indicating a significant improvement in dimer assembly capability
[86]. Furthermore, the HLH region and the LZ region form a continuous symmetric four-helix bundle structure; the spatial orientation difference between the two subunits is less than 2°, the "subunit asymmetry" phenomenon observed in wild-type MITF disappears, and the overall conformation more closely approximates the symmetric structure of the MYC-MAX heterodimer
[87].
Functionally, MITF_Δ3 more closely resembles the "pan-specific" characteristics of the MYC/MAX family, with the functional specialization features of the original MiT/TFE subfamily disappearing: first, it breaks the rule of "self-limiting dimerization" of the MiT/TFE family and can form heterodimers with non-family bHLH-LZ members—such as binding with MAX to form the MITF_Δ3-MAX heterodimer (
Kd=17.3 nmol/L)
[83]; second, the selectivity for dimerization with members within the MiT/TFE family (such as TFEB, TFE3) is reduced, and the efficiency of heterodimer formation increases by 3~5 times
[86]; third, compared to the exclusive binding elements of MiT/TFE (CLEAR elements), the binding energy to MYC/MAX family target sequences (such as the classic E-box CACGTG) is significantly enhanced, with the binding efficiency to the MYC target gene E-box increasing by 2.3 times, indicating a shift of the DNA binding profile towards "pan-specificity"
[1,86-87].
The DNA-binding activity of the MiT/TFE subfamily is strictly dependent on spatial conformation; an intact dimeric conformation is a prerequisite for DNA binding. After family members form dimers, the basic regions of the two subunits are arranged symmetrically and inserted into the major groove of the DNA, recognizing target sequences through specific interactions. This family can not only bind to classic E-box elements (core sequence CANNTG) but also specifically recognize CLEAR elements exclusive to the MiT/TFE subfamily (core sequence GTCACGTGAC). This is specifically manifested by specific interactions between conserved residues in the basic region and DNA, such as R248 of TFEB forming a salt bridge with the DNA phosphate backbone, and E244 directly recognizing specific bases
[1]. In contrast, the isolated basic region, due to conformational instability, cannot achieve stable binding with DNA; it must rely on the dimerization process mediated by the HLH-LZ domain to form a "cooperative binding conformation." Therefore, once the dimer dissociates (e.g., disease-related mutations disrupt the dimer interface, or drug interventions interfere with subunit interactions), the conformation of the basic region rapidly becomes disordered, resulting in a complete loss of DNA-binding capacity
[86].
2.2 Structure and spatial conformation of USF family proteins
Unlike the dynamic dimeric structure of the MiT/TFE family, the core structural feature of the USF subfamily focuses on "LZ region extension and tetramerization capability," which enables it to efficiently mediate basal transcriptional regulation. The USF subfamily includes two major members, USF1 and USF2, whose domain compositions form unique functional modules based on a conserved core.
The basic region and HLH region sequences of USFs share certain homology with the MiT/TFE family, but the LZ region possesses two key specialized features: first, the LZ region is longer, containing 6–7 heptad repeat units, whereas conventional transcription factor LZ regions contain only 4–5; second, the C-terminus of the LZ region extends into an additional α-helix composed of 15–20 amino acids (named the Ext region), forming a unique "LZ-Ext" functional module (
Figure 2)
[40,76]. Similar to the MiT/TFE family, the LZ region of USFs also contains a three-amino-acid insertion sequence, but the insertion position and sequence differ; for instance, the insertion site in USF2 is located near
299ETF
301; moreover, it lacks the conserved leucine (Leu) residue adjacent to the insertion site found in the MiT/TFE family, resulting in a unique bending pattern in its LZ region
[40,86]. Furthermore, the N-terminus of USFs contains a transcriptional activation domain that can specifically recruit histone-modifying enzymes such as P300 and SET7/9; however, its N-terminus lacks an obvious regulatory region, and protein stability primarily depends on the structural integrity of the LZ-Ext module
[38].
The LZ-Ext module is the core functional unit enabling USFs to dimerize and tetramerize; its structural integrity directly determines the polymerization capacity and functional execution of USFs. Hydrophobic residues in the Ext region (such as L328 and H335 of USF2) can form specific interactions with the LZ region of another USF dimer, providing a critical structural basis for tetramer assembly. The Loop region of USFs contains highly conserved lysine residues (such as K271 of USF2), which can form salt bridges with the phosphate backbone of DNA molecules, assisting the specific binding of the basic region to DNA. This feature also exists in the MiT/TFE family, but the sequence conservation at this site is higher in the USF family, suggesting its more critical role in DNA binding.
