Ctsl, or Cathepsin L, is a lysosomal cysteine proteinase encoded by the Ctsl gene. It is involved in various physiological and pathological processes, including intracellular protein degradation, and has been implicated in regulating cancer progression and SARS-CoV-2 entry into cells [2,5]. In the immune system, T cell-expressed Ctsl processes C3 into biologically active C3a and C3b, which is crucial for T cell homeostasis and effector differentiation [3].

In Glioblastoma multiforme (GBM), GBM tissues have higher Ctsl expression levels than normal brain tissues, and high Ctsl expression is associated with a lower survival rate. Ctsl inhibitor significantly reduces GBM growth and induces mitochondrial apoptosis, indicating Ctsl could be a therapeutic target for GBM [1]. In lung cancer and glioma, high Ctsl expression significantly correlates with a short overall survival, suggesting it might play a role in the susceptibility of these cancer patients to SARS-CoV-2 uptake and COVID-19 severity [2]. Also, in gastric cancer, a CtslHighZBTB7BLow high-risk subgroup was identified based on Ctsl and ZBTB7B expressions, which has unique tumor microenvironment features [4].

In conclusion, Ctsl is a key lysosomal cysteine proteinase involved in multiple biological processes and diseases. Studies, especially those using inhibitors which mimic loss-of-function effects, have revealed its role in cancer progression and the susceptibility of cancer patients to SARS-CoV-2 infection. Understanding Ctsl's functions provides potential therapeutic targets for treating GBM, lung cancer, glioma, and gastric cancer, as well as implications for managing COVID-19 in cancer patients.

References:

1. Dong, Qiang, Li, Qiao, Duan, Lei, Yuan, Guoqiang, Pan, Yawen. 2021. Expressions and significances of CTSL, the target of COVID-19 on GBM. In Journal of cancer research and clinical oncology, 148, 599-608. doi:10.1007/s00432-021-03843-9. https://pubmed.ncbi.nlm.nih.gov/34807310/

2. Zhang, Lianmei, Wei, Chunli, Li, Dabing, Yu, Hong, Fu, Junjiang. 2022. COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2. In International journal of biological sciences, 18, 2362-2371. doi:10.7150/ijbs.70172. https://pubmed.ncbi.nlm.nih.gov/35414771/

3. Liszewski, M Kathryn, Kolev, Martin, Le Friec, Gaelle, Atkinson, John P, Kemper, Claudia. 2013. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. In Immunity, 39, 1143-57. doi:10.1016/j.immuni.2013.10.018. https://pubmed.ncbi.nlm.nih.gov/24315997/

4. Cui, Kaisa, Yao, Surui, Liu, Bingxin, Fei, Bojian, Huang, Zhaohui. 2022. A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer. In British journal of cancer, 127, 1450-1460. doi:10.1038/s41416-022-01936-x. https://pubmed.ncbi.nlm.nih.gov/35941174/

5. Kirschke, H, Langner, J, Riemann, S, Ansorge, S, Bohley, P. . Lysosomal cysteine proteinases. In Ciba Foundation symposium, , 15-35. doi:. https://pubmed.ncbi.nlm.nih.gov/399887/