Ctsh, also known as cathepsin H, is a lysosomal cysteine protease with unique aminopeptidase activity [5]. It is extensively expressed in various tissues like the lung, pancreas, and brain. Cathepsin H has critical effects on regulating cancer cell biological behaviors and pathological processes in brain diseases. It functions optimally at a neutral pH, suggesting activity in extra-lysosomal and extracellular spaces. It is involved in multiple pathways such as hedgehog signaling, cytokine-cytokine receptor interaction, and JAK-STAT signaling [2].

In bladder cancer, multi-omics analyses showed that Ctsh is correlated with chemoresistance and semi-squamatization. Inhibition of cathepsin by E64 treatment induced full squamous differentiation and pyroptosis, restraining chemoresistant muscle-invasive bladder cancers (MIBCs) [1]. In type 1 diabetes (T1D), the T allele of rs3825932 was associated with lower Ctsh expression. Proinflammatory cytokines decreased Ctsh expression in human islets and primary rat β-cells, and overexpression of Ctsh protected insulin-secreting cells against cytokine-induced apoptosis. The TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients [3]. In Alzheimer's disease, rs2289702 in Ctsh was identified as a significant functional variant with a protective effect. Ctsh mRNA expression was increased in AD patients and animal models, and the protective allele was associated with decreased Ctsh expression [4].

In conclusion, Ctsh plays essential roles in various biological processes and disease conditions. Its study using different models has revealed its significance in cancer, diabetes, and neurodegenerative diseases. In cancer, it is linked to chemoresistance; in T1D, it regulates β-cell function and disease progression; and in Alzheimer's disease, it is associated with genetic susceptibility. Understanding Ctsh provides insights into disease mechanisms and potential therapeutic strategies.

References:

1. Wang, Manli, Chen, Xuelan, Tan, Ping, Liu, Yu, Chen, Chong. . Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer. In Cancer cell, 40, 1044-1059.e8. doi:10.1016/j.ccell.2022.08.010. https://pubmed.ncbi.nlm.nih.gov/36099882/

2. Peng, Pai, Chen, Jiang-Yuan, Zheng, Kai, Hu, Chao-Hua, Han, Yun-Tao. 2021. Favorable Prognostic Impact of Cathepsin H (CTSH) High Expression in Thyroid Carcinoma. In International journal of general medicine, 14, 5287-5299. doi:10.2147/IJGM.S327689. https://pubmed.ncbi.nlm.nih.gov/34522128/

3. Fløyel, Tina, Brorsson, Caroline, Nielsen, Lotte B, Størling, Joachim, Pociot, Flemming. 2014. CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. In Proceedings of the National Academy of Sciences of the United States of America, 111, 10305-10. doi:10.1073/pnas.1402571111. https://pubmed.ncbi.nlm.nih.gov/24982147/

4. Li, Yu, Xu, Min, Xiang, Bo-Lin, Bi, Rui, Yao, Yong-Gang. 2023. Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer's disease. In Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48, 1555-1566. doi:10.1038/s41386-023-01542-2. https://pubmed.ncbi.nlm.nih.gov/36739351/

5. Wang, Yanfeng, Zhao, Juan, Gu, Yebo, Qing, Hong, Ni, Junjun. 2023. Cathepsin H: Molecular characteristics and clues to function and mechanism. In Biochemical pharmacology, 212, 115585. doi:10.1016/j.bcp.2023.115585. https://pubmed.ncbi.nlm.nih.gov/37148981/