HNRNPC promotes keloid progression via modulating the stability of m6A-modified WDR77 mRNA and expression of TGF-β and SMAD3.

Keloid is a cutaneous fibrotic disorder distinguished by uncontrolled dermal fibroblast proliferation and accumulation of collagen. M⁶A modification is the most prevalent epitranscriptomic modification of eukaryotic mRNAs. M⁶A modification participates in a variety of biological processes of cells, by influencing the stability, translation efficiency, splicing, and transport of mRNAs. Recently, m⁶A modification has garnered interest in keloids, but not fully understood. Here, we discovered that keloids were in hyper-m⁶A modified status, and heterogeneous nuclear ribonucleoprotein C (HNRNPC) was overexpressed in keloid tissues and keloid fibroblasts (KFs). The knockdown of HNRNPC inhibited the migration and proliferation of KFs. Through RIP-PCR and luciferase experiments, WD repeat domain 77 protein (WDR77) was identified as an m⁶A-dependent direct downstream target of HNRNPC. Furthermore, HNRNPC promoted the expression of WDR77 by increasing WDR77 stability, elevating the expression of TGF-β and SMAD3. In keloid xenograft nude mice, HNRNPC siRNAs significantly limited keloid development with reduced WDR77 and TGF-β expression. Thus, our study revealed that HNRNPC regulated the pathological functions of KFs through the m⁶A methylation of WDR77 mRNA, and that the inhibition of HNRNPC limited keloid progression in vivo. Our results decipher a m⁶A-related mechanism and potential therapeutic strategy for combating keloids.