Two independent reviewers conducted a comprehensive search across multiple electronic databases, including PubMed, Embase, Web of Science, and Cochrane, to identify relevant studies published after 2001. The search strategy employed the following terms: “MTA3,” “Metastasis-associated protein 3,” “MTA3 gene,” “NuRD complex,” “chromatin remodeling,” “transcriptional corepressor,” and “epigenetic regulation.” The search was restricted to literature published in English. Reference management was performed using EndNote 20 software. In instances of disagreement between the reviewers, a consensus was achieved through consultation with a third reviewer.

Selection inclusion criteria: (1) The research must directly address the expression, regulation, function, molecular mechanisms, or role of MTA3 (or its encoding gene) in the context of diseases. (2) Acceptable research models encompass, but are not limited to, in vitro cell line models, in vivo animal models (e.g., mice, rats), and human tissue samples (e.g., tumor specimens, blood samples). (3) Eligible research types include original research articles, review articles (utilized for background information and identification of primary literature), case reports (specifically if they pertain to MTA3 mutations or distinct clinical manifestations), and conference abstracts (solely for acquiring the latest advancements in early translational research). (4) The study must explicitly investigate the association between MTA3 and cancer or other relevant diseases (such as developmental or metabolic diseases, if identified during the search process).

Exclusion criteria: (1) Studies that do not specifically address MTA3 or merely refer to it as a non-specific element of the NuRD complex. (2) Literature for which the full text is inaccessible, such as abstracts lacking comprehensive information. (3) Redundant publications, with only the earliest or most comprehensive version being retained. (4) Non-research articles, including editorials and reviews (unless they provide significant expert opinions or valuable insights into the field), as well as news reports, among others.

MTA3 is an integral component of the nucleosome remodeling and deacetylase (NuRD) complex. The gene encoding MTA3 is located on human chromosome 2p21 and contains 20 exons. Its promoter region contains multiple transcription factor-binding sites, including those for Sp1, AP-1, and estrogen receptor (ER), suggesting a complex and multifactorial mechanism of transcriptional regulation (1, 6, 9). The MTA3 protein comprises 515 amino acids with a molecular weight of approximately 60 kDa, and is highly conserved across species, sharing about 80% sequence similarity with MTA1 and MTA2 (6).

MTA3 contains several functional domains (Figure 1): BAH domain mediates protein–protein interactions (PPIs) and gene regulation; SANT domain serves as a transcription factor scaffold involved in chromatin remodeling; ELM2 domain interacts with histone deacetylases, thereby influencing transcriptional activity and embryonic development. Additionally, GATA-type zinc finger domain (residues 379–406) is predicted to confer DNA-binding capability and contribute to tissue-specific functions (1, 6, 9, 10). MTA3 also contains an SH3-binding domain, acidic regions, and a nuclear localization signal, underscoring its critical role in chromatin remodeling and transcriptional regulation (6, 9).

At least seven alternative splicing variants of MTA3 have been identified to date. Notably, the shorter isoform, MTA3s, demonstrated elevated expression levels at the mRNA and protein levels. Variants such as MTA3L exhibit structural differences in their C-terminal regions, potentially affecting their protein interaction profiles and functional characteristics (9). MTA3 expression is modulated by various factors, including transcription factors (p53 and Kaiso), growth factors and their receptors (VEGF, EGFR, Heregulin β1, and ErbB2), and microRNAs (miRNAs; miR-661, miR-30c, and miR-125a-3p) (11–13). These elements form a complex regulatory network that supports MTA3’s extensive and context-dependent roles in physiological and pathological processes.

MTA3 contributes to the development and homeostasis of multiple tissues and organs through epigenetic regulatory mechanisms. It is critical in maintaining stem cell pluripotency, hematopoietic system development, immune cell differentiation, and reproductive system function.

In embryonic stem cells, MTA3 cooperates with MTA2 to maintain pluripotency. MTA3 knockdown induces mesodermal differentiation in a manner dependent on the activity of dual-specificity tyrosine-phosphorylation-regulated kinase DYRK4, an effect that can be reversed by the inhibitor ID8 (14). Furthermore, S-nitrosylation of MTA3 decreases the activity of the NuRD complex, thereby reducing the reprogramming efficiency of induced pluripotent stem cells (15).

