CXXC5, a member of the CXXC-type zinc-finger protein family, lacks a catalytic domain but can bind to DNA. It functions as a transcription and epigenetic factor through protein-protein interactions. By binding to unmethylated CpG islands in gene promoters, it plays a pivotal role in epigenetic regulation. CXXC5 is an important signal integrator as its expression is controlled by multiple signaling pathways. It regulates various signal transduction processes like TGF-β, Wnt, and ATM-p53 pathways, and is crucial for embryonic development and adult tissue homeostasis by modulating cell proliferation, differentiation, and apoptosis [1].

In hair-related studies, Cxxc5 knockout mice showed accelerated hair regrowth. CXXC5 mediates DHT-induced androgenetic alopecia via PGD2, and suppression of CXXC5 can restore hair growth inhibited by PGD2. This indicates CXXC5 is a negative regulator of the Wnt/β-catenin pathway in hair growth [2,3]. In metabolic diseases, Cxxc5-/-mice fed a high-fat diet exhibited resistance to metabolic dysregulation. Inhibiting the CXXC5-Dvl interaction with a small molecule can reverse metabolic abnormalities, suggesting CXXC5 is a potential therapeutic target for obesity-related diabetes [4]. For diabetic wound healing, KY19334, which inhibits the CXXC5-Dvl interaction, accelerates wound healing in diabetic mice by restoring the suppressed Wnt/β-catenin signaling [5].

In conclusion, CXXC5 is a significant regulator in multiple biological processes. Model-based research, especially using Cxxc5 KO mouse models, has revealed its role in diseases such as androgenetic alopecia, obesity-related diabetes, and diabetic wound healing. These findings suggest CXXC5 could be a potential target for treating these diseases.

References:

1. Xiong, Xiangyang, Tu, Shuo, Wang, Jianbin, Luo, Shiwen, Yan, Xiaohua. 2018. CXXC5: A novel regulator and coordinator of TGF-β, BMP and Wnt signaling. In Journal of cellular and molecular medicine, 23, 740-749. doi:10.1111/jcmm.14046. https://pubmed.ncbi.nlm.nih.gov/30479059/

2. Ryu, Yeong Chan, Park, Jiyeon, Kim, You-Rin, Lee, Soung-Hoon, Choi, Kang-Yell. 2023. CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2. In Cells, 12, . doi:10.3390/cells12040555. https://pubmed.ncbi.nlm.nih.gov/36831222/

3. Lee, Soung-Hoon, Seo, Seol Hwa, Lee, Dong-Hwan, Lee, Won-Soo, Choi, Kang-Yell. 2017. Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis. In The Journal of investigative dermatology, 137, 2260-2269. doi:10.1016/j.jid.2017.04.038. https://pubmed.ncbi.nlm.nih.gov/28595998/

4. Seo, Seol Hwa, Kim, Eunhwan, Lee, Soung-Hoon, Seong, Je Kyung, Choi, Kang-Yell. . Inhibition of CXXC5 function reverses obesity-related metabolic diseases. In Clinical and translational medicine, 12, e742. doi:10.1002/ctm2.742. https://pubmed.ncbi.nlm.nih.gov/35384342/

5. Kim, Eunhwan, Seo, Seol Hwa, Hwang, Yumi, Park, Kwang Hwan, Choi, Kang-Yell. 2023. Inhibiting the cytosolic function of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair. In Experimental & molecular medicine, 55, 1770-1782. doi:10.1038/s12276-023-01064-3. https://pubmed.ncbi.nlm.nih.gov/37524876/