[40].
The LZ structure of USFs exhibits a unique "slender and curved" conformation, which serves as the critical structural basis for mediating DNA looping. The LZ region and the Ext region together form a continuous α-helix with a total length of approximately 50–63 Å, which is twice the length of the LZ region in the MAX family (approximately 27 Å); influenced by an insertion sequence of three amino acids in the LZ region, this α-helix adopts a curved conformation of approximately 125°, and the bending sites differ between the two subunits, such as the bending site in USF2 chain A being
303EAE
305, while in chain B it is
299ETF
301, ultimately forming an asymmetric dimer (
Figure 5)
[40]. Despite the curved conformation, the LZ-Ext region significantly enhances the structural stability of the dimer through hydrophobic interactions (stacking effects of Leu and Ile residues) and hydrogen bonding (e.g., N336 of USF2 forming a hydrogen bond with the O atom of the adjacent subunit). Its thermal stability (
Tm ≈ 42.5 °C) lies between that of the MiT/TFE family and the MYC/MAX family
[40], ensuring functional stability while retaining a certain degree of conformational flexibility.
Two USF dimers can further assemble into a tetramer through multiple interactions in the LZ-Ext region; this tetramerization process is a key step for USFs to enhance transcriptional efficiency. The interface area is approximately 1135 Å
2, accounting for more than 35% of the total surface area of the dimer, providing ample space for interactions. The interaction types at this interface are diverse, including hydrophobic stacking (mediated by Leu residues in the LZ region), hydrogen bonds (e.g., N325 of USF2 forming a hydrogen bond with D249 of another dimer), and ionic bonds (e.g., electrostatic interactions between E312 and R288); these interactions collectively maintain the stability of the tetramer. The USF tetramer exhibits a symmetric distribution, where the two dimers can bind to two different E-box elements respectively, and mediate DNA looping through the bent conformation of the LZ-Ext region, bringing the promoter and enhancer regions of the target gene closer together, thereby significantly enhancing transcriptional regulation efficiency. Notably, this tetrameric conformation is unique to the USF subfamily; neither the MiT/TFE family nor the MYC/MAX family possesses this structural feature, marking it as an important sign of USF functional specialization
[40].
Similar to the MiT/TFE family, the basic region of USFs can insert into the major groove of DNA to specifically recognize the core sequence (CACGTG) of E-box elements; among them, conserved residues (such as R247 and R248) can form salt bridges with the DNA phosphate backbone
[40,90], ensuring binding specificity. Meanwhile, K271 in the Loop region can form additional salt bridges with the phosphate backbone in the non-core region of DNA, further enhancing the specificity and affinity of USF binding to DNA. Mutations at this site (such as K271A/E) can lead to a 5- to 9-fold decrease in the DNA-binding ability of USFs, fully confirming its functional importance
[40].
2.3 The regulatory significance of structural features on function
Based on their unique structural features, the MiT/TFE and USF subfamilies have evolved differentiated functional regulation patterns to adapt to the physiological needs of cellular stress response and basal transcriptional regulation, respectively.
The functional specificity of MiT/TFE subfamily transcription factors highly depends on the unique dynamic properties of their LZ domains. This structural feature enables them to precisely respond to intracellular microenvironmental signals (such as nutrient deprivation, oxidative stress, and calcium homeostasis imbalance) and undergo conformational rearrangement, thereby achieving fine-tuned regulation of downstream target pathways.
[23,91]. The unique "3-residue insertion" in their LZ domain forms a "staggered zipper" conformation, endowing this family with super-dynamic structures that result in lower dimer stability compared to conventional bHLH-LZ proteins.
[83]. This dynamic structure provides flexibility for functional regulation: under nutrient-sufficient conditions, mTORC1-mediated phosphorylation causes MiT/TFE proteins to bind with 14-3-3 proteins and remain retained in the cytoplasm.