In the hematopoietic system, MTA3 functions as a key regulator of primitive hematopoiesis. MTA3 knockdown in zebrafish models led to the absence of the primitive hematopoietic lineage and aberrant angiogenesis, whereas MTA3 overexpression improved the expression of hematopoietic transcription factors gata1 and hbbe3 (16). MTA3 cooperates with other components of the NuRD complex (MBD3 and HDAC1) to regulate the expression of early hematopoietic genes scl and lmo2, a process that depends on its histone deacetylase activity (17).

Within the immune system, MTA3 is co-expressed with the transcriptional repressor BCL-6 in germinal center B cells. It mediates BCL-6-dependent transcriptional repression via the NuRD complex, thereby preventing premature differentiation of B cells into plasma cells. MTA3 depletion mediated by RNA interference disrupts plasma cell-specific transcriptional programs and induces re-expression of cell surface markers (18). Recent studies have indicated that MTA3 indirectly modulates humoral immunity by regulating follicular helper T cell (Tfh) differentiation (19).

MTA3 exhibits diverse functions in reproductive and endocrine-related tissues. In the ovary, MTA3 is highly expressed in granulosa cells, where it regulates G2/M phase progression by interacting with the NuRD complex and desmin-containing structures, thereby modulating cell proliferation (20). In placental tissue, MTA3 is induced under hypoxic conditions and upregulates HIF1α expression, contributing to trophoblast differentiation and functional regulation (21). Aberrant MTA3 expression is associated with the pathogenesis of preeclampsia (22). During mammary gland development, MTA3 suppresses ductal branching by inhibiting the Wnt4 signaling pathway, indicating its potential role in regulating stem cell fate decisions (23). Moreover, MTA3 colocalizes with the chromatin remodeling factor CHD5 in brain tissue, implicating it in neural development and tumor suppression (6, 24).

In summary, MTA3 integrates epigenetic regulation with cellular signaling networks to mediate tissue-specific functions in various physiological contexts. Its mechanisms involve post-translational modifications, dynamic complex assembly, and selective repression of target genes, positioning MTA3 as a critical molecular node in developmental biology and a promising candidate for therapeutic intervention in diseases.

MTA3 regulates gene expression through epigenetic mechanisms and is implicated in both neoplastic and non-neoplastic diseases (Figure 2). In neoplastic conditions, such as breast cancer, MTA3 primarily acts as a tumor suppressor. Its core mechanism involves the MTA3/ERα/Snail signaling axis. Estrogen-activated ERα recruits the MTA3/NuRD complex to the Snail promoter region, where transcription is repressed via histone deacetylation. Suppression of Snail expression helps maintain the epithelial phenotype, inhibits epithelial-mesenchymal transition (EMT), and reduces tumor invasion and metastasis (10, 25). Moreover, MTA3 antagonizes the Wnt/β-catenin and TGF-β signaling pathways by promoting NuRD-mediated repression of downstream oncogenes, including c-Myc, thereby inhibiting cell proliferation and EMT (26).

In non-neoplastic diseases, MTA3 exerts regulatory effects by modulating inflammatory and fibrotic processes. In models of acute liver injury, MTA3 mitigates inflammation by suppressing NF-κB transcriptional activity and downregulating pro-inflammatory cytokines, including TNF-α and IL-6 (27). Similarly, MTA3 delays the progression of organ fibrosis by inhibiting transcriptional outputs of the TGF-β/Smad signaling pathway (28).

In summary, as a key adaptor within the NuRD complex, MTA3 precisely regulates multiple key signaling pathways by directing the recruitment of histone-modifying complexes to specific gene promoters.Its potential holds significant exploratory value and is anticipated to offer novel scientific foundations for the analysis of mechanisms and the development of therapeutic intervention strategies for related diseases, including breast cancer, hematological disorders, and various tumors.

Breast cancer, a malignant proliferative disorder of mammary epithelial tissue, involves dysregulation of multiple molecular pathways during its initiation and progression. MTA3 exhibits significant tumor-suppressive effects in breast cancer. Its expression is regulated by the transcription factors SP1 and ER and depends on ERα and estradiol signaling, positioning MTA3 as a key downstream effector in the ER signaling pathway (69, 70). At the molecular level, MTA3 directly represses transcription of Snail, a central regulator of EMT, thereby maintaining expression of the epithelial marker E-cadherin and inhibiting tumor cell invasion and metastasis (10, 25). Moreover, MTA3 is involved in multiple transcriptional repression complexes. For example, SIX3/LSD1/NuRD(MTA3) complex suppresses breast cancer initiation and metastatic progression (29); GATA3/G9A/NuRD(MTA3) complex inhibits tumor invasion in both in vitro and in vivo models, and its downregulation leads to ZEB2 upregulation and promotes malignant progression (13).

