CREBZF, including its isoforms SMILE (long) and Zhangfei (short), is a transcriptional coregulator. It is involved in multiple biological pathways, such as those related to metabolism, inflammation, and cell cycle regulation. It plays a significant role in various biological processes and diseases, highlighting its overall biological importance. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions [5,7].

In macrophages, CREBZF deficiency attenuates macrophage infiltration, proinflammatory activation, and hyperglycemia in diet-induced insulin-resistant mice, linking it to insulin resistance and type 2 diabetes [1]. In adipose tissue, glucose-induced CREBZF affects thermogenesis; adipose-specific CREBZF knockout (CREBZF FKO) mice show enhanced thermogenic gene expression and browning of inguinal white adipose tissue [2]. In the liver, CREBZF deficiency stimulates cyclin gene family expression and enhances liver regeneration after partial hepatectomy or carbon tetrachloride treatment, as it represses STAT3 dimerization and transcriptional activity [3]. In NASH models, CREBZF deficiency attenuates liver injury, fibrosis, and inflammation, and CREBZF promotes hepatocyte injury and NASH progression by stimulating osteopontin [4]. In Leydig cells, CREBZF silencing inhibits hCG-stimulated testosterone production [5]. In oocytes, inhibition of miR-425-5p, which targets Crebzf, improves impaired oocyte development in reproductively old females [6].

In conclusion, CREBZF is a key regulator in multiple biological processes. KO/CKO mouse models have revealed its roles in diseases like insulin resistance, type 2 diabetes, thermogenesis-related metabolic disorders, liver regeneration, NASH, and oocyte aging. Understanding CREBZF functions can provide insights into the mechanisms of these diseases and potential therapeutic strategies.