How to stop the cellular “limbo” that leads to lung scar tissue? A new study by a team from the University of California, San Francisco brings an important breakthrough in understanding why, in pulmonary fibrosis, normal alveolar cells get stuck in a transitional, dysfunctional state and how to pharmacologically interrupt this state. The mechanism in question involves the cellular stress sensor IRE1α and its RNase-dependent activity known as RIDD (regulated IRE1-dependent decay), which degrades specific messages (mRNA) and thereby redirects the cell's fate. The results, published on October 15, 2025, in the prestigious Journal of Clinical Investigation, show that selectively blocking RIDD with the experimental drug PAIR2 in mice protects lung tissue from scarring and preserves the identity of alveolar type 2 (AT2) cells.
Why is pulmonary fibrosis so devastating and why is the “transitional” cell the target
Pulmonary fibrosis represents a group of diseases in which lung tissue gradually becomes thickened and stiff, losing its elasticity and ability to exchange gas. Idiopathic pulmonary fibrosis (IPF) — the most common form — often affects older adults, progresses silently, and the median survival after diagnosis remains limited despite available antifibrotic therapies. In the last few years, advances in single-cell profiling and spatial transcriptomics have revealed that during tissue repair, a special population of “transitional” epithelial cells accumulates (designated in the literature as DATP, KRT8+, or “aberrant basaloid”), which are neither fully mature AT1 cells nor their original AT2 cells. It is precisely these transitional cells that secrete signals which promote fibroblasts, extracellular matrix remodeling, and the development of scar tissue.
Under healthy conditions, AT2 cells serve as the “service station” for the alveoli: they replenish surfactant and can differentiate into AT1 cells when repair is needed. But under chronic stress, they get stuck in a partial transformation — a “limbo” — in which they lose function without gaining a new one. Clarifying what pushes cells into such a limbo is one of the biggest challenges in pulmonology and regenerative medicine.
IRE1α: the master switch of the stress response that changes cell identity
IRE1α is a transmembrane protein of the endoplasmic reticulum and a key node of the unfolded protein response (UPR). When activated, IRE1α can act via two pathways: by splicing the mRNA for the transcription factor XBP1 — which usually helps the cell adapt to stress — and by the “RIDD” mechanism, which selectively cleaves certain mRNAs and microRNAs. The new study has precisely shown that it is RIDD that pushes AT2 cells off their normal trajectory, pushing them towards a pro-fibrotic, transitional phenotype.
A particularly important finding concerns the FGFR2 receptor: thanks to comprehensive experiments on primary AT2 cells and biochemical systems, the authors confirmed that Fgfr2 mRNA is a direct target of the IRE1α RNase. When RIDD “cuts up” the instructions for FGFR2, the AT2 cell loses the signaling anchor point that normally maintains its identity. Consequently, the cell gets stuck in the transitional state that is strongly linked to fibrotic remodeling. Supplementing/enhancing FGF signaling protects against this unwanted turn, while the loss of the FGF signal accelerates the degradation of AT2 cell identity.
From molecular distinction to a therapeutic idea: selective “silencing” of RIDD
The clinical challenge is: how to selectively interfere with the harmful RIDD activity without completely shutting down the beneficial adaptive function of IRE1α (XBP1 splicing)? The answer comes through a compound called PAIR2, a carefully designed partial antagonist of the IRE1α kinase that “shifts” the protein's conformation so that RIDD is silenced, while simultaneously preserving the XBP1-dependent adaptation. In mice exposed to the standard model for inducing fibrosis (bleomycin), PAIR2 significantly reduced the differentiation of AT2 cells into pro-fibrotic transitional cells and mitigated the accumulation of scar tissue.
This precise modulation is not the first attempt to interfere with IRE1α for antifibrotic purposes, but it is the most selective to date in terms of “separating” functions (the so-called Goldilocks approach). Earlier compounds of the KIRA class (kinase-inhibiting RNase attenuators), for example, KIRA7 or KIRA8, showed that interfering with IRE1α could prevent or even reverse fibrotic changes in animal models, but at the same time, the challenge of how to preserve the beneficial adaptive branches of the UPR remained. PAIR2 was designed precisely to strike that balance.
What are AT2 cells and why are they at the center of the story
AT2 cells are located on the surface of the alveoli and are responsible for synthesizing surfactant, a substance that prevents alveolar collapse. In addition to their role as “servicers,” they also represent a reservoir of progenitor cells from which AT1 cells — thin, flat cells that cover most of the alveolar surface and enable the exchange of oxygen and carbon dioxide — are created during repair. When an AT2 cell loses the FGFR2 signal or enhances stress characteristics (e.g., due to toxins, infections, chemotherapy, smoking, or age), the IRE1α-RIDD mechanism can sever key instructions and rearrange the programmatic flows of transcription and translation, thereby “freezing” the cell in a transitional phenotype.
Such a limbo is not the same in every situation: there are “regenerative” transitional cells that participate in normal repair, and “fibrotic” transitional cells that dominate in pathological conditions like idiopathic pulmonary fibrosis. The new analysis of differential expression and regulatory networks shows that the latter are strongly associated with the signature of IRE1α activation, markers of cellular stress (UPR/ISR), senescence, and inflammatory signals, which helps explain why their accumulation correlates with a poor outcome of tissue repair.
From mouse to human: cautious optimism and the questions that follow
Translating such insights into therapy for humans involves several steps. First, the safety profile of long-term, partial inhibition of the IRE1α kinase in multiple tissues and systems needs to be confirmed (as UPR is a universal mechanism). Second, the best route of administration and pharmacokinetics that target the respiratory epithelium, while avoiding systemic effects, must be developed. Third, the identification of biomarkers that track the “silencing” of RIDD and the preserved XBP1 branch would be crucial for early assessment of the response. In their indication experiments, the authors used single-cell profiling to quantify the IRE1α signature in AT2 cells and the so-called “aberrant basaloid” population in IPF samples, suggesting that similar signatures could become diagnostic or pharmacodynamic tools in clinical trials as well.
