RESEARCHERS at Vanderbilt University Medical Center, the University of Michigan Medical School, and the Translational Genomics Research Institute (TGen) have made significant strides in understanding idiopathic pulmonary fibrosis (IPF), an incurable and progressive lung disease. Their findings offer new hope for developing disease-modifying therapies.
IPF affects approximately 50,000 new patients annually in the U.S., causing chronic scarring in the lungs that leads to coughing, breathlessness, and, ultimately, loss of lung function. Despite existing treatments, many patients still require lung transplants or face poor outcomes. The latest research focuses on the role of hypoxia-inducible factor (HIF) signaling in lung repair and fibrosis.
Using advanced techniques like single-cell RNA sequencing (scRNA-seq), researchers analyzed lung samples from IPF patients and mouse models of repetitive lung injury. They discovered that aberrant epithelial cells—dysfunctional lung cells that drive fibrosis—exhibited persistent activation of HIF2 signaling, encoded by the Epas1 gene.
The research highlights that HIF2 signaling, under chronic injury conditions, disrupts normal lung repair mechanisms, leading to fibrosis. However, interventions targeting HIF2 could reverse this process. In mice, genetic deletion of Hif2a or administration of the small-molecule HIF2 inhibitor PT-2385 significantly reduced fibrosis, decreased the prevalence of abnormal epithelial cells, and promoted alveolar repair.
Notably, human lung organoids treated with PT-2385 demonstrated enhanced maturation of alveolar cells and suppressed emergence of fibrosis-associated epithelial cells. These findings suggest that HIF2 inhibition could restore lung function and potentially halt disease progression in IPF and other interstitial lung diseases.
The research team continues to explore the molecular drivers of pulmonary diseases, supported by $22 million in NIH funding. Their work represents a promising step toward improving outcomes for patients with IPF, offering hope for enhanced lung regeneration therapies in the future.
Reference: McCall AS et al. Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models. Sci Trans Med. 2025;17(780).
Anaya Malik | AMJ
