What does this research mean for the field?

Dual pharmacological inhibition of HIF1A and HIF2A attenuates fibrotic remodeling and restores alveolar epithelial integrity by regulating epithelial-mesenchymal homeostasis in lung fibrosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand how the HIF pathway contributes to epithelial-mesenchymal homeostasis in lung fibrosis.

May 20, 2026

B77-19 Targeting HIF Pathway to Restore Epithelial Mesenchymal Homeostasis

Key Points

This research aims to understand how the HIF pathway contributes to epithelial-mesenchymal homeostasis in lung fibrosis.
3D human induced pluripotent stem cell-derived alveolar type 2 cells were used in experiments.
Cells were treated with HIF inhibitors and exposed to hypoxia and TGF-β1.
Gene and protein levels were measured using qPCR, Western blotting, and RNA-seq.
Hypoxia reduced SFTPC expression in cells, which persisted after reoxygenation.
HIF2A inhibition restored SFTPC expression, while dual HIF1A/HIF2A blockade decreased profibrotic gene expression.
In vivo, dual HIF inhibitors reduced fibrosis in aged mice and improved alveolar cell populations.

Abstract

Abstract Introduction The hypoxia-inducible factor (HIF) pathway plays a pivotal role in the pathogenesis of lung fibrosis. In fibrotic lungs, HIF activation promotes the expression of profibrotic mediators such as connective tissue growth factor (CTGF) and transforming growth factor-beta (TGF-β), which drive fibroblast proliferation, myofibroblasts differentiation, excessive extracellular matrix (ECM) deposition and tissue remodeling. Despite these advances, the role of the HIF pathway in disrupting epithelial-mesenchymal homeostasis remains poorly understood. Elucidating the contribution of HIF signaling to alveolar epithelial dysfunction and fibroblast activation may uncover novel therapeutic opportunities. Targeting HIF or its downstream effectors represents a promising strategy to attenuate fibrotic remodeling and improve outcomes in patients with interstitial lung diseases. Methods Three-dimensional (3D) human induced pluripotent stem cell-derived alveolar type 2 (iAT2; SFTPC+) cells were exposed to hypoxia, fibrotic stimuli, or co-cultured with human lung fibroblasts (hLFs). Pharmacological inhibitors of HIF1A and/or HIF2A were applied to iAT2 cultures and an aged murine bleomycin-induced pulmonary fibrosis model. Gene and protein expression levels of SFTPC, HIFs, and profibrotic markers were assessed using quantitative PCR, Western blotting, immunofluorescence microscopy, and flow cytometry. Chromatin accessibility and transcriptional changes were analyzed by RNA-seq and ATAC-seq. Results Exposure of iAT2 cells to hypoxia significantly reduced SFTPC expression, which remained suppressed even after reoxygenation. Transcriptomic and epigenomic analyses confirmed that hypoxia led to SFTPC silencing through chromatin condensation at its promoter locus. Pre-exposure of iAT2 cells to hypoxia potentiated TGF-β1-induced profibrotic responses in co-cultured hLFs. Treatment with HIF inhibitors mitigated these effects: HIF2A inhibition only restored SFTPC expression suppressed by hypoxia or TGF-β1-induced pseudohypoxia, while dual HIF1A/HIF2A blockade markedly reduced the profibrotic gene expression and enhanced SFTPC expression in iAT2-hLF co-cultures. In vivo, intraperitoneal administration of dual HIF1A/HIF2A inhibitors in aged mice significantly attenuated bleomycin-induced fibrosis and restored alveolar type 2 cell populations. Conclusion These findings identify the HIF pathway as a central regulator of epithelial-mesenchymal imbalance in lung fibrosis. Dual inhibition of HIF1A and HIF2A effectively attenuates fibrotic remodeling while preserving alveolar epithelial integrity. Targeting HIF signaling to restore epithelial-mesenchymal homeostasis represents a promising therapeutic approach for idiopathic pulmonary fibrosis and related fibrotic lung diseases. This abstract is funded by: NIH

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