Malignant tumors have become a major global public health issue that seriously threatens human health. According to the latest statistical data from the World Health Organization’s International Agency for Research on Cancer (IARC), there are over 19 million new cancer cases and nearly 10 million cancer-related deaths worldwide each year. Cancers such as lung cancer, Colorectal Cancer (CRC), Hepatocellular Carcinoma (HCC), and prostate cancer rank among the most prevalent in terms of both incidence and mortality rates [1]. Due to the complex pathogenesis and poor prognosis of malignant tumors, identifying reliable prognostic markers across various cancer types is a crucial approach to achieving effective prevention and treatment. Among the numerous molecules closely associated with tumorigenesis and progression, the MYC-Associated Zinc finger protein (MAZ), a key transcription factor, has garnered increasing attention. MAZ recognizes GC-rich regions in target genes through its C2H2-type zinc finger domain, thereby extensively regulating gene transcription [2][3]. Studies have revealed that MAZ is aberrantly overexpressed in various highly prevalent malignant tumors—such as colorectal, lung, prostate, and liver cancers—and is significantly associated with poor patient prognosis, indicating its critical role in the progression of malignancies [4]-[6]. Further experiments have revealed the cancer-specific mechanisms of MAZ. For instance, in lung cancer, knockdown of MAZ significantly inhibits tumor cell proliferation and migration [6]; in prostate cancer, MAZ has been shown to promote bone metastasis [7]; while in colon cancer, MAZ can mediate the STAT3 signaling pathway to regulate inflammatory responses and tumor progression [8]. Importantly, MAZ can also form a complex interaction network with other key oncoproteins such as MYC, collectively regulating tumorigenesis and development [9]. These findings demonstrate that MAZ may serve as a molecular target with significant research value and potential therapeutic promise.

However, although numerous studies have confirmed the central role of MAZ in the pathogenesis and progression of various malignant tumors, the complex regulatory networks underlying its function and its translational value remain underexplored. Moreover, in contrast to its well-established prognostic value, studies targeting MAZ itself are scarce, making its translation into an effective interventional target a primary challenge in the field. This review systematically analyzes the role of MAZ in tumor development, integrating recent advances in molecular mechanisms and clinical translation. The analysis provides an important reference for a deeper understanding of the role of MAZ in tumors and offers new ideas for developing novel anti-tumor strategies based on MAZ.

MAZ, a transcription factor ubiquitously expressed across major human tissues and organ systems, has a biological function that is intricately tied to its distinct molecular structure [10][11]. The most prominent structural feature of this protein is the presence of multiple canonical C2H2-type zinc finger domains at its carboxyl terminus. These domains enable specific recognition and binding to GC-rich cis-regulatory elements (such as the 5’-GGGAGGG-3’ sequence) in the promoter regions of target genes. Consequently, the protein plays a dual role in transcriptional regulation—it can both facilitate transcription initiation and mediate transcription termination [10][12]. MAZ exhibits context-dependent regulatory functions in tumors, and the mechanisms underlying its dual roles primarily stem from the following factors. First, MAZ interacts with different protein cofactors to exert distinct functions. For instance, MAZ not only assembles a transcriptional activation complex with C-MYC to drive proliferation-related gene expression [9], but also recruits HDAC1/RBBP7/CUL4B to form a repression complex [13]. This complex facilitates histone deacetylation, resulting in chromatin conformational changes and subsequent transcriptional repression. Second, the different isoforms generated by alternative splicing of the MAZ gene (e.g., MAZ-1, MAZ-2, and MAZ-3) exhibit varying expression levels in the tumor microenvironment. These isoforms may possess distinct DNA-binding properties or protein interaction interfaces, ultimately leading to completely opposite biological effects [14]. Due to its structural and target-binding diversity, MAZ can extensively participate in multiple malignant biological processes of tumor cells—including proliferation, migration, invasion, apoptosis, and drug resistance—by regulating key cellular processes such as replication, repair, transcription, and translation (Figure 1) [6][15][16]. In tumorigenesis and development, MAZ plays a central role by regulating the expression of multiple key oncogenes. Studies have shown that it can not only directly bind to the promoter region of the c-Myc gene to maintain its basal transcription level, but also regulate the expression of Ras gene family members, thereby activating key signaling pathways such as MAPK [17][18]. Adding another layer of complexity, a single MAZ molecule can simultaneously activate pro-cancer genes such as Vascular Endothelial Growth Factor (VEGF) [19] and Recombination Activation Gene 2 (RAG-2) [20], while also suppressing the expression of genes like Endothelial Nitric Oxide Synthase (eNOS) [21] and the proto-oncogene C-MYB [22]. This dual regulatory capability not only establishes MAZ as a critical focus in cancer research but also provides a theoretical foundation for its potential as a therapeutic target.

