Authors
Ying Zhou, Yixin Huang, Jiangpo Ma, Wei Wang, Zhongkai Tong, Yong Zhou, Yu Cao, Zhaoxing Dong
Published in
Non-coding RNA research. Volume 21. Pages 11-27. Epub Sep 18, 2026.
Abstract
Idiopathic pulmonary fibrosis (IPF) is fatal with limited treatments. circHIPK3 is upregulated in fibrotic lungs, but its role in lung epithelial cells and connection to TGF-β/SMAD signaling are unclear.
We used TGF-β1-stimulated lung epithelial cells (A549, BEAS-2B) and a bleomycin-induced mouse model. circHIPK3 was silenced with ASOs. Direct interactions were assessed using luciferase reporter and RNA pull-down assays, and functional intervention experiments were performed to investigate the proposed regulatory axis. TGF-β/SMAD activity was measured by CAGA reporter, and SPARC-TGFBR2 association by co-IP/colocalization.
circHIPK3 was upregulated in TGF-β1-treated epithelial cells and fibrotic lungs. Silencing circHIPK3 reduced epithelial reprogramming, migration, and fibrotic markers. circHIPK3 directly bound miR-29a-3p, increasing SPARC. SPARC silencing phenocopied circHIPK3 knockdown or miR-29a-3p overexpression. SPARC overexpression enhanced TGF-β/SMAD signaling and colocalized with TGFBR2. In vivo, miR-29a-3p blockade exacerbated fibrosis, which was attenuated by SPARC knockdown, supporting a downstream role of SPARC in miR-29a-3p-mediated fibrotic responses.
We identify a circHIPK3/miR-29a-3p/SPARC axis driving pro-fibrotic epithelial reprogramming and TGF-β/SMAD enhancement in experimental pulmonary fibrosis, revealing a mechanism and potential therapeutic target.
PMID:
42819420
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.
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