CHAC1, also known as glutathione-specific γ-glutamylcyclotransferase 1, is a key regulator in multiple biological processes. As a γ-glutamyl cyclotransferase, it degrades glutathione, thereby influencing calcium signaling and mitochondrial function. It is involved in the unfolded protein response pathway and is crucial for maintaining redox balance and regulating cell death pathways [2].

In ischemic stroke, bioinformatic analysis identified CHAC1 as a key gene in ferroptosis progress. ADSC-Exo containing miR-760-3p can inhibit CHAC1 expression, improving neurobehavior function and ferroptosis-related outcomes in I/R mice [1]. In gastric cancer, ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress, suggesting CHAC1 modulates intracellular ROS levels and chemotherapy sensitivity [3]. In lung adenocarcinoma, CHAC1 expression is higher in tumor tissues, and its blockade suppresses tumor progression by interfering with glucose metabolism through PKM2 nuclear translocation [4]. In thyroid carcinoma, overexpression of CHAC1 promotes cell ferroptosis and enhances radiation sensitivity [5]. In breast cancer, high CHAC1 expression is associated with poor prognosis [6]. In LPS-induced HK-2 cells, CHAC1 exacerbates ferroptosis and apoptosis by promoting oxidative stress [7]. Also, short-term methionine starvation accelerates tumoral ferroptosis by stimulating CHAC1 transcription, while intermittent methionine deprivation synergizes with checkpoint blockade therapy through CHAC1 upregulation [8].

In summary, CHAC1 plays essential roles in oxidative stress, ferroptosis, and cell death regulation across various diseases including stroke, cancer, and kidney-related conditions. The study of CHAC1 in these disease models helps understand its biological functions and offers potential therapeutic targets for treatment.

References:

1. Wang, Yong, Niu, Huicong, Li, Luyu, Sha, Xianyi, Zhao, Jing. 2023. Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis. In Journal of nanobiotechnology, 21, 109. doi:10.1186/s12951-023-01862-x. https://pubmed.ncbi.nlm.nih.gov/36967397/

2. Sun, Jiasen, Ren, Hui, Wang, Jiawen, Wang, Yanyan, Yang, Lili. 2024. CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers. In Frontiers in cell and developmental biology, 12, 1458716. doi:10.3389/fcell.2024.1458716. https://pubmed.ncbi.nlm.nih.gov/39534397/

3. Chen, Chunting, Zhai, Ertao, Liu, Yinan, Chen, Jianhui, Cai, Shirong. 2023. ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer. In Cancer cell international, 23, 293. doi:10.1186/s12935-023-03129-9. https://pubmed.ncbi.nlm.nih.gov/38007439/

4. Pan, Junfan, Wu, Sixuan, Pan, Qihong, Li, Jiancheng, Xu, Yiquan. 2024. CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation. In Cell death & disease, 15, 728. doi:10.1038/s41419-024-07114-6. https://pubmed.ncbi.nlm.nih.gov/39368995/

5. Yang, Xinlin, Zhang, Miao, Xia, Wei, Zhao, Bin, Song, Yanan. . CHAC1 promotes cell ferroptosis and enhances radiation sensitivity in thyroid carcinoma. In Neoplasma, 70, 777-786. doi:10.4149/neo_2023_230103N4. https://pubmed.ncbi.nlm.nih.gov/38247333/

6. Mehta, Vikrant, Meena, Jaipal, Kasana, Harit, Munshi, Anjana, Chander, Harish. 2022. Prognostic significance of CHAC1 expression in breast cancer. In Molecular biology reports, 49, 8517-8526. doi:10.1007/s11033-022-07673-x. https://pubmed.ncbi.nlm.nih.gov/35729480/

7. Zhou, Zhihui, Zhang, Hongwei. 2023. CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress. In Allergologia et immunopathologia, 51, 99-110. doi:10.15586/aei.v51i2.760. https://pubmed.ncbi.nlm.nih.gov/36916093/

8. Xue, Ying, Lu, Fujia, Chang, Zhenzhen, Chen, Jing, Wang, Weimin. 2023. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. In Nature communications, 14, 4758. doi:10.1038/s41467-023-40518-0. https://pubmed.ncbi.nlm.nih.gov/37553341/