[92]; however, when nutrients are scarce or cells encounter stress, calcineurin-mediated dephosphorylation relieves this inhibition, promoting LZ domain-driven dimerization and nuclear translocation. Nuclear MiT/TFE dimers can activate the transcription of genes involved in the autophagy-lysosome pathway (such as CLEAR network genes) and genes related to glycolipid metabolic reprogramming (such as HK2 and FASN), thereby maintaining cellular metabolic homeostasis.
[93-95]. In contrast, due to its stable structure, MITF_Δ3 exhibits reduced sensitivity to phosphorylation and maintains a high level of dimerization even under stress conditions, leading to functional dysregulation, such as the abnormal activation of autophagy genes.
[86], which conversely confirms the importance of dynamic structures for the precise functional regulation of the MiT/TFE family.
In stark contrast to the dynamic conformations of the MiT/TFE subfamily, the USF subfamily forms stable homotetramers through the bent structure of its leucine zipper extension region (LZ-Ext). This conformational feature serves as the structural basis for its fundamental transcriptional regulatory functions. The bHLH-LZ domain of USFs first forms a parallel left-handed four-helix bundle homodimer via the LZ domain, which then assembles into a divalent homotetramer through hydrophobic interactions of the LZ-Ext. This complex can simultaneously bind two E-box elements, enhancing transcriptional regulatory efficiency via DNA looping.
[40,76]. This tetrameric conformation exhibits high stability under physiological nuclear concentrations, enabling it to continuously regulate the basal expression levels of housekeeping genes and development-related genes during cell growth, embryonic development, and tissue homeostasis maintenance, thereby ensuring the stable operation of fundamental cellular physiological processes.
[40,73].
Notably, the "3-residue insertion" structure in the LZ domain of the MiT/TFE subfamily and the LZ-Ext bent structure of the USFs subfamily have both been confirmed as drug targets with significant application prospects, providing precise intervention points for disease treatment. Within the MiT/TFE family, the "3-residue insertion" in MITF leads to dimer interface instability; the compound TT-012 can specifically bind to the dynamic region of its LZ domain, disrupting dimer formation and DNA binding, thereby effectively inhibiting tumors in melanoma models
[86]. For the USF subfamily, key residues (such as Glu312 and Glu320) at the LZ-Ext interface of USF2 stabilize the tetramer via a hydrogen bond network; site-directed mutations or small-molecule interference targeting these residues can significantly weaken their DNA-binding activity and transcriptional regulatory functions, providing specific tools for investigating the oncogenic mechanisms of the USFs subfamily in tumorigenesis (e.g., liver cancer, colorectal cancer)
[96].
In summary, although the MiT/TFE and USF subfamilies both belong to the bHLH-LZ transcription factor superfamily and share commonalities in their core domain composition, they have achieved precise functional differentiation and biological synergy through divergent evolution of the spatial conformation of their LZ domains (dynamic dimers versus stable tetramers). The MiT/TFE subfamily focuses on adaptive regulation of stress responses and metabolic reprogramming, whereas the USF subfamily governs basal transcriptional regulation during cellular homeostasis and development. These structural features not only provide clues for elucidating mechanisms of functional specialization but also establish a foundation for mechanistic research and targeted drug development for diseases such as melanoma and metabolism-related tumors, given their well-defined drug target epitopes.
3 Development Strategies and Progress of Small Molecule Inhibitors
The development of small-molecule inhibitors targeting the MiT/TFE/USF family has formed a multi-dimensional strategic framework, effectively breaking through the traditional bottleneck of transcription factors being "undruggable." These strategies include not only precise interventions directly targeting unique domains of family members but also indirect means regulating activity via upstream signaling pathways. Furthermore, the application of emerging technologies such as combination therapy and PROTACs has further expanded therapeutic potential. A number of representative compounds have emerged under these various strategies (
Table 1), providing an intuitive reference for research and translational applications in this field.
3.1 Direct targeting strategy
The development of small-molecule inhibitors directly targeting transcription factors faces numerous challenges, primarily because such proteins lack typical small-molecule binding pockets, and the protein-protein interaction interfaces they mediate exhibit flat characteristics
[105-106]. Nevertheless, by leveraging innovative screening strategies and the application of structure-guided drug design techniques, researchers have achieved several breakthroughs. To date, in the study of direct inhibitors for the MiT/TFE/USF family, only inhibitors targeting MITF and TFEB have been reported
[86,107-108], while no publicly available research results exist yet for direct small-molecule inhibitors targeting the remaining transcription factors in this family. The following section will introduce the development process and mechanisms of action of direct inhibitors for these two transcription factors.