Figure 1. Various biological functions of Myc-associated zinc finger proteins in malignancies.

MAZ’s central role in tumorigenesis and its characteristic persistent overexpression endow it with dual value as both a therapeutic target and a diagnostic biomarker. Consequently, exploring the clinical application of MAZ as a liquid biopsy marker holds significant translational medical importance. Cancer remains a leading cause of mortality worldwide. Tissue biopsy has long been regarded as the gold standard in tumor diagnosis due to its accuracy, high standardization, and reliability. However, its invasive nature and limited ability to comprehensively reflect tumor heterogeneity pose significant challenges in clinical practice. In this context, Liquid biopsy is a minimally invasive technique that analyzes circulating tumor components in blood and other bodily fluids for non-invasive, dynamic tumor monitoring. This approach provides new opportunities for early cancer screening, treatment efficacy assessment, and prognosis evaluation [64][65]. The core of this technology lies in the integrated analysis of two key biomarkers: circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA). CtDNA, a component of cell-free DNA (cfDNA) released by tumor cells into the circulatory system, carries genetic and epigenetic modifications that may reflect the genomic or epigenomic characteristics of their cells of origin. This underpins its significant value in prognostic assessment, minimal residual disease detection, treatment strategy selection, and early warning of recurrence risk [66]. Beyond ctDNA, ctRNA also constitutes a crucial component of liquid biopsy testing systems. ctRNA, a subset of cell-free RNA (cfRNA) released into bodily fluids via apoptosis, necrosis, or active secretion from cancer cells, includes molecules such as microRNA (miRNA) and long non-coding RNA (lncRNA). It can be isolated from multiple biofluid sources, including blood and urine [67]. ctDNA and ctRNA serve as dual biomarkers in liquid biopsy, capturing tumor-specific genetic alterations at the genomic and transcriptional levels respectively. Together, they enhance tumor diagnosis, prognosis assessment, and heterogeneity analysis. Particularly, ctDNA has been extensively validated as an excellent tumor biomarker due to the characteristic that all tumor sites release cfDNA into the bloodstream [64][65][68][69]. Consequently, compared to tissue biopsy, liquid biopsy provides a more comprehensive representation of tumor heterogeneity.

