{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZinc fingers and homeoboxes 2 (ZHX2) is a member of a transcription factor family characterized by its zinc‐finger motifs and homeodomains, which enable it to function as a transcriptional repressor. Early studies using yeast two‐hybrid screening demonstrated that ZHX2 interacts with the activation domain of NF‐YA and forms both homodimers and heterodimers with ZHX1, thereby modulating the expression of numerous target genes involved in differentiation and development. Moreover, differential expression of ZHX2 has been associated with developmental programs such as hemoglobin switching, underscoring its regulatory versatility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n \nDisparate roles for ZHX2 have been uncovered in various cancers. In hepatocellular carcinoma (HCC), ZHX2 acts predominantly as a tumor suppressor by repressing the transcription of oncogenic targets such as alpha‐fetoprotein (AFP), glypican 3 (GPC3), and lipid lipase (LPL). Its expression can be inhibited by hepatitis B virus–encoded proteins via upregulation of oncomiRs (for example, miR‑155), leading to dysregulated lipid homeostasis and increased tumor cell proliferation. In clear cell renal cell carcinoma (ccRCC), however, loss of von Hippel–Lindau function permits ZHX2 hydroxylation, accumulation in the nucleus, and subsequent activation of NF‑κB signaling, which drives VEGF expression, cell growth, and even resistance to therapeutics such as Sunitinib. In other hematopoietic malignancies such as Hodgkin lymphoma, chromosomal rearrangements disrupt regulatory elements of ZHX2, suggesting it may normally help constrain malignant transformation. Consistent with its context‐dependent activity, diminished ZHX2 expression in glioma and ovarian cancer correlates with enhanced proliferation, migration, and invasiveness, while repression of multidrug resistance gene (MDR1) by ZHX2 can increase chemosensitivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "16"}]}, {"type": "t", "text": "\n \nBeyond its oncogenic or tumor‐suppressive roles, ZHX2 is increasingly recognized as a key mediator of normal cellular differentiation and tissue homeostasis. In the liver, for example, ZHX2 modulates gene expression programs that control the abundance of major urinary proteins and lipid metabolism, the latter being linked to its repression of SREBP1c via upregulation of miR‑24‑3p. In dental mesenchymal cells, ZHX2 restricts proliferation while promoting osteo/odontogenic differentiation, a balance essential for tooth root development. ZHX2 also influences immune cell maturation—as evidenced by its regulation of podocyte gene expression via heterodimer formation and its role in restraining natural killer cell differentiation—and may participate in the maintenance of liver cancer stem cell properties, further highlighting its context‐dependent functionality."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroko Kawata, Kazuya Yamada, Zhangfei Shou, et al. 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