3.1.1 Direct MITF-targeting inhibitors
As a core regulator of the melanocyte lineage, MITF plays a key role in the initiation and progression of melanoma: approximately 20% of melanomas exhibit MITF amplification, and its abnormal expression is not only closely associated with tumorigenesis but also constitutes a major mechanism underlying resistance to MAPK inhibitors.
[109-110]. However, for a long time, MITF has been classified as an "undruggable" target due to the lack of traditional small-molecule binding pockets.
In 2023, the Wang team
[86]while resolving the bHLH-LZ domain of MITF using X-ray crystallography, discovered fundamental differences compared to MYC/MAX/MAD family proteins: the LZ region of MITF contains a unique insertion of three residues (
264AKE
266), causing misaligned pairing of the leucine zipper and forming a highly dynamic dimer interface. This dynamic structural feature neither affects MITF's binding to DNA nor provides a specific target for small-molecule intervention, completely overturning the perception that MITF is undruggable.
Based on the necessity of MITF dimerization for its function, the Wang team
[86]developed a fluorescence-based AlphaScreen assay targeting the MITF dimerization process (MIDAS). Through high-throughput screening of 654,650 compounds, they ultimately identified the candidate compound TT-012 (
Scheme 1). This is the first specific small-molecule inhibitor targeting MITF, a key oncogenic transcription factor in melanoma.
The core mechanism of action of TT-012 features clear target specificity and molecular logic: by precisely binding to the dynamic dimer interface formed by the insertion of three residues within the MITF leucine zipper (LZ) domain, it achieves a half-maximal inhibitory concentration (IC50value) that directly blocks MITF dimer formation; the disruption of the MITF dimerization process leads to the loss of its effective binding capacity to the promoter regions of downstream target genes, thereby significantly inhibiting MITF's transcriptional regulatory activity and ultimately achieving selective killing of MITF-dependent tumor cells.
In preclinical studies, TT-012 demonstrated favorable anti-tumor activity and safety: it exhibited potent selective cytotoxicity against melanoma cells with high MITF expression, showing significant MITF expression-dependent inhibition in cellular models; in animal models, it significantly suppressed tumor growth and metastasis, with controllable toxicity to the liver and immune cells. Currently, TT-012 has been granted a US patent and is in the preclinical development stage, not yet entering human clinical trials. Its related research provides a new paradigm and direction for the development of targeted drugs against "undruggable" transcription factors. In the future, if this compound can overcome subsequent development bottlenecks, it may offer a potential therapeutic strategy for MITF-abnormal melanoma and bring new research insights for treating patients resistant to MAPK inhibitors, while also possessing exploratory potential for combination with immunotherapy or other targeted drugs. However, further structural optimization is required to enhance its targeting selectivity for MITF and broaden the in vivo toxicity window. Systematic pharmacokinetic (PK) and pharmacodynamic (PD) studies must be conducted, potential resistance mechanisms arising from long-term application must be thoroughly elucidated, and clinical trials must be advanced to verify its safety and efficacy before it can be translated into precision therapy.
3.1.2 TFEB-targeted direct inhibitor
EO autophagy, as a key process in the tumor microenvironment that supports tumor growth and mediates therapeutic resistance, represents an important direction in cancer therapy. However, currently available clinical autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) suffer from limitations including low efficiency and unclear mechanisms
[111]; furthermore, inhibitors targeting kinases such as vacuolar protein sorting-associated protein 34 (VPS34) and Unc-51-like kinase 1 (ULK1) raise safety concerns due to their non-autophagy-related functions. Therefore, there is an urgent need to discover novel highly specific autophagy targets and inhibitors
[112-114].
Transcription factor EB (TFEB) is a core transcriptional regulator of autophagy, which binds to CLEAR elements in the promoter regions of lysosome-related genes
[24], systematically regulating lysosomal biogenesis and the expression of autophagy-related genes, and directly responding to changes in nutrient status to modulate cellular autophagy levels
[115-116]. Although TFEB is crucial for autophagy regulation, as a transcription factor, it lacks known drug-designable active pockets, and no direct and efficient small-molecule inhibitors have been reported for a long time.
