Gsdmc, or gasdermin C, is a member of the gasdermin family involved in pyroptosis, a form of regulated cell death. It is associated with multiple pathways, such as the caspase-8-mediated cleavage pathway, which links it to the metabolite α-ketoglutarate (α-KG) and death receptor 6 (DR6) [1]. Pyroptosis is crucial for host defense against pathogens, but excessive pyroptosis can lead to cytokine storm and tissue damage [3].

In pancreatic adenocarcinoma (PAAD), depletion of Gsdmc inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells, suggesting it may promote the proliferation and migration of PAAD cell lines [2]. In breast cancer, antibiotic chemotherapy drugs can induce pyroptosis, and high expression of Gsdmc correlates with poor survival. PD-L1 under hypoxia enhances Gsdmc transcription, leading to TNFα-induced pyroptosis in cancer cells [4]. In colon epithelial cells, N6-adenomethylation of Gsdmc by Mettl14 is essential for Lgr5+ stem cell survival and normal colonic epithelial morphogenesis [5]. Gsdmc also sensitizes tumor cells to PARP inhibitor therapy in various cancer types, and T cell-derived granzyme B can activate caspase-6 to cleave Gsdmc, inducing pyroptosis [6]. During helminth infection, intraepithelial mast cells drive Gsdmc-mediated type 2 immunity through the release of interleukin-33 (IL-33) [7].

In conclusion, Gsdmc plays a significant role in pyroptosis-related biological processes. Its functions have been revealed through various in vivo studies, especially in relation to cancer development and progression, colonic epithelial morphogenesis, and type 2 immunity. Understanding Gsdmc's role in these processes may provide new therapeutic targets for treating related diseases.

References:

1. Zhang, Jia-Yuan, Zhou, Bo, Sun, Ru-Yue, Chen, Hang-Zi, Wu, Qiao. 2021. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. In Cell research, 31, 980-997. doi:10.1038/s41422-021-00506-9. https://pubmed.ncbi.nlm.nih.gov/34012073/

2. Yan, Cheng, Niu, Yandie, Li, Feng, Zhao, Wei, Ma, Liukai. 2022. System analysis based on the pyroptosis-related genes identifies GSDMC as a novel therapy target for pancreatic adenocarcinoma. In Journal of translational medicine, 20, 455. doi:10.1186/s12967-022-03632-z. https://pubmed.ncbi.nlm.nih.gov/36199146/

3. Vasudevan, Swathy O, Behl, Bharat, Rathinam, Vijay A. 2023. Pyroptosis-induced inflammation and tissue damage. In Seminars in immunology, 69, 101781. doi:10.1016/j.smim.2023.101781. https://pubmed.ncbi.nlm.nih.gov/37352727/

4. Hou, Junwei, Zhao, Rongce, Xia, Weiya, Tainer, John A, Hung, Mien-Chie. 2020. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. In Nature cell biology, 22, 1264-1275. doi:10.1038/s41556-020-0575-z. https://pubmed.ncbi.nlm.nih.gov/32929201/

5. Du, Jie, Sarkar, Rajesh, Li, Yan, He, Chuan, Li, Yan Chun. 2022. N6-adenomethylation of GsdmC is essential for Lgr5+ stem cell survival to maintain normal colonic epithelial morphogenesis. In Developmental cell, 57, 1976-1994.e8. doi:10.1016/j.devcel.2022.07.006. https://pubmed.ncbi.nlm.nih.gov/35917813/

6. Wang, Shuanglian, Chang, Chiung-Wen, Huang, Juan, Hung, Mien-Chie, Hou, Junwei. 2024. Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models. In The Journal of clinical investigation, 134, . doi:10.1172/JCI166841. https://pubmed.ncbi.nlm.nih.gov/37883181/

7. Yang, Liu, He, Huabin, Guo, Xue-Kun, Liu, Wanli, Hu, Xiaoyu. 2024. Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity. In Immunity, 57, 1056-1070.e5. doi:10.1016/j.immuni.2024.03.017. https://pubmed.ncbi.nlm.nih.gov/38614091/