{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVGLL4 functions primarily as a tumor suppressor by antagonizing oncogenic transcriptional programs. In numerous cancers—including gastric, lung, colorectal, esophageal, bladder, breast, and triple‐negative breast cancers—VGLL4 directly competes with YAP (and in some contexts other factors such as STAT3) for binding to TEAD transcription factors. This competition disrupts the formation of YAP–TEAD (or related) complexes that otherwise drive cell proliferation, migration, invasiveness, epithelial–mesenchymal transition, and tumor progression. Notably, VGLL4’s two conserved Tondu (TDU) domains are both essential and sufficient for its inhibitory activity, and peptides mimicking these domains have shown potent anticancer effects in vitro and in vivo. Furthermore, post‐translational modifications (for instance, mitotic phosphorylation) can attenuate its tumor‐suppressive capacity by altering its affinity for TEADs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its anticancer roles, VGLL4 is crucial for normal cellular differentiation and tissue homeostasis. In cardiomyocytes and skeletal muscle cells, VGLL4 interacts with members of the TEF‐1 transcription factor family and modulates adrenergic signaling–responsive gene expression. Furthermore, in muscle cells VGLL4 forms complexes with TEAD4 and IRF2BP2 to regulate VEGFA expression, a key factor in post‐ischemic revascularization. VGLL4 is also upregulated during mesenchymal stem cell differentiation towards the osteogenic lineage and enhances the survival and colony formation of human embryonic stem cells, highlighting its importance in early stem cell maintenance and vascular smooth muscle differentiation. The presence of dual TEAD-binding regions underpins its ability to engage transcription factors and modulate diverse gene networks during development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nVGLL4 also connects oncogenic signaling with immune regulation. Its deficiency leads to reduced PD-L1 expression on tumor cells through mechanisms that involve stabilization of key transcriptional co-regulators, thereby influencing T cell–mediated antitumor immunity. This mechanistic link between VGLL4 and immune checkpoint regulation underscores its potential role in improving responses to immunotherapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, genetic association studies have linked VGLL4 to neurodevelopmental and psychiatric conditions. Altered expression and genetic variations in VGLL4 have been found in contexts associated with schizophrenia, suggesting that beyond its established roles in cancer and tissue differentiation, VGLL4 may also contribute to neuronal development and brain function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenjing Zhang, Yijun Gao, Peixue Li, et al. 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