In 2023, the Wang team
[97]By establishing a high-sensitivity screening model and conducting high-throughput screening on an FDA-approved drug library, they discovered that eltrombopag (EO), a small-molecule drug used to treat thrombocytopenia, can significantly inhibit TFEB function. This discovery breaks through the technical bottleneck of targeting TFEB, a transcription factor, with small molecules, providing new insights for autophagy inhibition and tumor treatment.
EO (
Scheme 2) As the first identified small-molecule inhibitor directly targeting the transcription factor TFEB, it features a well-defined mechanism and high specificity. By precisely binding to the bHLH-LZ domain of TFEB, particularly the bottom surface of the HLH domain, it forms a stable complex mediated by hydrophobic interactions and hydrogen bonds, generating a steric hindrance effect that blocks the binding of TFEB to CLEAR elements in the promoter regions of target genes. This process selectively inhibits TFEB transcriptional activity at the genomic level without affecting its phosphorylation status or nuclear localization, thereby achieving efficient regulation of autophagy.
In terms of efficacy, EO potently inhibits autophagy in a dose-dependent manner; a concentration of 10 μmol/L completely blocks starvation-induced LC3-II formation. Simultaneously, in glioblastoma cell models, it significantly enhances tumor sensitivity to the chemotherapeutic drug temozolomide (TMZ). In vivo experiments further confirmed that combination therapy reduces tumor proliferation and extends the survival time of tumor-bearing mice, with no obvious neurotoxicity, demonstrating good safety.
Current research has clearly identified its targets and molecular mechanisms. Leveraging the clinical foundation of FDA-approved drugs, EO exhibits favorable drug-like properties and translational potential; however, the efficacy of combination therapy in specific tumor types (such as elderly acute myeloid leukemia) still requires further validation. Future efforts should expand indication exploration in autophagy-dependent tumors like pancreatic and lung cancers, and optimize drug delivery systems to enhance penetration into solid tumors. Derivative design based on crystal structures can further improve targeting specificity to reduce off-target risks. Additionally, exploring the value of combination with immunotherapy and clarifying biomarker screening strategies through clinical trials will promote its development as a novel synergistic agent for precision oncology.
3.2 Indirect control strategy
Given the challenges of directly targeting transcription factors, an alternative strategy is to indirectly influence their activity by regulating their upstream signaling pathways; this approach has become a crucial supplement to the current development of MiT/TFE/USF family inhibitors. The core logic lies in circumventing the inherent obstacles of transcription factors themselves as drug targets—most transcription factors (such as MITF and TFEB) lack classic ligand-binding pockets, and their interaction with DNA relies on highly conserved domains, making direct intervention prone to causing cross-reactivity within the family. By targeting upstream signaling pathways as intervention nodes, mechanisms such as mature kinase inhibition can be employed to indirectly regulate the phosphorylation status, dimerization capability, or nuclear transport processes of transcription factors, thereby achieving precise control over their activity.
Indirect regulation targeting MITF primarily focuses on intervention in the MAPK signaling pathway. MEK inhibitors (such as Trametinib) and BRAF inhibitors (such as Vemurafenib) significantly reduce MITF phosphorylation levels and protein stability by inhibiting the MAPK signaling cascade.
[98]For example, in BRAF-mutant melanoma, the abnormally activated BRAF-MEK-ERK pathway continuously upregulates MITF expression, while these inhibitors can directly weaken MITF's transcriptional activation of downstream anti-apoptotic genes (such as BCL2) and proliferation-related genes (such as CDK2) by blocking signal transduction.
[117-118]Clinical data show that the BRAF-MEK dual inhibition regimen of dabrafenib combined with trametinib achieves an objective response rate of over 50% in BRAF V600E-mutant solid tumors; its efficacy depth relies on sustained inhibition of the MITF pathway and can delay the occurrence of drug resistance caused by MITF re-expression.
[99-100].