MTA3 expression is significantly associated with breast cancer prognosis. In ERα-positive tumors, high MTA3 expression is positively correlated with E-cadherin levels, indicating a favorable clinical outcome (12, 30). Loss of MTA3 expression is frequently observed in advanced-stage cancers and is accompanied by reduced E-cadherin expression and aberrant β-catenin localization (11). Furthermore, therapeutic agents, including the histone deacetylase inhibitor LBH589 and the natural compound β-elemene, modulate cancer cell migration and invasion by regulating the MTA3–Snail–E-cadherin axis (12, 31). MTA3 also interacts with proteins such as MTA1 and TRIM21 to regulate breast cancer stemness and EMT, and this regulatory equilibrium is modulated by estrogen signaling (32) (see Table 1, Figure 3).

Currently, the majority of research concerning MTA3 in breast cancer remains at the preclinical exploration and early translational stages. Future investigations should prioritize elucidating the regulatory mechanisms of MTA3 expression and its functional characteristics in estrogen receptor-negative breast cancer, particularly in triple-negative breast cancer. Employing preclinical research methodologies, such as cell-based assays and animal models, could facilitate the initial clarification of MTA3’s specific roles across various molecular subtypes in epithelial-mesenchymal transition (EMT), invasion, metastasis, and the maintenance of stemness. Concurrently, a range of technical approaches could be utilized to dissect the composition and dynamic regulatory networks of MTA3-containing complexes. Through preclinical studies and preliminary translational research, the potential of MTA3 as a prognostic biomarker or therapeutic target could be cautiously assessed, thereby providing a foundational theoretical basis and guiding future research directions for the precision treatment of breast cancer. Nonetheless, to enable its widespread clinical application, extensive, in-depth, and rigorous research is essential for validation.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all cases. Its development and progression are linked to multiple molecular aberrations (71). In NSCLC, MTA3 exhibits oncogenic properties. Numerous clinical studies have reported frequent overexpression of MTA3 in tumor tissues, which is significantly associated with advanced p-TNM stage, lymph node metastasis, and poor prognosis (33, 34). MTA3 promotes NSCLC progression through several mechanisms. MTA3 knockdown induces G1/S phase arrest and downregulates the expression of cyclin A, cyclin D1, and phosphorylated Rb, thereby suppressing cell proliferation (33). Concurrently, MTA3 inhibits apoptosis by downregulating pro-apoptotic proteins, such as BAX and cleaved PARP, while upregulating the anti-apoptotic protein Bcl-2 (35). Additionally, MTA3 increases cell migration and invasion by interacting with HDAC2 (36). Moreover, MTA3 has been identified as a direct target of miR-495, forming a regulatory axis that plays a critical role in lung cancer growth and metastasis (37).

MTA3, functioning as an oncogene, is critically implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and may have a potential association with anti-tumor immunity. The overexpression of MTA3 is hypothesized to modulate the expression of immune-related molecules on the tumor cell surface, thereby impacting immune cell recognition and cytotoxic activity. Specifically, MTA3 may regulate the expression of major histocompatibility complex (MHC) molecules, facilitating immune evasion by tumor cells (see Table 1, Figure 3). Additionally, MTA3 might influence cytokine secretion, contributing to the establishment of an immunosuppressive microenvironment that impedes the infiltration and activation of immune cells, consequently attenuating the anti-tumor immune response (see Table 1, Figure 3).

