Gzma-flox Mouse

Granzyme A (GZMA), a serine protease, is mainly secreted by cytotoxic lymphocytes such as natural killer cells and cytotoxic T lymphocytes. It plays a crucial role in immune-mediated cell death and is involved in multiple pathways, including those related to cell apoptosis, pyroptosis, and ferroptosis [2,1]. GZMA's activity is essential for the immune system's defense against pathogens and tumor cells, and its study using genetic models like KO/CKO mouse models can reveal its role in specific biological processes and disease conditions.

In inflammatory bowel disease (IBD), GZMA secreted by CD8+CD39+ T cells suppresses GPX4-mediated ferroptosis, thereby improving intestinal mucosal barrier function. GZMA inhibits intestinal epithelial cellular PDE4B activation, triggering the cAMP/PKA/CREB cascade signaling to increase CREB nuclear translocation and initiate GPX4 transactivity. Administration of GZMA can alleviate DSS-induced colitis in vivo [1].

In chronic apical periodontitis, GZMA promotes osteoclast cell proliferation while inhibiting cell apoptosis. Inhibition of GZMA using crRNA/Cas13d leads to increased miR-25-3p expression, down-regulation of TGF-β, and subsequent decrease in PAR1 expression within the PARs pathway [3].

In hepatocellular carcinoma, the interaction between GZMA secreted by cytotoxic cells and F2R expressed by tumor cells activates the JAK2/STAT1 signaling pathway, inducing tumor suppression and T cell-mediated killing of tumor cells. Low expression of GZMA and F2R in tumor tissues is correlated with aggressive clinicopathological characteristics and poor prognosis [4].

In conclusion, GZMA is a key molecule in the immune response and is involved in diverse biological processes. Through model-based research, its functions in diseases such as IBD, chronic apical periodontitis, and hepatocellular carcinoma have been revealed. These findings suggest that GZMA could potentially be a therapeutic target for these diseases, highlighting the importance of further research on GZMA's role and mechanism in various pathological conditions.