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

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 SNHG26 as an essential regulator of fibroblast fate maintenance and fibrogenic activity. SNHG26 is markedly enriched in CD90+ fibroblasts within human hypertrophic scars and keloids. Genetic deletion of Snhg26 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 SNHG26 promotes a mesenchymal-to-papillary fibroblast transition, indicating that SNHG26 enforces lineage stability within the scar-forming fibroblast pool. Mechanistically, SNHG26 functions as a nuclear scaffold that binds the RNA-binding protein PTBP1, enabling PTBP1-directed alternative polyadenylation of AKT3. This interaction favors distal polyadenylation site usage, generating a long 3'UTR AKT3 isoform with enhanced stability, thereby sustaining AKT3 expression and downstream pro-fibrotic signaling. Upstream, TNFα-ERK-STAT3 signaling induces SNHG26 transcription, linking chronic inflammation to persistent posttranscriptional activation of fibrogenic pathways. Collectively, these findings define a lncRNA-based regulatory checkpoint in which the SNHG26-PTBP1-AKT3 axis stabilizes mesenchymal fibroblast identity and drives extracellular matrix accumulation. Targeting SNHG26 offers a promising therapeutic strategy for preventing pathological scar formation.