Currently, the majority of research concerning MTA3 in non-small cell lung cancer (NSCLC) is focused on preclinical exploration and early translational stages. Future investigations could utilize advanced technologies, such as gene editing and proteomics, to conduct an in-depth analysis of the transcriptional and post-transcriptional regulatory networks associated with MTA3 in NSCLC. Additionally, structural biology techniques may be employed to elucidate the molecular structural basis of interactions between MTA3 and proteins like HDAC, further identifying its downstream signaling pathways. Preclinical studies, including cellular and animal model experiments, could provide preliminary evaluations of the therapeutic potential of targeting MTA3 in vivo, as well as cautiously explore its potential clinical applications. Concurrently, clinical sample studies should be undertaken to assess the feasibility of employing MTA3 as a prognostic biomarker for NSCLC in preliminary clinical applications. Furthermore, the role of MTA3 within the tumor microenvironment and its involvement in immune regulation should be investigated to establish a foundational theoretical basis for its potential as a target in combination therapies. However, to facilitate the broad application of MTA3-related research findings in clinical practice, extensive rigorous and in-depth studies are still required for validation.

HCC is a highly aggressive malignant tumor, and its pathogenesis is closely associated with multiple molecular alterations. MTA3 has emerged as a molecule of growing interest due to its aberrant expression and functional significance in HCC, with accumulating evidence highlighting its critical role in tumor progression. MTA3 is frequently overexpressed in the nuclei of HCC cells and is significantly associated with tumor metastasis and adverse patient prognosis (38). In vivo and in vitro functional studies demonstrated that MTA3 knockout significantly suppresses the proliferative, invasive, and metastatic potential of HCC cells (38). At the cellular level, siRNA-mediated silencing of MTA3 expression significantly reduces the viability and migratory capacity of both HepG2 and Hepa1–6 cell lines (39), indicating that MTA3 plays a critical regulatory role in maintaining the malignant phenotype of HCC.

Mechanistic studies have elucidated the pathological significance of MTA3. Tunicamycin exerts antitumor effects by modulating the miR-22-3p/MTA3 axis (40), whereas the transient receptor potential channel TRPC1 may promote HCC progression by upregulating MTA3 and other associated genes (41), highlighting its central role in complex regulatory networks. Prior to clinical application, numerous critical issues remain in the research concerning MTA3. It is imperative to elucidate the regulatory mechanisms and functional distinctions associated with its nuclear/cytoplasmic localization switch in hepatocellular carcinoma (HCC) to gain a comprehensive understanding of its mechanism of action. A systematic analysis of the signaling networks in which MTA3 is involved is required, including the investigation of interactions between upstream and downstream molecules within the miR-22-3p/MTA3 axis and its downstream effector molecules, to construct a complete signaling map. Furthermore, there is a need to actively explore targeted strategies, such as the development of small molecule inhibitors or gene silencing therapies, and to assess their in vivo efficacy to identify novel therapeutic targets (see Table 1, Figure 3). Early translational research should also focus on a thorough evaluation of MTA3’s potential as a prognostic marker and therapeutic target to facilitate its clinical application.

MTA3 has been identified as a key regulator of the TME and immune modulation in TETs (63, 80, 81). Bioinformatics analysis revealed that MTA3 expression was significantly correlated with immune scores in TETs, where low expression levels were associated with impaired TME function, decreased cytotoxic activity, and poor patient prognosis. Further analyses revealed that MTA3 expression was positively correlated with the infiltration levels of multiple immune cell populations, including cytotoxic T cells, and co-expressed with corresponding immune markers (64). Gene set enrichment analysis revealed that MTA3 may significantly affect the TME by positively regulating multiple immune response pathways (64). These findings imply that MTA3 not only functions as a potential prognostic biomarker in TETs but also plays a critical role in modulating tumor immune surveillance by regulating immune cell infiltration and function. This regulatory role likely stems from MTA3’s function as a core component of the NuRD complex, participating in chromatin remodeling and transcriptional regulation of immune-related genes (see Table 1, Figure 3). Future studies should use clinical specimens and animal models to validate the specific molecular mechanisms underlying MTA3-mediated immune modulation in the TET microenvironment. Furthermore, investigating the relationship between MTA3 expression levels and response to immune checkpoint inhibitors may provide novel theoretical foundations and actionable targets for immunotherapy.