A valuable insight is also that the RIDD–FGFR2 axis is linked to maintaining the identity of epithelial cells not only in the lungs but also in other endodermal tissues, which opens up a research area for diseases of the liver, pancreas, or digestive system, where the loss of cellular identity and the transition into dysfunctional states is a recognized pattern of pathophysiology.
Where the concept fits into the bigger picture of diseases that “start” with cellular stress
Cellular stress and UPR are not exclusive to the lungs. Numerous conditions — from metabolic diseases like diabetes to neurodegeneration and chronic liver damage — share a common motif: a long-term burden on proteostasis, oxidative stress, inflammation, and changes in intercellular communication. The IRE1α/XBP1/RIDD node appears in this context as a “dispatcher” that can direct the outcome towards adaptation or damage. In the lungs, where the epithelium is exposed to inhalational irritants, this “switch” is particularly prominent. The new findings precisely point the finger at RIDD as the culprit for the degradation of critical messages (such as Fgfr2) and provide a clear therapeutic target.
PAIR2: what we know about the compound and why “partiality” is an advantage
PAIR2 is described as a potent and selective partial antagonist of the RNase activity of IRE1α, designed to occupy the kinase's ATP-binding site and disable the conformational state required for RIDD, while preserving XBP1 splicing. Unlike global inhibitors that “silence” the entire IRE1α program, PAIR2 targets the pathological modality, i.e., the destructive degradation of specific transcripts, without compromising the cell's basal ability to overcome moderate stress. In models of bleomycin-induced pulmonary fibrosis, this was reflected as less scarring and better preservation of alveolar architecture.
For comparison, earlier generations of small molecules (KIRA7, KIRA8, and related compounds) provided early proof-of-concept that inhibiting IRE1α could prevent or reverse fibrosis, but only recent modulatory strategies have allowed for the fine-tuning of the balance between adaptation and pathological mRNA degradation. This opens up space for “precision” antifibrotic therapy, at least in the early phase of clinical development.
From the lab to patients: key steps towards first trials
Although the results from animal models are encouraging, the path to human trials involves standard hurdles: toxicology in multiple species, studying the long-term effects on other organ systems that depend on UPR, defining the dosage and route of administration, and validating biomarkers. The research team emphasizes that the goal is to controlledly switch off RIDD without “shutting down” XBP1-dependent adaptation, which requires precise dosing and pharmacokinetics. In parallel, advances in imaging and sequencing (single-cell RNA-seq, spatial transcriptomics) could provide early windows into efficacy — for example, a decrease in the number of pro-fibrotic transitional cells or the preservation of the AT2 identity signature — before changes are visible on high-resolution CT scans or spirometry.
Why the date October 15, 2025, is important and what we have learned by October 19, 2025
The publication in the Journal of Clinical Investigation on October 15, 2025, consolidated the multi-year work of several groups in the field: from the discovery of transitional populations in fibrotic lungs to the mapping of regulatory networks that separate the healthy regenerative pathway from the pathological one. Today, October 19, 2025, the message is clear: it is crucial to differentiate between good and bad transitional states and to selectively silence those signals that push cells into a dead end. The IRE1α-RIDD–FGFR2 axis provides an example of how a single molecular “switch” can be turned into a therapeutic target.
Implications for other organs and diseases associated with loss of cell identity
Although the focus is on the lungs, the principle is broader: endoderm cells (e.g., hepatocytes, cholangiocytes, pancreatic ductal epithelium) also depend on the fine regulation of identity through signaling axes like FGF. If RIDD can also target other mRNAs crucial for “staying on course,” similar strategies of partial IRE1α inhibition might one day play a role in diseases of the liver or pancreas, as well as in chronic complications of metabolic disorders. In this context, understanding the network of RIDD targets (beyond Fgfr2) becomes the next logical step.
Methodological strength: from the single-cell level to biochemical proof
One of the strengths of the work is its combination of methods: a single-cell RNA-seq map that separates “fibrotic” from “regenerative” transitional populations; interventional experiments with IRE1α activators/inhibitors that map the point of no return; and a biochemically reconstituted system that directly showed Fgfr2 mRNA to be a legitimate substrate of the IRE1α RNase. Such a multi-layered chain of evidence avoids the pitfalls of mere correlations and provides credible causality between stress, RIDD, the loss of the FGFR2 signal, and the diversion of AT2 cells into a pro-fibrotic transitional state.
Where the translational research scene is heading: from patent to platform
The progress in modulating the IRE1α kinase did not happen in a vacuum: researchers and partners have spent previous years developing an entire library of small molecules and protecting them with patents, and knowledge has spilled over from basic biochemistry into therapeutic concepts. This translational path — from mechanism discovery, through structured molecule design, to disease models — suggests that the platform of partial IRE1α antagonists could generate more candidates, not just for the lungs, but also for other organs where the epithelium is under chronic stress.
What it could mean for practice: early intervention and personalization
In practice, the fragility of the lung architecture dictates that intervention must happen early, before scar tissue “locks in” the mechanical properties of the lungs. If safety and efficacy are confirmed, drugs like PAIR2 could be investigated as an adjunct to standard antifibrotics, especially in patients with biomarkers of high IRE1α/RIDD activity or with a transcriptomic signature of “fibrotic” transitional cells. This is a framework for personalized medicine: selecting therapy based on cellular states, and not just clinical symptoms or images.
Links for further reading and a glossary for readers
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