The RNA methyltransferase NSUN2 catalyzes 5-methylcytosine (m(5)C) on IL1B mRNA to promote transcript stability.

Among the plethora of RNA modifications, 5-methylcytosine (m(5)C) has held substantial roles in some biological processes, yet its impact on inflammation remains largely uncharted. Here, we reported an m(5)C-related epitranscriptomic regulatory axis in inflammatory pathogenesis. Bacterial lipopolysaccharides (LPS) challenge induces marked elevation in RNA m(5)C abundance as well as the expression of NOP2/Sun RNA methyltransferase 2 (NSUN2), an essential enzyme catalyzing m(5)C modification. Nsun2 deficient mice showed significantly reduced inflammatory response in the models of systemic inflammation and local pulpitis compared with wild-type control mice. Mechanistically, NSUN2 installs m(5)C modifications on interleukin 1 beta (IL1B) mRNA. These modifications are selectively recognized by the m(5)C reader Y-box binding protein 1 (YBX1), thereby enhancing transcript stability and promoting substantial elevation of IL1B, which might further drive inflammation cascades. Our research highlights a pivotal role of NSUN2-mediated m(5)C RNA modification in regulating inflammatory responses, offering fresh perspectives for the treatment of inflammatory diseases.