Leukemia is a group of malignant clonal disorders arising from hematopoietic stem or progenitor cells. Its hallmark features include aberrant proliferation and accumulation of leukemic cells in hematopoietic tissues, such as the bone marrow, infiltration into extramedullary organs and tissues, and suppression of normal hematopoiesis. MTA3, a cell type-specific subunit of the Mi-2/NuRD transcriptional corepressor complex, is co-expressed with the transcriptional repressor BCL-6 in germinal center B cells and plays a critical role in regulating B lymphocyte differentiation. BCL-6 suppresses terminal differentiation of B cells into plasma cells in an MTA3-dependent manner, and its repressive activity is modulated by acetylation status (18). Patients with high lipoprotein lipase mRNA expression in B-cell chronic lymphocytic leukemia (B-CLL) demonstrate significantly higher MTA3 signaling activity, which is associated with adverse cytogenetic profiles, shorter time to first treatment, and reduced overall survival (65). MTA3 knockdown impairs BCL-6-mediated transcriptional repression and disrupts normal B-cell gene expression programs. Conversely, ectopic expression of BCL-6 in plasma cells reverses cellular differentiation in an MTA3-dependent manner. By enhancing BCL-6 function, MTA3 promotes a dedifferentiated state in leukemic cells and contributes to disease progression, highlighting its potential as a prognostic biomarker and therapeutic target (see Table 1, Figure 3). Future research should prioritize elucidating the fundamental molecular mechanisms underlying the MTA3 signaling pathway, alongside other preclinical investigations. Additionally, efforts should be directed towards the exploration of small molecule inhibitors or antibody-based therapeutics, coupled with early translational assessments to evaluate their efficacy and safety.

Lymphoma is a malignant neoplasm of the lymphoid hematopoietic system, characterized by uncontrolled lymphocyte proliferation, immune dysregulation, and multi-organ involvement (82) (see Table 2, Figure 3). MTA3 is highly expressed in B cells and physically interacts with the transcription factor BCL6, forming a functional complex that co-regulates key biological processes in germinal center B cells and contributes to lymphomagenesis (66). Evidence indicates that MTA3 is specifically overexpressed in germinal center B-cell-like diffuse large B-cell lymphoma, with expression levels positively correlated with cellular proliferation (66). BCL6 performs transcriptional regulation by recruiting different corepressor complexes, including SMRT/N-CoR and MTA3-containing NuRD complexes, enabling context-specific gene repression. This mechanistic insight provides a rationale for developing combination therapies targeting the BCL6 co-regulatory network (67). Moreover, MTA3 participates in regulating Tfh cell-associated gene expression programs, thereby modulating the tumor immune microenvironment (68). Future research should aim to elucidate the subtype-specific regulatory mechanisms of MTA3 across lymphoma entities, characterize the molecular basis of its interaction with BCL6, and evaluate the therapeutic potential of targeting the MTA3-BCL6 axis in precision oncology approaches (see Table 1, Figure 3).

Liver fibrosis is a pathological consequence of chronic hepatic injury, characterized by excessive accumulation of extracellular matrix (ECM) components, and is primarily driven by the activation of hepatic stellate cells (HSCs). MTA3 plays a multifaceted inhibitory role in the development and progression of liver fibrosis through several molecular mechanisms. First, MTA3 epigenetically suppresses HSC activation by downregulating the expression of α-smooth muscle actin (α-SMA) and collagen type I alpha 1 chain, which are key markers of HSC transdifferentiation into myofibroblasts, thereby reducing ECM overproduction at its source (83, 84). Second, MTA3 promotes apoptosis in activated HSCs by modulating the expression of apoptotic regulators, specifically by upregulating pro-apoptotic Bax and downregulating anti-apoptotic Bcl-2, thereby overcoming the apoptosis resistance commonly observed in activated HSCs and limiting fibrotic expansion (85). Third, MTA3 negatively regulates EMT by directly interacting with Snail, a master transcription factor of EMT, preventing its binding to target gene promoters. Concurrently, MTA3 recruits the NuRD complex to repress Snail gene transcription, leading to reduced Snail protein levels. This dual mechanism helps preserve epithelial cell identity (as evidenced by sustained E-cadherin expression), suppresses mesenchymal transition, and indirectly mitigates liver fibrosis (27). Future research should prioritize elucidating the fundamental molecular mechanisms underlying the MTA3 signaling pathway, alongside other preclinical investigations. It should also explore the development of small molecule inhibitors or antibody-based therapeutics and undertake preliminary translational assessments to evaluate their efficacy and safety (see Table 2, Figure 3).

