<i>SNHG26</i> orchestrates pro-fibrotic fibroblast maintenance via PTBP1-mediated alternative polyadenylation of <i>AKT3</i> in dermal fibrosis.

Abstract

Fibroblasts are heterogeneous stromal cells with remarkable lineage plasticity, generating distinct subsets that orchestrate either regenerative repair or fibrotic remodeling. However, how the pro-fibrotic fibroblast state is molecularly stabilized after activation remains poorly defined. Here, we identify the long noncoding RNA <i>SNHG26</i> as an essential regulator of fibroblast fate maintenance and fibrogenic activity. <i>SNHG26</i> is markedly enriched in CD90+ fibroblasts within human hypertrophic scars and keloids. Genetic deletion of <i>Snhg26</i> in fibroblasts or antisense oligonucleotide-mediated silencing disrupts mesenchymal identity, suppresses extracellular matrix synthesis, and dramatically attenuates scar formation in murine and xenograft models. Single-cell transcriptomics reveal that loss of <i>SNHG26</i> promotes a mesenchymal-to-papillary fibroblast transition, indicating that <i>SNHG26</i> enforces lineage stability within the scar-forming fibroblast pool. Mechanistically, <i>SNHG26</i> functions as a nuclear scaffold that binds the RNA-binding protein PTBP1, enabling PTBP1-directed alternative polyadenylation of <i>AKT3</i>. This interaction favors distal polyadenylation site usage, generating a long 3'UTR <i>AKT3</i> isoform with enhanced stability, thereby sustaining AKT3 expression and downstream pro-fibrotic signaling. Upstream, TNFα-ERK-STAT3 signaling induces <i>SNHG26</i> transcription, linking chronic inflammation to persistent posttranscriptional activation of fibrogenic pathways. Collectively, these findings define a lncRNA-based regulatory checkpoint in which the <i>SNHG26</i>-PTBP1-AKT3 axis stabilizes mesenchymal fibroblast identity and drives extracellular matrix accumulation. Targeting <i>SNHG26</i> offers a promising therapeutic strategy for preventing pathological scar formation.