This review published in Genes & Diseases by researchers from Chongqing University Cancer Hospital, Chongqing University of Technology, and Chongqing Medical University provides an in-depth synthesis of TBX4’s biological functions and its expanding relevance across developmental biology, respiratory medicine, orthopedics, and oncology.
The authors highlight TBX4 as a core transcriptional coordinator that integrates Wnt/β-catenin, FGF10, BMP–Smad, and Shh–Foxf1 pathways to regulate mesenchymal–epithelial communication during organogenesis. Through these mechanisms, TBX4 directs tracheal cartilage formation, airway branching, smooth muscle differentiation, and extracellular matrix remodeling. Its dosage-sensitive function is particularly critical in the respiratory system, where TBX4 mutations, deletions, and enhancer variants represent one of the most prevalent genetic causes of pediatric pulmonary arterial hypertension (PAH). TBX4 dysregulation is also linked to tracheal stenosis, lung hypoplasia, neonatal respiratory failure, and impaired post-injury tissue repair.
Beyond the respiratory system, the review highlights TBX4’s critical involvement in hindlimb identity, skeletal patterning, and soft tissue morphogenesis. Its coordinated activity with PITX1 and HOXC transcription factors shapes limb-specific features, while genetic disruptions manifest clinically as small patella syndrome (SPS), developmental dysplasia of the hip (DDH), and congenital clubfoot. Evolutionary studies show that alterations in TBX4 enhancer elements even contributed to the hindlimb reduction seen in cetaceans.
A rapidly growing area of interest is TBX4’s role in cancer biology. The review synthesizes recent findings demonstrating that TBX4 often acts as a tumor suppressor, with reduced expression linked to poor prognosis in pancreatic ductal adenocarcinoma, lung adenocarcinoma, intrahepatic cholangiocarcinoma, and breast and thyroid cancers. TBX4 methylation patterns show potential as diagnostic and prognostic biomarkers across tumor types.
The review also explores TBX4’s emerging roles outside traditional developmental pathways, including its involvement in craniofacial development, anorectal formation, female reproductive structures, immune cell transcriptional programming, and host defense pathways. These findings broaden the physiological relevance of TBX4 and point to significant gaps in understanding how TBX4 mutations translate into variable clinical outcomes.
Ultimately, the authors emphasize future priorities, including organ-specific TBX4 knockout models, enhancer mapping, and integrative multi-omics approaches to clarify TBX4’s cell-type-specific functions. By connecting developmental pathways to disease mechanisms, TBX4 is emerging as a promising biomarker and therapeutic target with broad clinical impact.
Reference
Title of Original Paper: Multifaceted role of T-box transcription factor 4: From embryonic development to disease pathogenesis
Journal
Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101811
Funding Information:
The National Natural Science Foundation of China (No. 82172619)
The Natural Science Foundation of Chongqing, China (No. CSTC2021jscx-gksb-N0023)
# # # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus Cite Score: 8.4
Impact Factor: 9.4
# # # # # #
More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Disease may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx ).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.com
X (formerly Twitter): @GenesNDiseases (https://x.com/GenesNDiseases )
# # # # # #