Preserving Cell Identity: A Precision Strike Against Pulmonary Fibrosis

A new study offers compelling evidence that precisely targeting a cellular stress pathway could protect the lungs from the scarring seen in pulmonary fibrosis without disrupting vital physiological processes elsewhere in the body. The research, led by scientists at UCSF and published in The Journal of Clinical Investigation, identifies a selective molecular switch that governs the fate of alveolar cells in the injured lung and opens the door to a promising new class of antifibrotic therapies.

Idiopathic pulmonary fibrosis (IPF) is marked by irreversible scarring of the lung’s delicate alveolar surfaces. The process often begins with injury to alveolar type 2 (AT2) cells, which normally regenerate the lung epithelium. But in fibrosis, these cells can shift into a dysfunctional transitional state, known as damage-associated transient progenitors (DATPs), which fail to complete repair and instead help sustain the fibrotic environment.

At the heart of this cellular derailment lies IRE1α, a conserved stress sensor embedded in the endoplasmic reticulum. IRE1α responds to misfolded proteins by activating two key outputs: one that helps restore balance by splicing XBP1 mRNA, and another that degrades selected RNAs through a process known as regulated IRE1α-dependent decay (RIDD). While both functions are part of the unfolded protein response (UPR), this study reveals that only RIDD—rather than XBP1 splicing—is responsible for promoting the harmful transition of AT2 cells into profibrotic DATPs.

Using advanced single-cell RNA sequencing, the researchers found that AT2 cells exposed to injury—and high IRE1α activity—showed marked loss of their normal identity and increased expression of DATP markers. Notably, this shift was accompanied by increased RIDD activity but not XBP1 splicing, suggesting that RIDD specifically drives the maladaptive cell fate change. To test this, the team used PAIR2, a novel molecule that selectively inhibits RIDD while sparing the beneficial XBP1 pathway. In mice exposed to bleomycin, a chemical that induces pulmonary fibrosis, treatment with PAIR2 significantly reduced the number of DATPs and preserved normal AT2 cell identity. This also led to less collagen deposition and improved lung structure.

Mechanistically, the study zeroed in on the fibroblast growth factor receptor 2 (Fgfr2) as a critical RIDD target. Fgfr2 is essential for maintaining AT2 cell identity and their regenerative potential. The team showed that IRE1α directly cleaves Fgfr2 mRNA via RIDD, both in live cells and in cell-free assays. Inhibiting RIDD preserved Fgfr2 expression, while experimentally reducing Fgfr2 signaling was sufficient to induce AT2-to-DATP transition. Conversely, enhancing Fgfr2 signaling through downstream effectors like phospholipase C activation protected cells from undergoing fibrotic differentiation—even under IRE1α activation.

Crucially, blocking XBP1 alone did not protect against fibrosis in vivo. Mice with targeted deletion of Xbp1 in lung epithelial cells actually exhibited worse fibrotic outcomes, highlighting the protective role of this adaptive branch of the UPR and underscoring the precision of PAIR2’s selective RIDD inhibition.

The authors suggest that IRE1α’s role in mediating epithelial plasticity may be conserved across other organs, including pancreatic islets and airway basal cells, where Fgfr2 expression is also regulated by this pathway. They propose that what evolved as a protective stress mechanism may, under chronic or unresolved injury, be hijacked into promoting disease.

By isolating RIDD as the pathological effector and sparing XBP1's homeostatic functions, PAIR2 and related molecules may offer a more targeted and tolerable approach to treating fibrotic lung disease. The study paves the way for future therapies that modulate stress responses not by shutting them down entirely, but by surgically removing their most harmful outputs.