Regarding the indirect regulation of TFEB, research has primarily focused on interventions targeting kinases. By modulating TFEB phosphorylation and subcellular localization, these interventions achieve regulation of the autophagy-lysosome pathway. The natural flavonoid budleoside (Bud)
[103], tyrosine kinase (c-Abl) inhibitors (such as imatinib, Neurotinib)
[104], and glycogen synthase kinase 3β (GSK-3β) inhibitors (such as CHIR-99021)
[101]activate the autophagy-lysosome pathway (ALP) by targeting relevant kinases to regulate the phosphorylation status and subcellular localization of TFEB. For example, in Parkinson's disease (PD) models, GSK-3β inhibitors promote phosphorylation at the Ser9 site of GSK-3β, leading to its inactivation. This subsequently reduces TFEB phosphorylation, decreases the binding of TFEB to 14-3-3 proteins, and promotes the translocation of TFEB into the nucleus. Nuclear-activated TFEB upregulates the transcription of ALP-related genes (such as LAMP1), repairing impaired ALP function in PD models. Simultaneously, it inhibits the suppression of ALP caused by excessive MTORC1 activation, forming a positive regulatory cycle of enhanced ALP function.
[101,117]. Although GSK-3β inhibitors have not yet entered clinical application for PD treatment, they have demonstrated clear development potential and are expected to become novel therapeutic agents targeting the pathological roots of PD (α-synuclein clearance impairment and ALP dysfunction).
[119-120].
Furthermore, regulatory strategies targeting USF2 are being explored. Studies have reported that USF2 acts as a transcriptional repressor of lysosomal and autophagy-related genes, exhibiting a competitive relationship with TFEB in regulating these genes.
[121-122]. USF2 exerts transcriptional repression in nutrient-rich environments through a dual mechanism: first, by binding to the NuRD (Nucleosome Remodeling and Deacetylase) complex; and second, by competitively binding with TFEB to the CLEAR motif in target gene promoters, synergistically inhibiting the transcription of lysosomal and autophagy-related genes. GSK3β-mediated phosphorylation at the Ser155 site of USF2 is a key post-translational modification for its functional regulation.
[122]. Inhibiting USF2 combined with activating TFEB can enhance the clearance of misfolded proteins, providing potential therapeutic targets and intervention directions for protein aggregation-related diseases such as alpha-1 antitrypsin deficiency.
[121].
However, although indirect modulation strategies offer higher technical feasibility and R&D convenience compared to direct targeting strategies, they generally suffer from limited specificity and the risk of off-target effects, a problem that is particularly prominent in transcription factor families with cross-regulation across multiple pathways. The intervention case of the mTOR signaling pathway is highly representative: mTOR inhibitors such as rapamycin inhibit mTORC1 activity, thereby relieving its phosphorylation-mediated inhibition of TFEB/TFE3, leading to nuclear translocation and activation of these two transcription factors
[123-124]. However, this activation effect creates a significant contradiction in cancer therapy—while inhibition of the mTOR pathway can suppress tumor cell proliferation, abnormal activation of TFEB/TFE3 may exert pro-tumorigenic effects. For example, in clear cell renal cell carcinoma, TFEB activation induced by mTOR inhibitors significantly upregulates PD-L1 expression, suppressing CD8
+T cell cytotoxic function (by downregulating effector molecules such as CD107a and Granzyme B) to promote tumor immune escape, directly undermining therapeutic efficacy
[125-126]; in glioblastoma, TFEB activation-mediated enhancement of autophagy can also lead to tumor resistance to chemotherapeutic agents such as temozolomide
[107,127]. Thus, developing precise modulation strategies remains the core focus of research in this field.
3.3 Combination therapy strategies
In response to the technical challenges of direct targeting strategies and the inherent limitations of indirect regulatory strategies, combination therapy strategies are gradually becoming a more practical R&D path through synergistic intervention at multiple targets and pathways, providing new solutions for overcoming drug resistance and improving efficacy.
For instance, addressing the issue of TFEB activation-mediated resistance to mTOR inhibitor therapy in renal cancer, the Yang team
[128]experimentally confirmed that the combined application of mTOR inhibitors and PD-L1 antibodies can effectively restore CD8
+T cell anti-tumor function, achieving potent inhibition of tumor growth in mouse xenograft models. This combination strategy, through the dual effects of "inhibiting tumor proliferation + reversing immune escape," resolves the compensatory resistance issues triggered by single-pathway intervention. Furthermore, the BRAF-MEK dual inhibition regimen, by synergistically blocking key nodes upstream and downstream of the MAPK pathway, not only significantly enhances the inhibition efficiency of MITF but also effectively reduces the risk of pathway feedback activation induced by the application of single inhibitors.
