Blocking a cellular switch to halt lung scarring
Pulmonary fibrosis is a devastating lung disease where the tissue thickens and scar tissue progressively limits oxygen delivery. In a new study from UC San Francisco, researchers have identified a pivotal cellular switch that drives this damaging process and demonstrated that blocking it can protect lung function in a mouse model. The findings, published in the Journal of Clinical Investigation, offer a promising molecular target that could one day lead to new therapies for people living with this often fatal disease.
At the heart of the discovery is a protein called IRE1α, which normally helps cells cope with stress in the endoplasmic reticulum, a cellular organelle that folds proteins. In the context of lung injury, however, IRE1α triggers a destructive response known as RIDD (regulated IRE1α-dependent decay), which shreds certain genetic instructions and disrupts how cells maintain their identity. In alveolar type 2 (AT2) cells, which are essential for keeping the air sacs healthy and capable of repairing damage, this degradation pushes cells into a hazardous “in-between” state. Those intermediary cells not only fail to repair properly but also emit signals that accelerate scarring.
How losing identity fuels disease
Lead investigator Vincent Auyeung, MD, PhD, explains that when IRE1α cuts FGFR2, a gene that normally helps AT2 cells hold on to their identity, the cells lose their bearings. “They stop being the cell they were, but they don’t become the cell they’re supposed to be either,” he notes. That transitional state appears to drive the fibrosis process, creating a self-perpetuating cycle of damage and scarring. The team’s work provides a clear mechanistic link between cellular stress responses and the aberrant cell states that characterize pulmonary fibrosis.
A precision drug approach to interrupt the destructive switch
To test whether suppressing this pathway could benefit diseased lungs, the UCSF team used a drug called PAIR2. This compound selectively blocks IRE1α’s harmful RIDD activity while sparing its normal protective functions. PAIR2 is designed to operate in a “Goldilocks Zone,” dampening the damaging parts of IRE1α without fully turning off its beneficial duties. This nuanced approach aims to minimize potential side effects while still delivering therapeutic benefit.
In mice with established lung scarring, PAIR2 slowed further fibrosis and, in many cases, partially reversed some of the existing damage. The treatment helped AT2 cells retain their identity, reduced the population of intermediary, dysfunctional cells, and significantly decreased scar tissue buildup. Importantly, the researchers emphasized that their goal was to block only the RIDD-driven misdirection, not to shut down all of IRE1α’s cellular duties.
What this means for patients and future work
While this work is in preclinical models, it provides a compelling proof of concept that a targeted molecular intervention can alter the course of pulmonary fibrosis. The findings also illuminate a broader principle: cellular stress not only damages cells but can drive them to adopt maladaptive identities with harmful consequences across multiple organ systems, including diabetes and neurodegenerative diseases. The UCSF team stresses that additional work is needed to evaluate safety, dosing, and delivery of PAIR2 or similar molecules in humans and to determine whether the benefits seen in mice translate to people.
From bench to bedside: a hopeful path forward
As co-senior author Dean Sheppard, MD, points out, this study underscores the long arc from basic science to potential therapies. By clarifying how a single protein’s activity can toggle the fate of lung cells, the research opens doors to new strategies that could complement existing treatments and, for some patients, slow or halt disease progression. The team is pursuing further preclinical development and planning to address the delivery and safety considerations necessary before any human trials could begin.
Why this breakthrough matters
Pulmonary fibrosis remains one of the most challenging lung diseases, with limited options and a median survival around five years after diagnosis. A targeted approach that preserves normal lung cell identity while preventing harmful transitions represents a meaningful advance. The UCSF findings emphasize the power of fundamental science to uncover actionable targets, offering fresh hope to patients and families affected by this relentless illness.