Cardiac fibrosis is a prevalent pathological feature of various cardiovascular diseases, characterized by the transdifferentiation of cardiac fibroblasts into activated myofibroblasts and the excessive deposition of ECM proteins, particularly type I and type III collagen. These changes contribute to increased myocardial stiffness, impaired compliance, and progressive deterioration of cardiac function (86, 87). MTA3 plays a critical regulatory role in this process; its expression is significantly downregulated in fibrotic cardiac tissues, whereas experimental overexpression of MTA3 suppressed the expression of α-SMA and collagen I, thereby attenuating fibrotic remodeling and improving cardiac performance. This protective effect may be mediated by the modulation of the p38 MAPK-E2F1 signaling pathway (88). E2F1 functions as a pro-fibrotic transcription factor that represses MTA3 expression; however, emodin derivatives restored MTA3 levels by inhibiting E2F1 activity, consequently delaying cardiac fibrosis progression (89). Emerging evidence indicates that MTA3 may exert context-dependent effects on fibrotic processes, with some studies reporting that its overexpression can paradoxically promote fibrosis under specific conditions (90). Additionally, natural bioactive compounds, such as genistein, ameliorate cardiac fibrosis and improve cardiac function by activating the MTA3/TAK1/MKK4/JNK signaling cascade (104). Future preclinical investigations should focus on elucidating the bidirectional regulatory mechanisms of MTA3. Additionally, research should aim to develop strategies for drug development and early translational interventions targeting the associated signaling pathways.

IHPS is a gastrointestinal disorder primarily affecting infants and young children. It is characterized by hypertrophy of the smooth muscle layer of the pyloric sphincter, leading to gastric outlet obstruction. Although several genetic loci have been associated with IHPS, they account for only a small proportion of disease risk. To identify additional susceptibility loci, Fadista J. et al. (91) performed a genome-wide meta-analysis involving 1,395 surgically confirmed cases and 4,438 controls, followed by independent validation in a replication cohort of 2,427 cases and 2,524 controls. Two novel risk loci, BARX1 and EML4-MTA3, were identified in this comprehensive genetic study, which were significantly associated with IHPS susceptibility (91). These findings provide important insights into the genetic architecture of IHPS and serve as a valuable foundation for future functional and mechanistic studies (see Table 2, Figure 3).

Stroke is an acute cerebrovascular event characterized by the sudden rupture or occlusion of cerebral blood vessels, resulting in focal cerebral ischemia or hemorrhage and subsequent neuronal injuries. It is a major global health burden, marked by high incidence, mortality, disability, and recurrence rates. It is currently among the leading causes of long-term disability and death in adults worldwide (105). Zhou et al. (92) discovered in a murine model that transfection with miR-138 promotes degradation of the GATAD2B protein, destabilizes the NuRD complex, and induces nuclear-to-cytoplasmic translocation of MTA3. This cascade activates the Wnt signaling pathway, driving the differentiation of dental pulp stem cells into gamma-aminobutyric acid-ergic neurons. Consequently, this process facilitates structural reorganization and functional recovery of neural networks after a stroke and contributes to the repair of ischemic neuronal loss. These findings reveal a novel molecular mechanism underlying post-stroke neuro-regeneration and propose potential therapeutic targets for neural repair. Future studies should elucidate the clinical relevance of this pathway using human tissue samples, evaluate the safety, specificity (see Table 2, Figure 3), and delivery efficiency of miR-138-based vectors, and assess their therapeutic efficacy in diverse preclinical stroke models.

The invasion of extravillous trophoblast (EVT) cells is a critical process during early placentation, essential for the physiological remodeling of uterine spiral arteries and the establishment of adequate maternal-fetal circulation. Impaired EVT invasiveness is involved in the pathogenesis of several pregnancy-specific disorders, most notably preeclampsia (106, 107). Accumulating evidence indicates that MTA3 expression is significantly downregulated in placental tissues from patients with preeclampsia (93, 94). In MTA3-deficient trophoblast cells, key genes associated with invasive potential, such as matrix metalloproteinases-2 (MMP2) and MMP9, as well as the transcription factor Snail, are upregulated, indicating that MTA3 may act as a negative regulator of EVT invasion by repressing these pro-invasive factors (94). Moreover, as an integral component of the NuRD complex, MTA3 not only modulates EVT invasiveness and the expression of associated genes but also plays a critical role in the differentiation of cytotrophoblasts into syncytiotrophoblast and mature EVT lineages (21, 95). These findings highlight the multifaceted regulatory role of MTA3 in placental development. Future research should concentrate on elucidating the specific molecular mechanisms by which MTA3 regulates cellular invasion and differentiation (see Table 2, Figure 3). Additionally, further preclinical studies are warranted to assess its potential translational value as an early diagnostic marker or therapeutic target.

