SNORD99 promotes endometrial cancer development by inhibiting GSDMD‐mediated pyroptosis through 2'‐O‐methylation modification

Eukaryotic cells possess multiple mechanisms of self‐destruction, including pyroptosis and necroptosis. Pyroptosis is a type of programmed cell death characterized by cellular rupture and linked to inflammation. SnoRNA, a small non‐coding RNA in the nucleolus, can dysregulate specific RNAs through 2'‐O‐methylation, contributing to tumorigenesis. Our StarBase and qRT‐PCR analysis revealed SNORD99 upregulation in endometrial cancer (EC) tissue compared to normal tissue, suggesting its role in pathogenesis. SNORD99 overexpression enhanced migration and proliferation of EC cells, while ASO‐mediated suppression reduced malignant cell spread and division. RNA‐seq and base‐comparing analysis identified GSDMD's differential expression upon SNORD99 overexpression, forming the SNORD99‐FBL RNP complex. RTL‐P experiments showed SNORD99 increased GSDMD's 2'‐O‐methylation. SNORD99 reduced GSDMD, caspase‐1, and NLRP3 protein levels, implicating its role in pyroptosis. Optical and electron microscopy confirmed enhanced pyroptosis features. In summary, SNORD99 modifies GSDMD via 2'‐O‐methylation, suppressing pyroptosis and promoting EC progression. Developing pyroptosis‐inducing drugs may offer new cancer treatment avenues.