Pharmacologic METTL3 inhibition attenuates TGF-beta-driven profibrotic signature in systemic sclerosis

Systemic sclerosis (SSc) is a devastating fibrosing disorder affecting the skin and internal organs, associated with the highest mortality among all rheumatic diseases. The mechanisms underlying excessive fibrogenesis in SSc are incompletely defined and treatment options are limited. N6-methyladenosine (m6A), the most abundant internal mRNA modification, is a reversible and pharmacologically tractable determinant of RNA fate. Here we mapped the m6A epitranscriptome of peripheral blood mononuclear cells (PBMCs) from patients with SSc using two orthogonal single-nucleotide-resolution platforms, a MazF-based m6A microarray and nanopore direct RNA sequencing. SSc PBMCs showed coordinated upregulation of the m6A writer complex (METTL3, METTL14, WTAP), a two-fold increase in global m6A, and redistribution of m6A marks from 3' untranslated regions toward coding sequences. Both platforms converged on TGF-b signaling as the most enriched pathway among differentially methylated transcripts, with hypermethylation of TGFB1, JUNB and KLF10 transcripts. Pharmacologic inhibition of METTL3 with STM2457 significantly reversed TGF-b-induced transcriptomic changes in skin fibroblasts preventing their transformation into pathological myofibroblasts. Together, these findings uncover an epitranscriptomic signature driving profibrotic transcriptional alterations in SSc, including enhanced TGF-b signaling, which can be effectively reversed by clinically available enzymatic m6A inhibitors. Our data suggest that targeting m6A methylation may offer a novel therapeutic strategy to mitigate fibrosis in SSc.