To investigate the molecular mechanisms underlying placental development in IUGR and the potential involvement of metastatic tumor antigen (MTA) family proteins, Alqaryyan et al. (96) established a dexamethasone-induced murine model of IUGR. They utilized quantitative real-time PCR, Western blotting, and immunohistochemistry to assess the expression levels of MTA1–3 in the basal and labyrinth zones of the placenta. Their results revealed increased MTA3 expression in the labyrinth zone of IUGR placentas, accompanied by reduced β-catenin levels and impaired proliferation. Alawadhi et al. (97) validated these findings and discovered that progesterone treatment normalizes dysregulated MTA1 and MTA3 expression, leading to improved placental function and pregnancy outcomes. These observations indicate a potential regulatory role for MTA proteins in placental pathophysiology associated with IUGR (see Table 2, Figure 3). Future studies should aim to elucidate the signaling pathways through which MTA3 modulates placental development and evaluate the translational potential of targeting the MTA family or implementing progesterone-based interventions for IUGR prevention and management.

MTA3, a multifunctional transcriptional co-regulator, is predominantly expressed in Leydig cells (LCs) and plays a critical role in regulating testicular steroidogenesis and spermatogenesis. Its expression is regulated at multiple levels: Insulin downregulates MTA3 in a concentration- and time-dependent manner; oxidative stress suppresses transcriptional activation through the nuclear receptor NR4A1, leading to reduced MTA3 expression, whereas NR4A1 overexpression counteracts this inhibition; miR-146a-5p directly targets the 3’ untranslated region of MTA3 to repress its expression, and this miRNA exhibits specific expression in LCs (98–100). Dysregulated MTA3 expression disrupts the balance of histone acetylation, characterized by decreased H4K5ac and H4K12ac and increased H3K9ac levels, thereby impairing spermatogenic progression. Environmental toxicants, such as arsenic exposure, induce male reproductive toxicity through mechanisms involving MTA3 downregulation, altered histone acetylation patterns, and disruption of intercellular junctions. Notably, exogenous MTA3 supplementation partially restored steroidogenic capacity and improved markers of male fertility in a murine model of diabetic testicular dysfunction (99, 101). Future research should systematically investigate the regulatory network linking MTA3 to key factors, such as NR4A1 and miR-146a-5p, to identify its downstream target genes in the steroid biosynthesis pathway (see Table 2, Figure 3). More research is required to elucidate the long-term effects and underlying molecular mechanisms by which environmental toxins (arsenic and heavy metals) and metabolic disorders (diabetes and obesity) modulate MTA3 expression. Given its central regulatory role, MTA3 is a promising therapeutic target, and researchers should focus on developing small-molecule agonists or miRNA antagonists to evaluate their potential for treating male infertility and hypogonadism.

As a key component of CHD5, the rat brain-specific homolog, MTA3, integrates into the Mi2/NuRD chromatin remodeling complex and regulates gene expression through epigenetic mechanisms, potentially contributing to AD pathogenesis (24, 108). This complex modulates chromatin architecture, thereby influencing transcriptional programs governing neuron-specific, cell cycle-related, and aging-associated genes (109, 110). In the context of AD, MTA3 may contribute to neurodegenerative processes by regulating gene networks involved in synaptic function, neuronal survival, and β-amyloid metabolism (24). Functional impairment of MTA3 may lead to aberrant silencing of neuronal genes, inappropriate re-entry of post-mitotic neurons into the cell cycle, and compromised chromatin stability, all of which can exacerbate neuropathological alterations. Accordingly, MTA3 represents a pivotal molecular link between chromatin remodeling and AD pathogenesis. However, its precise mechanistic role requires further experimental validation (see Table 2, Figure 3).

