Glis1, also known as Gli-like transcription factor 1, is a member of the Krüppel-like zinc finger proteins family and functions as a transcription factor. It plays a crucial role in various biological processes such as cell fate determination, mitochondrial quality control, and immune cell regulation, and is associated with pathways like glycolysis, PGC1-α mediated mitochondrial regulation, and SGK1-STAT3-PD1 pathway [1,2,3]. Glis1 is important in embryonic development, iPSC generation, and has implications in several diseases, making genetic models valuable for its study [4].

In kidney aging, Glis1 knockout (KO) or conditional knockout (CKO) models showed that lower Glis1 expression was accompanied by mitochondrial quality control dysfunctions, including enhanced mitochondrial fission, reduced mitochondrial biogenesis and mitophagy. Over-expressed Glis1 inhibited extracellular matrix accumulation and alleviated renal fibrosis, while siGlis1 (a form of loss-of-function) inhibited PGC1-α transcription and its mitochondria-protective functions, suggesting Glis1 mediates mitochondrial quality control through targeting PGC1-α [2]. In CD8+ T cells of hepatocellular carcinoma (HCC), knocking down Glis1 repressed cancer development, elevated CD8+ T cell infiltrate ability, mitigated cell exhaustion and improved anti-PD1 reaction, as Glis1 promoted CD8+ T cell exhaustion through transcriptional regulating SGK1-STAT3-PD1 pathway [3]. In diabetic kidney disease (DKD), Glis1-CKO mice had increased renal tubular epithelial cell (RTEC) senescence and renal fibrosis, while Glis1 over-expression alleviated these, and Glis1 inhibited tubular accelerated senescence by downregulating histone lactylation [5].

In summary, Glis1 is essential for processes like mitochondrial quality control, immune cell regulation in cancer, and prevention of cellular senescence in the context of kidney-related diseases. The study of Glis1 KO and CKO mouse models has significantly contributed to understanding its role in age-related renal fibrosis, HCC, and DKD, providing potential therapeutic targets for these diseases.

References:

1. Li, Linpeng, Chen, Keshi, Wang, Tianyu, Pan, Guangjin, Liu, Xingguo. 2020. Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade. In Nature metabolism, 2, 882-892. doi:10.1038/s42255-020-0267-9. https://pubmed.ncbi.nlm.nih.gov/32839595/

2. Xu, Li, Wang, Jiao, Yu, Hongyuan, Li, Yanqiu, Liu, Fan. 2023. GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging. In Free radical biology & medicine, 209, 171-184. doi:10.1016/j.freeradbiomed.2023.09.037. https://pubmed.ncbi.nlm.nih.gov/37852548/

3. Rong, Dawei, Wang, Yuliang, Liu, Li, Tang, Weiwei, Wang, Xuehao. . GLIS1 intervention enhances anti-PD1 therapy for hepatocellular carcinoma by targeting SGK1-STAT3-PD1 pathway. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2022-005126. https://pubmed.ncbi.nlm.nih.gov/36787938/

4. Dey, Chandrima, Thummer, Rajkumar P. . An Insight into the Role of GLIS1 in Embryonic Development, iPSC Generation, and Cancer. In Advances in experimental medicine and biology, 1470, 97-113. doi:10.1007/5584_2023_793. https://pubmed.ncbi.nlm.nih.gov/37978100/

5. Chen, Juan, He, Junling, Wang, Xiaoyue, He, Yani, Chen, Kehong. 2024. Glis1 inhibits RTEC cellular senescence and renal fibrosis by downregulating histone lactylation in DKD. In Life sciences, 361, 123293. doi:10.1016/j.lfs.2024.123293. https://pubmed.ncbi.nlm.nih.gov/39643036/