Fgf9, or Fibroblast growth factor 9, is a cytokine involved in multiple biological processes. It modulates cell proliferation, differentiation, and motility, and is associated with pathways like ERK1/2-GSK-3β, PI3K/AKT/Hippo, MAPK/ERK, and Wnt/β-catenin. It is crucial for maintaining normal physiological functions and its dysregulation is linked to various diseases [1,2,3,5]. Genetic models, especially KO/CKO mouse models, have been instrumental in understanding its functions.

In NASH-driven HCC, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden in mouse models, indicating its role in promoting tumor formation via the ECM pathway [1]. In osteoporosis, Fgf9 loss-of-function mutation (S99N) in mice inhibited bone marrow adipose tissue formation and alleviated ovariectomy-induced bone loss, revealing its role in regulating bone-fat balance [2]. Fgf9-/-mice exhibited 100% penetrance of cleft palate, highlighting its importance in palatogenesis through regulating HAS2 expression via the Wnt/β-catenin/TCF7L2 pathway [3]. The Fgf9S99N mutation in mice led to reduced ameloblasts, impaired enamel formation, and increased apoptosis in the cervical loop, showing its essentiality for dental epithelial stem cell survival and enamel formation [4]. In TM3 mouse Leydig progenitor cells, FGF9 promoted cell proliferation and tumorigenesis, and in allograft mouse models, it enhanced the tumorigenesis of TM3 cells [5]. Hepatic FGF9 knockdown in DIO mice aggravated the fatty liver phenotype, while its overexpression alleviated hepatic steatosis, suggesting its role in regulating hepatic lipid metabolism [6]. Deletion of Fgf9 in GABAergic neurons in mice caused epilepsy, indicating its role in GABAergic neuron survival and epilepsy pathology [7].

In conclusion, Fgf9 plays essential roles in various biological processes such as tissue development, metabolism, and maintaining cellular homeostasis. Studies using KO/CKO mouse models have significantly contributed to understanding its role in diseases like NASH-driven HCC, osteoporosis, cleft palate, dental development, fatty liver, and epilepsy, providing potential therapeutic targets for these conditions.