Zhx2, or Zinc fingers and homeoboxes 2, is a transcriptional factor and the negative regulator of alpha fetal protein (AFP). It has a significant role in multiple cellular processes, including cell proliferation, differentiation, lipid metabolism, and immunoregulation [1].

In clear cell renal cell carcinoma (ccRCC), VHL loss-of-function mutations lead to increased ZHX2 abundance and nuclear localization, and ZHX2 depletion inhibits VHL-deficient ccRCC cell growth in vitro and in vivo, suggesting it as an oncogenic driver [2]. In triple-negative breast cancer (TNBC), ZHX2 is amplified or overexpressed, and its depletion inhibits cell growth, invasion, orthotopic tumor growth, and lung metastasis. ZHX2 promotes HIF1α oncogenic signaling in TNBC [3]. In thyroid cancer, ZHX2 expression is decreased, and its knockdown promotes cell migration. ZHX2 inhibits metastasis by transcriptionally inhibiting S100A14 [4]. In islet β-cells, β-cell-specific knockout of Zhx2 (Zhx2BKO) mice show decreased β-cell proliferation and glucose intolerance, indicating Zhx2 maintains β-cell function by regulating Pax6 [5]. In macrophages, myeloid-specific deletion of Zhx2 (MKO) makes mice more resistant to sepsis, as Zhx2 promotes macrophage glycolysis via Pfkfb3 [6].

In conclusion, Zhx2 is a multifunctional transcriptional factor. Studies using gene knockout mouse models have revealed its roles in various diseases such as cancer and sepsis, as well as in metabolic regulation in islet β-cells. These findings contribute to understanding the biological functions of Zhx2 and offer potential therapeutic targets for related diseases.