Non-coding RNA research · 2026
circHIPK3 promotes pro-fibrotic epithelial reprogramming via the miR-29a-3p/SPARC axis with associated enhancement of TGF-β/SMAD signaling.
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Zhou Ying, Huang Yixin, Ma Jiangpo, Wang Wei, Tong Zhongkai, Zhou Yong, Cao Yu, Dong Zhaoxing
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.