Cyp4x1, a member of the cytochrome P450 family, was initially identified in EST databases. It has a unique localization, being highly expressed in the brain, especially in neurons, choroid epithelial cells, and vascular endothelial cells [4,5]. It may play roles in fatty acid metabolism, endocannabinoid signaling, and neurovascular function [4,5,7]. Its gene expression can be affected by PPARα activation [6].

In a Cyp4x1 knockout mouse model, both male and female knockout mice gained significantly more body weight on a normal lab chow diet compared to control flox mice. Male knockout mice had greater intra-abdominal fat deposits and enlarged adipocytes, suggesting Cyp4x1 plays a role in regulating fat metabolism [7]. In the context of PD-1/PD-L1 inhibitor-related cardiotoxicity, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages through down-regulation of the PPARα-Cyp4x1 axis, while Prevotellaceae-produced butyrate alleviated cardiotoxicity via this axis [1]. In glioma, inhibition of Cyp4x1 in tumor-associated macrophages (TAMs) by flavonoid CH625 prolonged survival and normalized tumor vasculature via the CB2 and EGFR-STAT3 axis [2]. Also, in colorectal cancer, high Cyp4x1 expression was associated with advanced TNM stage, poor tumor differentiation, deeper invasion, lymph node metastasis, and shorter survival times, and its down-regulation inhibited cell proliferation, invasion, migration, and colony formation [3].

In summary, Cyp4x1 is crucial in regulating fat metabolism, and its dysregulation is implicated in various disease conditions such as PD-1/PD-L1 inhibitor-related cardiotoxicity, glioma, and colorectal cancer. The use of knockout mouse models has been instrumental in uncovering these functions, providing potential therapeutic targets for these diseases.

References:

1. Chen, Yaxin, Liu, Yanzhuo, Wang, Yang, Yang, Jing, Zhou, Xiaoyang. 2022. Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages. In Journal of experimental & clinical cancer research : CR, 41, 1. doi:10.1186/s13046-021-02201-4. https://pubmed.ncbi.nlm.nih.gov/34980222/

2. Wang, Chenlong, Li, Ying, Chen, Honglei, Yang, Yuqing, Yang, Jing. 2018. CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis. In The Journal of pharmacology and experimental therapeutics, 365, 72-83. doi:10.1124/jpet.117.247130. https://pubmed.ncbi.nlm.nih.gov/29437915/

3. Kim, Sooyoun, Kim, Hakchun, Hong, Inpyo, Baek, Moojun, Jeong, Dongjun. 2025. CYP4X1 Expression Is Associated with Metastasis and Poor Prognosis in Patients with Colorectal Cancer. In International journal of molecular sciences, 26, . doi:10.3390/ijms26051867. https://pubmed.ncbi.nlm.nih.gov/40076494/

4. Al-Anizy, Mohammed, Horley, Neill J, Kuo, C-W S, Parker, Terry, Bell, David R. . Cytochrome P450 Cyp4x1 is a major P450 protein in mouse brain. In The FEBS journal, 273, 936-47. doi:. https://pubmed.ncbi.nlm.nih.gov/16478468/

5. Bylund, Johan, Zhang, Chenyang, Harder, David R. . Identification of a novel cytochrome P450, CYP4X1, with unique localization specific to the brain. In Biochemical and biophysical research communications, 296, 677-84. doi:. https://pubmed.ncbi.nlm.nih.gov/12176035/

6. Savas, Uzen, Hsu, Mei-Hui, Griffin, Keith J, Bell, David R, Johnson, Eric F. . Conditional regulation of the human CYP4X1 and CYP4Z1 genes. In Archives of biochemistry and biophysics, 436, 377-85. doi:. https://pubmed.ncbi.nlm.nih.gov/15797250/

7. Kharkwal, Himanshu, Batool, Farhat, Koentgen, Frank, Ebling, Francis J P, Duce, Ian R. 2017. Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse. In PloS one, 12, e0187959. doi:10.1371/journal.pone.0187959. https://pubmed.ncbi.nlm.nih.gov/29227996/