Gsdme, also known as Gasdermin E, is a crucial component of the gasdermin family proteins. It plays a significant role in the caspase-dependent programmed cell death pathways, particularly in the switch between apoptosis and pyroptosis. When Gsdme is highly expressed and caspase-3 is activated, Gsdme is cleaved, releasing the N-terminal domain that punches holes in the cell membrane, leading to pyroptosis. When Gsdme expression is low, apoptosis occurs instead [2,4].

In atherosclerosis, ApoE and GSDME dual deficiency mice showed a reduction in atherosclerotic lesion area and inflammatory response when fed a high-fat diet, indicating that Gsdme-mediated pyroptosis promotes the progression of atherosclerosis [1]. In obstructive nephropathy, deletion of Caspase-3 or Gsdme alleviated renal tubule damage, inflammation, and the development of hydronephrosis and kidney fibrosis after ureteral obstruction, suggesting that Gsdme-mediated pyroptosis in renal parenchymal cells contributes to the disease process [3]. In chemotherapy-induced nephrotoxicity, silencing Gsdme alleviated cisplatin-or doxorubicin-induced HK-2 cell pyroptosis, and treatment with a polypeptide targeting mouse caspase 3-Gsdme signaling inhibited caspase 3 and Gsdme activation, alleviating kidney function deterioration in vivo [5].

In conclusion, Gsdme is a key regulator in the apoptosis-pyroptosis switch. Gene knockout mouse models, such as ApoE and GSDME dual deficiency mice, Caspase-3 or Gsdme deletion mice, and Gsdme-silenced models, have revealed its role in diseases like atherosclerosis, obstructive nephropathy, and chemotherapy-induced nephrotoxicity. These studies provide insights into potential therapeutic strategies targeting Gsdme in these disease areas.

References:

1. Wei, Yuanyuan, Lan, Beidi, Zheng, Tao, Yuan, Zuyi, Wu, Yue. 2023. GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis. In Nature communications, 14, 929. doi:10.1038/s41467-023-36614-w. https://pubmed.ncbi.nlm.nih.gov/36807553/

2. Jiang, Mingxia, Qi, Ling, Li, Lisha, Li, Yanjing. 2020. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. In Cell death discovery, 6, 112. doi:10.1038/s41420-020-00349-0. https://pubmed.ncbi.nlm.nih.gov/33133646/

3. Li, Yinshuang, Yuan, Ying, Huang, Zhong-Xing, Mak, Tak W, Xu, Yanfang. 2021. GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy. In Cell death and differentiation, 28, 2333-2350. doi:10.1038/s41418-021-00755-6. https://pubmed.ncbi.nlm.nih.gov/33664482/

4. Bhat, Asif Ahmad, Thapa, Riya, Afzal, Obaid, Dua, Kamal, Gupta, Gaurav. 2023. The pyroptotic role of Caspase-3/GSDME signalling pathway among various cancer: A Review. In International journal of biological macromolecules, 242, 124832. doi:10.1016/j.ijbiomac.2023.124832. https://pubmed.ncbi.nlm.nih.gov/37196719/

5. Shen, Xiujin, Wang, Haibing, Weng, Chunhua, Jiang, Hong, Chen, Jianghua. 2021. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. In Cell death & disease, 12, 186. doi:10.1038/s41419-021-03458-5. https://pubmed.ncbi.nlm.nih.gov/33589596/