New Target in the Fight Against Pulmonary Fibrosis
Pulmonary fibrosis is a devastating lung disease characterized by thickened, scarred lungs that struggle to deliver oxygen. In a new study, researchers at the University of California, San Francisco (UCSF) identified a cellular switch that drives this harmful remodeling and demonstrated a way to block it in mice. The findings, published in the Journal of Clinical Investigation, offer a promising molecular target for therapies aimed at halting disease progression and restoring lung function.
The Cellular Switch Behind Fibrosis
The UCSF team zeroed in on a protein called IRE1α, which normally helps cells cope with stress in the endoplasmic reticulum and maintain protein quality. In the context of lung injury, IRE1α activates a process known as RIDD (regulated IRE1α-dependent decay) that can degrade specific genetic messages. One critical target is FGFR2, a receptor that helps alveolar type 2 (AT2) cells retain their identity. When IRE1α cleaves FGFR2’s instructions, AT2 cells lose their footing and stall in a transitional “in-between” state that fuels scar formation rather than repair.
According to Vincent Auyeung, MD, PhD, the study’s first author, blocking FGFR2 degradation prevents AT2 cells from drifting into this harmful limbo, thereby reducing fibrosis. “If the cell loses its bearings due to the loss of FGFR2 guidance, it neither stays the AT2 cell nor becomes the next proper cell type. That transitional state itself drives fibrosis,” Auyeung explained.
A Precision Therapy in the Lab
To test whether blocking IRE1α’s RIDD activity could protect the lungs, the researchers used PAIR2, a selective IRE1α kinase inhibitor designed to suppress the damaging RIDD function while preserving the protein’s normal stress-relief role. The drug’s developers—PAIRED scientists at UCSF and collaborators—describe PAIR2 as a “Goldilocks” inhibitor that tunes IRE1α’s activity rather than shutting it off completely.
In mice with established lung fibrosis, PAIR2 treatment slowed further scarring and, in many cases, partially reversed existing damage. The AT2 cell population stabilized, fewer cells adopted the problematic transitional identity, and scar tissue accumulation decreased significantly. The researchers emphasize that PAIR2’s selective design was crucial to avoid compromising essential cellular stress responses.
Implications for Patients and Beyond
Pulmonary fibrosis affects roughly one in 5,000 people and typically presents in older adults. Patients face a median survival of about five years post-diagnosis, with limited treatment options. The UCSF work suggests a new molecular target that could lead to therapies capable of slowing, stopping, or even reversing fibrosis progression, moving us closer to clinical trials in humans.
Lead investigators Feroz Papa, MD, PhD, and co-senior author Dean Sheppard, MD, stress that this research bridges basic science and potential clinical applications.
“This work highlights how fundamental science can illuminate new paths to treat diseases that once seemed untreatable,” Sheppard said. The authors also note that the IRE1α–RIDD pathway may influence other diseases where cell identity shifts under stress, including diabetes, neurodegeneration, and chronic liver disease.
Next Steps on the Road to the Clinic
While the results are encouraging, substantial work remains before PAIR2 or similar compounds can be tested in people. Key questions include safety, delivery methods, and efficacy across diverse genetic backgrounds and stages of disease. The team remains hopeful that ongoing studies will refine this approach and bring it closer to trials in humans.
About the Researchers
The study was led by UCSF physicians and scientists who are committed to translating bench findings into potential therapies. Their work underscores the importance of maintaining cell identity during tissue repair and reveals how disrupting maladaptive stress responses can yield meaningful clinical benefits.