These research advances indicate that precise intervention strategies based on signaling pathway network analysis and transcription factor structural features are driving MiT/TFE/USF family regulation research from "compromises of indirect regulation" toward "breakthroughs in precise intervention," providing more efficient approaches for the treatment of complex diseases.
3.4 Emerging targeted protein degradation strategies
In recent years, emerging targeted degradation technologies represented by proteolysis-targeting chimeras (PROTACs) and molecular glues have provided innovative research ideas for the therapeutic development of transcription factors, which are traditionally considered "undruggable" targets
[106,129], and have also opened up new dimensions for targeted intervention in the MiT/TFE/USF family. Unlike traditional small-molecule inhibitors that merely block target protein function, the core advantage of such technologies lies in their clever utilization of the cell's endogenous ubiquitin-proteasome system (UPS). By specifically inducing ubiquitination of target transcription factors, they trigger selective degradation within the proteasome, thereby fundamentally eliminating the biological functions of the target proteins
[130-131].
The development of targeted degraders for MiT/TFE and USF subfamily proteins has received significant attention. By 2025, the Ding team and the Wang team
[102]collaboratively developed WZS0347 (
Scheme 3), which was reported as the first class of PROTAC degraders targeting MITF, filling a gap in this field. This degrader primarily uses the MITF inhibitor TT-012 as the warhead for target protein binding, conjugated with a CRBN (Cereblon) E3 ubiquitin ligase ligand, thereby specifically recruiting CRBN and MITF to form a ternary complex, and subsequently inducing MITF ubiquitination and degradation via the CRBN-dependent ubiquitin-proteasome pathway. Furthermore, this mechanism has been confirmed through pretreatment experiments (reversal by TT-012 or lenalidomide), proteasome inhibitor (MG-132) blockade experiments, and half-life shortening validation
[102], ensuring the reliability of the mechanism.
In terms of efficacy, WZS0347 not only reduces MITF protein levels in a concentration- and time-dependent manner in melanoma cell lines such as B16F10, A375, and GAK, but also significantly downregulates the expression of the downstream MITF target genes TYR and Trpm1. Furthermore, it inhibits melanoma cell colony formation and migration capabilities in a dose-dependent manner, with superior migration inhibition effects compared to the parent inhibitor TT-012.
[102]. Currently, this study has completed the molecular design, synthesis, and screening of WZS0347, clarified its mechanism of action and core biological effects, and confirmed its potential as a chemical probe for studying MITF-related biological functions. This also provides a candidate drug for the treatment of melanoma (particularly BRAF/MEK inhibitor-resistant types). Future research could focus on improving the potency, selectivity, and pharmacokinetic properties of WZS0347, defining its selectivity for other members of the MiT/TEF family, conducting in-depth validation of efficacy in in vivo tumor models, refining the mechanism of action, and promoting its clinical translation.
Furthermore, studies have shown that the U-box domain protein 1 (STUB1) can specifically recognize and bind to phosphorylated TFEB (with key phosphorylation sites at S142 and S211), initiating proteasome-dependent degradation of TFEB by mediating ubiquitination, thereby achieving precise regulation of TFEB's biological activity.
[132]. This study not only clarifies the specific degradation targets and molecular mechanisms of TFEB, providing a solid theoretical basis and feasibility support for developing TFEB-targeted degraders based on PROTAC technology, but also holds significant translational value for treating malignancies driven by TFEB hyperactivation, opening up new directions for precise intervention in related diseases.
[133].
4 Conclusion and Outlook
As important branches of the bHLH-LZ transcription factor superfamily, the MiT/TFE and USF subfamilies share a core structural domain framework but have formed functionally specialized regulatory systems through divergent structural evolution, playing irreplaceable roles in physiological and pathological processes. The MiT/TFE family is structurally characterized by dynamic dimers formed by a three-amino acid insertion in the LZ region; it focuses on cellular stress response and metabolic reprogramming, exerting key roles in physiological processes such as melanocyte development and metabolic homeostasis maintenance by regulating the autophagy-lysosome pathway and tissue-specific target gene networks. Its functional abnormalities are closely related to tumors such as melanoma and renal cancer, as well as metabolic diseases.
