SNHG26 orchestrates pro-fibrotic fibroblast maintenance via PTBP1-mediated alternative polyadenylation of AKT3 in dermal fibrosis
- 1Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing 210042, China
- 2Jiangsu Provincial Key Laboratory of Dermatology, Nanjing 210042, China
- 3Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China
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 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.
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BibTeX
@article{pan2026snhg26,
title = {{SNHG26 orchestrates pro-fibrotic fibroblast maintenance via PTBP1-mediated alternative polyadenylation of AKT3 in dermal fibrosis}},
author = {Ling Pan and Xilong Ren and Jiating Wang and Yunting Xiao and Liping Zhu and Xiya Zhang and Leqi Qian and Yejing Huang and Li Li and Heng Sun and Renkai Yang and Yi Liu and Xinfeng Wu and Hongsheng Wang and Dongqing Li},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = aug,
doi = {10.1073/pnas.2601536123},
url = {https://doi.org/10.1073/pnas.2601536123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SNHG26 orchestrates pro-fibrotic fibroblast maintenance via PTBP1-mediated alternative polyadenylation of AKT3 in dermal fibrosis
AU - Ling Pan
AU - Xilong Ren
AU - Jiating Wang
AU - Yunting Xiao
AU - Liping Zhu
AU - Xiya Zhang
AU - Leqi Qian
AU - Yejing Huang
AU - Li Li
AU - Heng Sun
AU - Renkai Yang
AU - Yi Liu
AU - Xinfeng Wu
AU - Hongsheng Wang
AU - Dongqing Li
PY - 2026
DA - 2026/08/27
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2601536123
UR - https://doi.org/10.1073/pnas.2601536123
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -