CARS1, cysteinyl-tRNA synthetase 1, is an enzyme that attaches cysteine to its cognate tRNA, a crucial step in protein synthesis [1,3]. It is also involved in multiple biological pathways, and its dysregulation has implications in various diseases. Ferroptosis-related pathways seem to be significantly associated with CARS1, as emerging evidence indicates its role in this form of regulated cell death [4,5,6,7,8].

Autoantibodies to cytoplasmic CARS1 were identified as a new antisynthetase autoantibody (ASA) specificity, named anti-Ly, in a patient with antisynthetase syndrome (ASyS) features, suggesting its role in autoimmune-related pathologies [1]. A patient with microcephaly, developmental delay, and brittle hair was found to have compound heterozygous CARS1 variants, expanding the allelic and phenotypic heterogeneity of CARS1-associated disease [3]. In esophageal squamous cell carcinoma (ESCC), CARS1 promotes ferroptosis-induced cell death by regulating GPX4 expression, inhibiting cell proliferation, and migration [4]. High CARS1 expression is associated with an unfavorable prognosis in mesothelioma as part of a ferroptosis-related prognostic gene signature [5]. In a patient with metastatic inflammatory myofibroblastic tumor harboring a CARS1-ALK fusion, targeted therapy with alectinib led to significant tumor regression [2].

In summary, CARS1 has diverse functions in protein synthesis and is involved in multiple disease-related processes such as autoimmunity, developmental disorders, and cancer. Studies on CARS1, including those involving gene-associated fusions and loss-of-function variants, have provided insights into its role in specific disease conditions, highlighting its potential as a therapeutic target in various diseases.

References:

1. Vulsteke, Jean-Baptiste, Derua, Rita, Dubucquoi, Sylvain, Fabien, Nicole, Bossuyt, Xavier. 2022. Mass spectrometry-based identification of new anti-Ly and known antisynthetase autoantibodies. In Annals of the rheumatic diseases, 82, 546-555. doi:10.1136/ard-2022-222686. https://pubmed.ncbi.nlm.nih.gov/36572507/

2. Choi, Songji, Kim, Miso, Kim, Sheehyun, Yun, Hongseok, Kim, Jee Hyun. 2024. ALK Inhibition in a Patient with Inflammatory Myofibroblastic Tumor Harboring CARS1-ALK Fusion. In Cancer research and treatment, , . doi:10.4143/crt.2024.1184. https://pubmed.ncbi.nlm.nih.gov/39701088/

3. Del Greco, Christina, Kuo, Molly E, Smith, Desiree E C, Stancheva, Malina, Antonellis, Anthony. . Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype. In Molecular genetics & genomic medicine, 13, e70078. doi:10.1002/mgg3.70078. https://pubmed.ncbi.nlm.nih.gov/39963003/

4. Zhang, Wanfei, Lin, Xianzuan, Chen, Shaogeng. 2022. Cysteinyl-tRNA Synthetase 1 Promotes Ferroptosis-Induced Cell Death via Regulating GPX4 Expression. In Journal of oncology, 2022, 4849174. doi:10.1155/2022/4849174. https://pubmed.ncbi.nlm.nih.gov/36213827/

5. Wang, Zairui, Huang, Jialin, Fu, Liren, Han, Jingjing, Zhao, Xiaohui. 2024. Identification of the ferroptosis-related prognostic gene signature in mesothelioma. In Gene, 919, 148498. doi:10.1016/j.gene.2024.148498. https://pubmed.ncbi.nlm.nih.gov/38670397/

6. Nie, Jianhua, Shan, Dan, Li, Shun, Zhang, Yanqiao, Zheng, Tongsen. 2021. A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer. In Frontiers in oncology, 11, 654076. doi:10.3389/fonc.2021.654076. https://pubmed.ncbi.nlm.nih.gov/34046350/

7. Zhu, Lei, Yang, Fugui, Wang, Lingwei, Chen, Guohan, Li, Qinchuan. 2021. Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma. In Cancer cell international, 21, 124. doi:10.1186/s12935-021-01821-2. https://pubmed.ncbi.nlm.nih.gov/33602233/

8. Zhao, Guo-Jiang, Wu, Zonglong, Ge, Liyuan, Zhang, Shudong, Ma, Lulin. 2021. Ferroptosis-Related Gene-Based Prognostic Model and Immune Infiltration in Clear Cell Renal Cell Carcinoma. In Frontiers in genetics, 12, 650416. doi:10.3389/fgene.2021.650416. https://pubmed.ncbi.nlm.nih.gov/34178024/