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. Here, TGFB1 is linked to rheumatic heart disease.