Foxk1, a forkhead/winged helix transcription factor, is involved in regulating multiple cellular processes such as cell proliferation, differentiation, and metabolism [1,2,3,5,6,7,8,9]. It is associated with pathways like mTORC1-dependent lipid metabolism, Wnt/β-catenin signalling, and aerobic glycolysis, and holds great biological importance in development and disease-related processes. Genetic models, especially KO and CKO mouse models, have been crucial in unravelling its functions [1,2,3,9].

In bone formation, Foxk1 expression decreases in aged mice and osteoporosis patients. Conditional knockout of Foxk1 in pre-osteoblasts and mature osteoblasts in mice leads to decreased bone mass and mechanical strength due to reduced bone formation, as it targets the promoter region of glycolytic enzyme genes, and its absence reduces aerobic glycolysis in osteoblasts [1]. In non-alcoholic fatty liver disease (NAFLD), hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates hepatic steatosis, inflammation, fibrosis, and tumorigenesis, identifying lipid metabolism-related genes as its direct targets [2]. For cardiogenesis, Foxk1 KO in mouse embryoid bodies perturbs cardiogenesis, as it is an important regulator that represses the Wnt/β-catenin signalling pathway to promote differentiation [3]. In rheumatoid arthritis, propionate from B. fragilis disrupts the HDAC3-Foxk1 interaction, reducing Foxk1 stability and blocking interferon signalling in fibroblast-like synoviocytes [4]. In Parkinson's disease, circSV2b upregulates Foxk1 by sponging miR-5107-5p, which in turn positively regulates Akt1 transcription to resist oxidative stress damage [5]. In ovarian cancer, Aurora-A promotes chemoresistance by enhancing Foxk1 expression, which is involved in regulating cell senescence and glycolysis-related genes [8]. In heart regeneration, cardiomyocyte-specific knockout of Foxk1 impairs neonatal heart regeneration after myocardial infarction, while its overexpression enhances cardiac repair in adult mice by promoting cardiomyocyte cell cycle progression and glycolysis [9].

In summary, Foxk1 is a key regulator in multiple biological processes. Studies using KO and CKO mouse models have revealed its significance in diseases such as osteoporosis, NAFLD, congenital heart disease, rheumatoid arthritis, Parkinson's disease, ovarian cancer, and cardiac injury, providing insights into potential therapeutic strategies for these conditions.

References:

1. Liu, Chungeng, Feng, Naibo, Wang, Zhenmin, Long, Houqing, Peng, Songlin. 2024. Foxk1 promotes bone formation through inducing aerobic glycolysis. In Cell death and differentiation, 31, 1650-1663. doi:10.1038/s41418-024-01371-w. https://pubmed.ncbi.nlm.nih.gov/39232134/

2. Fujinuma, Shun, Nakatsumi, Hirokazu, Shimizu, Hideyuki, Ohkawa, Yasuyuki, Nakayama, Keiichi I. 2023. FOXK1 promotes nonalcoholic fatty liver disease by mediating mTORC1-dependent inhibition of hepatic fatty acid oxidation. In Cell reports, 42, 112530. doi:10.1016/j.celrep.2023.112530. https://pubmed.ncbi.nlm.nih.gov/37209098/

3. Sierra-Pagan, Javier E, Dsouza, Nikita, Das, Satyabrata, Gong, Wuming, Garry, Daniel J. . FOXK1 regulates Wnt signalling to promote cardiogenesis. In Cardiovascular research, 119, 1728-1739. doi:10.1093/cvr/cvad054. https://pubmed.ncbi.nlm.nih.gov/37036809/

4. Chen, Hongzhen, Fu, Xuekun, Wu, Xiaohao, Lu, Aiping, Liang, Chao. 2024. Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis. In Bone research, 12, 31. doi:10.1038/s41413-024-00336-6. https://pubmed.ncbi.nlm.nih.gov/38782893/

5. Cheng, Quancheng, Wang, Jianwei, Li, Man, Chen, Chunhua, Zhang, Weiguang. 2022. CircSV2b participates in oxidative stress regulation through miR-5107-5p-Foxk1-Akt1 axis in Parkinson's disease. In Redox biology, 56, 102430. doi:10.1016/j.redox.2022.102430. https://pubmed.ncbi.nlm.nih.gov/35973363/

6. Sukonina, Valentina, Ma, Haixia, Zhang, Wei, Kanduri, Chandrasekhar, Enerbäck, Sven. 2019. FOXK1 and FOXK2 regulate aerobic glycolysis. In Nature, 566, 279-283. doi:10.1038/s41586-019-0900-5. https://pubmed.ncbi.nlm.nih.gov/30700909/

7. Sakaguchi, Masaji, Cai, Weikang, Wang, Chih-Hao, Enerbäck, Sven, Kahn, C Ronald. 2019. FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism. In Nature communications, 10, 1582. doi:10.1038/s41467-019-09418-0. https://pubmed.ncbi.nlm.nih.gov/30952843/

8. Sun, Huizhen, Wang, Husheng, Wang, Xue, Wang, Ziliang, Wang, Xipeng. 2020. Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. In Theranostics, 10, 6928-6945. doi:10.7150/thno.43811. https://pubmed.ncbi.nlm.nih.gov/32550913/

9. Cai, Dongcheng, Liu, Chungeng, Li, Haotong, Zhang, Yuhui, Nie, Yu. 2025. Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration. In Nature communications, 16, 2877. doi:10.1038/s41467-025-57996-z. https://pubmed.ncbi.nlm.nih.gov/40128196/