Overall, our data suggests that PRKCA can be hypermethylated by PRKCA-AS1-meidated DNMT1 through p38/MAPK/TGF-β1/Smad signaling pathway against RHD, which advance the understanding of pathogenesis and progression of RHD, and provide the potential therapeutic targets for RHD. This evidence concerns the gene PRKCA and rheumatic heart disease.