Granzyme A (GZMA), a serine protease, is crucial in the immune response, particularly in cytotoxic lymphocyte-mediated immunity. It is involved in multiple pathways, such as those related to cell death and inflammation regulation. GZMA is important for maintaining normal physiological functions and its dysregulation may lead to various disease states [2].

In inflammatory bowel disease (IBD), GZMA secreted by CD8+CD39+ T cells suppresses GPX4-mediated ferroptosis, enhancing intestinal epithelial barrier function by inducing Occludin and Zonula Occludens-1 expression. Mechanistically, it inhibits PDE4B activation, triggering the cAMP/PKA/CREB cascade signaling to increase GPX4 transactivity. Administration of GZMA alleviates DSS-induced colitis in vivo, suggesting its potential as a treatment strategy for IBD [1].

In chronic apical periodontitis, GZMA promotes osteoclast cell proliferation and inhibits apoptosis. Inhibiting GZMA using crRNA/Cas13d increases miR-25-3p expression, downregulating TGF-β and PAR1 in the PARs pathway, indicating GZMA could be a therapeutic target for this oral disease [3].

For sepsis, IL7R, GZMA and CD8A may serve as potential molecular biomarkers, which are key genes associated with sepsis development [4].

In breast cancer, GZMA expression is lower in cancer tissue, and its overexpression is associated with better prognosis. It is significantly correlated with immune cell infiltration and T-cell checkpoints, suggesting it may be a promising therapeutic target [5].

In allergic rhinitis, GZMA is highly expressed in an AR mouse model. Silencing GZMA reduces inflammatory cytokines, inhibits cell apoptosis and promotes cell proliferation by inhibiting the JAK2/STAT1 pathway [6].

In hepatocellular carcinoma, GZMA secreted by cytotoxic cells interacts with F2R on tumor cells, activating the JAK2/STAT1 signaling pathway to induce tumor suppression. Low GZMA and F2R expression in tumors is associated with poor prognosis, and their interaction provides a novel immunotherapy strategy [7].

In rheumatoid arthritis, GZMA, along with CXCR4, CCL5, and CD8A, can be used as a diagnostic biomarker. GZMA is positively correlated with follicular helper T cells, potentially participating in the early pathogenesis of RA [8].

In conclusion, GZMA is involved in a variety of biological processes and disease conditions. Through studies in disease models, it has been shown to play important roles in maintaining the integrity of the intestinal mucosal barrier, regulating osteoclast function, potentially serving as a biomarker in sepsis, influencing prognosis and immune infiltration in breast cancer, affecting allergic rhinitis through the JAK2/STAT1 pathway, providing a novel immunotherapy strategy in hepatocellular carcinoma, and being a diagnostic biomarker in rheumatoid arthritis. These findings highlight the significance of GZMA in understanding disease mechanisms and developing potential treatments.

References:

1. Niu, Rongwei, Lan, Jiaoli, Liang, Danxia, Gong, Sitang, Yang, Min. 2024. GZMA suppressed GPX4-mediated ferroptosis to improve intestinal mucosal barrier function in inflammatory bowel disease. In Cell communication and signaling : CCS, 22, 474. doi:10.1186/s12964-024-01836-y. https://pubmed.ncbi.nlm.nih.gov/39367435/

2. Zhou, Zhiwei, He, Huabin, Wang, Kun, Ding, Jingjin, Shao, Feng. 2020. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. In Science (New York, N.Y.), 368, . doi:10.1126/science.aaz7548. https://pubmed.ncbi.nlm.nih.gov/32299851/

3. Jia, Tingting, Yuan, Fang, Tao, Jingqiao, Zhang, Bin, Li, Hongbo. 2023. CRISPR/Cas13d targeting GZMA in PARs pathway regulates the function of osteoclasts in chronic apical periodontitis. In Cellular & molecular biology letters, 28, 70. doi:10.1186/s11658-023-00477-2. https://pubmed.ncbi.nlm.nih.gov/37626297/

4. Li, Jin, Wang, Lantao, Yu, Bin, Su, Jie, Dong, Shimin. 2024. IL7R, GZMA and CD8A serve as potential molecular biomarkers for sepsis based on bioinformatics analysis. In Frontiers in immunology, 15, 1445858. doi:10.3389/fimmu.2024.1445858. https://pubmed.ncbi.nlm.nih.gov/39654893/

5. Huo, Qin, Ning, Lvwen, Xie, Ni. 2023. Identification of GZMA as a Potential Therapeutic Target Involved in Immune Infiltration in Breast Cancer by Integrated Bioinformatical Analysis. In Breast cancer (Dove Medical Press), 15, 213-226. doi:10.2147/BCTT.S400808. https://pubmed.ncbi.nlm.nih.gov/36926265/

6. Li, Lin, Zhang, Yuhao, Wang, Jingyuan, Wang, Tian, Zhao, Fei. . GZMA silencing inhibits JAK2/STAT1 pathway and improves allergic rhinitis. In General physiology and biophysics, 44, 93-106. doi:10.4149/gpb_2024045. https://pubmed.ncbi.nlm.nih.gov/40116417/

7. Gao, Yuxue, Xu, Qingguo, Li, Xinqiang, Chen, Dexi, Yang, Tongwang. 2022. Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma. In Cell death & disease, 13, 213. doi:10.1038/s41419-022-04654-7. https://pubmed.ncbi.nlm.nih.gov/35256589/

8. Zhou, Sheng, Lu, Hongcheng, Xiong, Min. 2021. Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Rheumatoid Arthritis by Bioinformatics Analysis. In Frontiers in immunology, 12, 726747. doi:10.3389/fimmu.2021.726747. https://pubmed.ncbi.nlm.nih.gov/34484236/