[25,92,134]; In contrast, the USF family, relying on the stable tetrameric conformation mediated by the LZ-Ext module, dominates basal transcriptional regulation and multi-system physiological homeostasis. It enhances transcriptional efficiency through DNA looping mechanisms and participates in core processes such as embryonic development and cell cycle regulation. Dysregulation of its members is associated with the occurrence and progression of diseases such as liver cancer and colorectal cancer.
[122,135].
In the field of inhibitor development, targeting strategies against these two families have achieved breakthrough progress. The direct targeting strategy successfully broke the traditional perception that transcription factors are "undruggable"; the MITF inhibitor TT-012
[86]and the TFEB inhibitor Eltrombopag (EO)
[97,107]achieved precise inhibition of specific targets by intervening in protein dimerization and DNA binding processes, respectively, providing new tools for related tumor therapy
[136-137]; indirect regulation strategies provide a feasible path for modulating transcription factor activity by intervening in upstream signaling pathways (such as MAPK and GSK-3β pathways), but suffer from inherent limitations of limited specificity
[130]; combination therapies and emerging technologies such as PROTACs further expand therapeutic potential. WZS0347, as the first MITF-targeted PROTAC degrader
[102], demonstrates superior efficacy compared to traditional inhibitors, offering a new direction for treating drug-resistant tumors. These studies not only validate the feasibility of these two families as therapeutic targets but also establish a structure-oriented drug development paradigm.
Although significant progress has been made in current research, the elucidation of regulatory mechanisms and the development of targeted drugs for the MiT/TFE and USFs families still face numerous challenges and opportunities. At the level of basic research, it is still necessary to thoroughly clarify the molecular mechanisms of functional synergy and antagonism among family members, especially the regulatory network of TFEC as the sole inhibitor within the MiT/TFE family, as well as the precise molecular dynamics process of DNA looping mediated by USFs tetramers
[11]; the regulatory network of post-translational modifications on the conformation and activity of proteins in both families still requires systematic elucidation, and the crosstalk mechanisms between different modifications urgently need to be clarified
[138-139]. Furthermore, the mechanisms of action of the MiT/TFE and USFs families in immune regulation and neurodegenerative diseases have not yet been fully clarified, and their crosstalk relationships with other signaling pathways require further exploration.
In the field of drug development, the optimization and expansion of direct targeted inhibitors is a core direction. Currently reported direct inhibitors only cover MITF and TFEB; specific small molecules targeting TFE3, TFEC, and USF family members remain in a blank stage, requiring reliance on structural biology techniques to uncover more druggable target epitopes. For discovered inhibitors, structural modifications are needed to enhance their potency, selectivity, and pharmacokinetic properties, such as optimizing the tumor penetration of TT-012 and reducing the off-target risks of EO. Indirect regulation strategies must focus on precise intervention in signaling pathways, developing upstream kinase inhibitors with higher specificity to reduce therapeutic risks caused by cross-reactivity; combination therapy strategies should be based on pathway network analysis to explore synergistic combinations of inhibitors with immunotherapies and chemotherapeutic agents, with particular attention to the treatment needs of resistant tumors
[140-141].
Emerging technologies such as PROTAC provide a new dimension for transcription factor-targeted therapy. In the future, it is necessary to further expand their application scope, develop degraders targeting members such as TFE3 and USF1/USF2, and optimize the tissue targeting and bioavailability of these degraders.
[130]. At the same time, it is essential to establish a comprehensive biomarker screening system to identify suitable populations for different inhibitors, thereby achieving precision medicine. Furthermore, based on the structural homology and functional differences among family members, multi-target synergistic inhibition strategies can be explored to systematically intervene in the regulatory networks of complex diseases such as cancer.
Overall, structural biology research on the MiT/TFE and USF families has laid a solid foundation for targeted drug development. With deeper mechanistic insights and innovative technical approaches, it is expected that more efficient and specific therapeutic drugs will be developed, providing new solutions for the precision treatment of related diseases while simultaneously advancing the entire field of transcription factor-targeted therapy.
Strategic Priority Research Program of the Chinese Academy of Sciences(XDB1040000)
National Natural Science Foundation of China(22322706)
National Natural Science Foundation of China(22277134)
National Natural Science Foundation of China(82441039)
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