Based on brain transcriptomic data analysis in individuals with autism spectrum disorder (ASD), MTA3 has been identified as a central regulatory gene within a co-expression network (102). As a component of the Mi2/NuRD chromatin remodeling complex, MTA3 is involved in regulating neuronal gene expression through epigenetic mechanisms, including histone modifications and chromatin reorganization. Dysregulation of MTA3 function may disrupt mRNA surveillance pathways and compromise calcium signaling homeostasis, leading to defective processing of synapse-associated mRNAs and diminished neuronal plasticity. These alterations contribute to the pathological mechanisms underlying synaptic developmental deficits and behavioral impairments in autism. Furthermore, MTA3 interacts with genes such as PHB2 and TNXB, indicating potential cooperative roles in mitochondrial function and ECM organization (102). While these findings highlight the putative involvement of MTA3 in ASD pathophysiology, the precise molecular mechanisms require further validation through functional experimental approaches (see Table 2, Figure 3).

Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. It represents the progression of infection-induced systemic inflammatory response syndrome to a pathological state marked by multiple organ failure (111). The precise role and underlying mechanisms of MTA3 in sepsis remain unclear. Recent bioinformatics analyses indicate that MTA3 may be involved in the pathogenesis of sepsis through PPI networks, particularly those involving genes such as MAP1LC3A (103). As a component of the Mi-2/NuRD chromatin remodeling complex, MTA3 can regulate the expression of genes associated with immune and inflammatory responses, cellular autophagy, and endothelial barrier integrity via epigenetic regulatory mechanisms, thereby contributing to sepsis development and progression. However, the specific molecular actions and functional relevance of MTA3 in this context require further investigation (see Table 2, Figure 3).

Currently, while MTA3 has made significant advancements in disease research, it remains largely in the preclinical and early translational discovery phases. Consequently, substantial progress is required before it can be effectively applied in clinical settings. Future research endeavors should concentrate on several key areas to enhance our understanding and facilitate the translation of MTA3-related research into clinical applications. At the mechanistic level, it is imperative to employ multi-omics integration analysis methods, utilizing extensive clinical samples and suitable animal models, to thoroughly investigate the specific mechanisms by which MTA3 influences disease onset and progression. Particular attention should be given to elucidating the detailed mechanisms of MTA3 function at the cellular and molecular levels, including its involvement with cancer stem cells, interactions with non-coding RNAs, regulation through post-translational modifications, and its specific role within the tumor microenvironment. For example, utilizing single-cell sequencing and spatial transcriptomics methodologies allows for the analysis of the dynamic regulatory network of MTA3 within specific cell subpopulations, thereby offering a more precise theoretical foundation for targeted therapeutic interventions.

Regarding the optimization of experimental models, given the existing disparities among current models in replicating the onset and progression of human diseases, it is imperative to refine the selection and design of these models. Integrating multiple experimental models can enhance the reliability and reproducibility of research findings. In the context of tumor research, for instance, alongside traditional cell-based experiments and animal models, the incorporation of organoid models—which more closely mimic the physiological environment of the human body—can facilitate a more accurate simulation of the complex characteristics of tumors.

To standardize detection methodologies, it is imperative to develop uniform experimental protocols and implement robust quality control systems. This includes harmonizing detection techniques to mitigate the influence of methodological discrepancies on research outcomes. Concurrently, it is essential to enhance the comparison and validation of diverse detection methods to ensure the precision and comparability of research findings. Such standardization is vital for the accurate assessment of MTA3’s expression levels, protein activity, and molecular interactions, thereby providing reliable data to support future clinical applications.

In the pursuit of developing targeted therapeutic strategies, it is imperative to conduct comprehensive research into the composition and dynamic regulatory mechanisms of the MTA3-NuRD complex. This involves elucidating the specific role of each subunit within the complex to inform the proposal of innovative targeted therapeutic approaches. Concurrently, it is essential to engage in drug development research targeting MTA3, which includes the screening and design of small molecule agonists or antagonists characterized by high efficacy and low toxicity. Additionally, the development of regulatory drugs based on non-coding RNA should be pursued to furnish more effective modalities for disease treatment.

By conducting comprehensive research across the aforementioned dimensions, it is anticipated that the full mechanism of MTA3 in the pathogenesis and progression of diseases will be progressively elucidated. This endeavor aims to establish a robust foundation for its clinical application as a diagnostic marker and therapeutic target. Such advancements are expected to propel MTA3-related research from the preclinical and early translational discovery phases to well-established clinical applications, ultimately offering new prospects for enhancing patient health outcomes and prognoses.