ZHX2 is a zinc-finger transcription factor that acts primarily as a transcriptional repressor, regulating cell proliferation, differentiation, and metabolic processes across multiple tissues. It represses CDC25C promoter activity and inhibits mitochondrial oxidative phosphorylation during acute liver injury by suppressing electron transport chain genes and destabilizing PGC-1α 1. However, ZHX2 also exhibits context-dependent activation, positively regulating major urinary protein expression in liver 2. In cancer, ZHX2 functions as an oncogenic driver through multiple mechanisms. Hypoxia induces ZHX2 phase separation via a proline-rich intrinsically disordered region, enhancing its chr8 occupancy and activating metastatic genes in breast cancer 3. In clear cell renal cell carcinoma, loss of VHL allows ZHX2 accumulation, promoting tumor growth by activating nuclear factor κB 4; deubiquitination by USP13 further stabilizes ZHX2 protein in this context 5. In diffuse large B-cell lymphoma, ZHX2 phase separation protects cells against ferroptosis by inducing SLC3A2, and targeting ZHX2 with lipid-nanoparticle-delivered siRNA effectively suppresses tumor growth 6. ZHX2 expression in tumor-associated macrophages is reduced by lactate in the tumor microenvironment, promoting pro-tumor polarization; reduced ZHX2 in TAMs correlates with poor survival in hepatocellular carcinoma patients 7. In lung cancer, ZHX2 overexpression inhibits proliferation and promotes apoptosis via p38MAPK pathway inhibition 8. Recent evidence suggests ZHX2 hypomorphic mutations impair podocyte function, predisposing to minimal change nephrotic syndrome 9.