Liquid biopsy technology has enabled screening for various cancers such as lung cancer, BC, and CRC through the detection of circulating tumor markers in body fluids [70]-[73]. Against this backdrop, the transcription factor MAZ, with its characteristic high expression specific to multiple malignant tumors, demonstrates significant potential as a novel liquid biopsy biomarker. It should be specifically noted that the use of MAZ as a liquid biopsy biomarker remains a conceptual proposal at present. No studies have yet specifically detected MAZ expression levels through ctDNA or ctRNA analysis or validated its clinical application value. Current research indicates that cfDNA-based liquid biopsy exhibits excellent performance in early screening for different cancer types. In lung cancer, machine learning models incorporating multidimensional features of cfDNA achieved detection sensitivities of 95.1% for stage I lung cancer and 96.2% for minimally invasive adenocarcinoma [74]. Plasma ctDNA detection demonstrated 90% sensitivity in distinguishing lung cancer patients from healthy individuals [75], while maintaining a 50% detection rate even in stage I patients [76]. Regarding CRC screening, SEPT9 gene methylation testing has received FDA clinical approval [77][78]. Recently developed models utilizing 11 cfDNA methylation biomarkers have shown both high sensitivity and strong specificity in detecting early-stage CRC and advanced adenomas [79][80]. Notably, ctDNA has demonstrated unique value in dynamic monitoring. Studies have revealed that ctDNA levels significantly correlate with tumor volume and can reflect treatment response earlier than radiographic imaging [81][82]. In glioma research, tumor-derived DNA in cerebrospinal fluid showed significant correlation with tumor progression and patient survival [38], further confirming that ctDNA analysis can provide critical information on tumor progression. However, despite its considerable potential, liquid biopsy faces major challenges in standardization. Uniform protocols are urgently needed for sample collection procedures, biomarker isolation methods, and result interpretation criteria [83][84]. Moreover, the release of biological materials (e.g., urine and blood) can be influenced by microenvironmental factors [85]. Additionally, not all clinically relevant cancer biomarkers are detectable through liquid biopsy [86], and many detection methods still require further research and clinical validation. Despite these challenges, liquid biopsy is expected to become an important complement to tissue biopsy. This prospect depends on continuous improvements in monitoring efficiency and a deeper understanding of biomarker mechanisms. Ultimately, the technology will provide more comprehensive information support for tumor immunotherapy. In this developmental trajectory, MAZ—as a novel biomarker highly expressed across multiple tumors—warrants further validation of its clinical utility through large-scale clinical studies.

MAZ, a transcription factor characterized by its distinctive C2H2 zinc finger structure, serves as a transcriptional regulatory hub in multiple malignant tumors. It not only drives malignant tumor progression by regulating multiple pathways such as TK1-GDF15 and NEIL3-DNA damage repair, but also participates in key processes including chemotherapy resistance and immune regulation. These findings provide a solid theoretical foundation for the clinical application of MAZ. Based on current research advances, future studies could consider focusing on the following directions: Firstly, it is necessary to conduct a thorough analysis of the core role of MAZ in malignant tumors, and determine whether it plays a dominant role in the regulatory network of oncogenes. Secondly, it is essential to systematically clarify MAZ’s functional network in normal physiological processes to assess potential adverse effects associated with targeting it therapeutically. Finally, it is essential to explore specific therapeutic strategies targeting MAZ. Herein, we propose two strategic therapeutic approaches for targeting MAZ. The first strategy involves developing small-molecule inhibitors designed to specifically disrupt its DNA-binding domain. Alternatively, targeted protein degradation technologies, particularly PROTACs, could be employed to achieve precise control of MAZ protein levels. Although transcription factors have traditionally presented formidable challenges for drug development, these innovative strategies offer promising avenues to overcome the inherent “undruggable” nature of such targets. The pursuit of these approaches represents a paradigm shift in therapeutic development for transcription factor-related malignancies.

To address key challenges in clinical translation—including functional heterogeneity of MAZ across cancer types, disparities between animal models and human studies, and balancing targeting specificity with toxicity—these issues can be addressed by advancing through three stages: The first phase focuses on the development of diagnostic markers, establishing standardized MAZ detection protocols in liquid biopsy through multicenter clinical studies. The second phase aims to validate MAZ as a therapeutic target by utilizing organoid models and gene-editing technologies to elucidate its regulatory networks and develop specific inhibitors. The third phase involves systematic preclinical evaluation, verifying the safety and efficacy of MAZ-targeted therapies in advanced animal models. Through this stepwise research strategy, MAZ is expected to become an important target in the field of precision oncology, thereby providing new diagnostic and therapeutic options for cancer patients.

Yunxiao Zhang: Conceptualization, Writing—original draft. Yan Qin: Formal Analysis, Writing—original draft. Feng Gao: Formal Analysis, Writing—review & editing. Huihuang Shen, Siyuan Hou and Mingxue Zhang: Supervision, Writing—review & editing. Hongmei Wu and Linfeng Mo: Conceptualization, Project administration, Writing—review & editing.

The figures were created with BioGDP.com (https://biogdp.com/) [87]. We gratefully acknowledge the reviewers and the handling editor for their valuable contributions toward the successful publication of this article.

*These authors have contributed equally to this work and shared first authorship.

^#Corresponding authors.