IFN It Isn’t Broke, It May Still Be Driving Disease: IFNs as Mediators of Senescence in Chronic Obstructive Pulmonary Disease

Cellular senescence has emerged as a unifying mechanism that ties the “accelerated lung aging” phenotype of chronic obstructive pulmonary disease (COPD) to its persistent, low-grade inflammation. In the COPD lung, airway epithelial, endothelial, and mesenchymal cells exhibit canonical senescent signatures: irreversible cell cycle arrest, chronic DNA damage foci, and activation of the p53/p21 and p16/Rb checkpoints. Senescence can be induced by multiple insults characteristic of COPD pathogenesis, including cigarette smoke, oxidative stress, DNA damage, and mitochondrial dysfunction. Once senescent, these cells remain metabolically active and switch to a senescence-associated secretory phenotype (SASP), releasing a mixture of cytokines, chemokines, and matrix-remodeling enzymes. The SASP amplifies and sustains inflammation and can entrain a self-perpetuating loop that persists long after smoking cessation (1). Preclinical studies show that selectively clearing senescent cells dampens inflammation and limits airspace enlargement, highlighting cellular senescence and the SASP as a promising therapeutic target in COPD (2, 3).

Yet, despite its appeal as a unifying mechanism, senescence is not a singular or monolithic state. Tolstoy famously wrote, “Happy families are all alike; every unhappy family is unhappy in its own way.” Similarly, characteristics of senescent cells and their SASP vary widely, depending on the cell type, the inciting stressor, and the tissue microenvironment. Disentangling these context-specific drivers will be essential to define the characteristics of senescent populations that are pathogenic in COPD and help guide the development of targeted, disease-relevant senotherapies.

Although commonly appreciated for their antiviral tumor immunosurveillance roles, IFNs are increasingly recognized as key regulators of cellular senescence that may be relevant in the context of COPD (4). Type I IFNs (IFN-α/β) are frequently upregulated in response to persistent DNA damage through canonical cGAS-STING signaling as well as STING-independent pathways. Type II IFN (IFN-γ), although principally produced by activated lymphoid cells, has likewise been detected in the secretome of senescent structural cells. Once released, these cytokines act in autocrine and paracrine fashions via JAK-STAT cascades to augment and propagate senescence: They reinforce STAT-mediated p53 checkpoints, enhance reactive oxygen species–driven DNA damage, derepress retrotransposons, broaden the SASP transcriptome, and recruit innate and adaptive immune cells that perpetuate tissue inflammation (5–8). Although the interplay between IFN signaling and cellular senescence in COPD remains underexplored, it is plausible that in a microenvironment shaped by chronic injury and recurrent viral exacerbations, IFNs act not only as inflammatory mediators but also as upstream regulators of senescence. Indeed, although not evaluating cellular senescence per se, Wang and colleagues demonstrated suppression of alveolar stem cell growth through IFN-γ signaling (9).

In this issue of the Journal, Guo-Parke and colleagues (pp. 871–883) provide timely evidence for this hypothesis, showing that type I and type II IFN pathways promote features of cellular senescence in COPD bronchial epithelial cells (10) (Figure 1). The authors cultured primary bronchial epithelial cells at the air–liquid interface from subjects with and without COPD. Using single-cell RNA sequencing, they identified key senescence and SASP-related genes and associated this signature with type I and II IFN signals. The authors validated these findings using multiple complementary approaches, including RT-qPCR, senescence-associated β-galactosidase assays, proliferation assays, and validation of increased senescence markers p16, p53, and p21 at the protein level. To assess the functional relevance of this pathway, the authors pharmacologically inhibited JAK/STAT and cGAS-STING signaling using baricitinib, a U.S. Food and Drug Administration–approved JAK inhibitor, and C-176, a STING inhibitor. Both compounds attenuated inflammation and the senescence phenotype, supporting a causal role for IFN-mediated signaling in COPD-associated senescence. These findings suggest that IFN signaling may act as a sustaining factor of cellular senescence in disease and that targeting these upstream pathways could provide a more effective therapeutic strategy than senolytics by preventing the initiation or spread of senescence.

Figure 1.

IFN signaling promotes bronchial epithelial senescence in chronic obstructive pulmonary disease. Stressors, such as cigarette smoke, induce DNA damage and oxidative stress, leading to the release of proinflammatory cytokines and chemokines, contributing to chronic inflammation and cellular injury. Elevated IFN levels activate JAK/STAT and cGAS-STING signaling pathways, triggering senescence and the release of senescence-associated secretory phenotype (SASP) factors. This initiates a self-perpetuating inflammatory loop that further promotes senescence. Inhibitors of these pathways, such as baricitinib and C-176, attenuate the senescent phenotype, highlighting a potential therapeutic strategy that targets upstream drivers of senescence. COPD = Chronic obstructive pulmonary disease. Created with BioRender.com.

A major strength of this study lies in its implementation of functional assays to assess the cellular biology of COPD epithelial cells rather than snapshot assessments, as well as the multiple methods of validation and the potential therapeutic implication of targeting these pathways in COPD. In addition, the use of primary human cells is to be commended. Still, these findings should be interpreted with caution. Although p16, p21, and related SASP factors are hallmark features of COPD, there is growing appreciation that a multimodality approach is required to define a senescent cell (11). In addition, many of the differentially expressed genes identified in COPD bronchial epithelial cells also function in inflammation and stress responses independent of cellular senescence. It remains unclear whether the observed changes reflect senescence in the classical sense initially as laid out by Hayflick and colleagues or whether the transcriptional signature simply reflects broader epithelial dysfunction (12). The relatively small sample size, lack of in vivo validation, and lack of attention to sex differences also limit broader interpretation. This is particularly important because sex contributes to disease heterogeneity, with chronic bronchitis more common in females and emphysema in males (13). Integrating sex as a biological variable in future studies may help clarify differential senescence patterns and inform more tailored interventions.

In addition, therapeutic implementation will require careful pharmacological planning. Baricitinib, for instance, is currently approved only for short-term use in COVID-19, and its long-term use in COPD will necessitate rigorous evaluation of dosing, safety, and tolerability (14). IFNs are essential for antiviral defense, and both IFN signaling and cellular senescence contribute to tumor immunosurveillance. Thus, attenuating IFN pathways in COPD could increase susceptibility to respiratory infections or impair cancer surveillance, risks already elevated in this population. Any therapeutic benefit must therefore be carefully balanced against these immunologic liabilities. Further insights are expected from ongoing trials of JAK-STAT inhibitors, particularly baricitinib in rheumatoid arthritis–associated interstitial lung disease and other autoimmune conditions, as well as from early-phase studies of cGAS-STING antagonists in autoimmunity and oncology (15). Close monitoring of infection rates, cancer incidence, and immune competence in these cohorts, especially among individuals with impaired airway immunity or elevated cancer risk, will be pivotal before translating IFN-targeted therapies to COPD.

Collectively, these findings position IFN signaling as a critical upstream regulator of senescence in COPD, linking chronic injury to persistent inflammation through cell-intrinsic and paracrine mechanisms. Although therapeutically targeting this pathway holds promise, its implementation must be guided by a nuanced understanding of cellular context, patient heterogeneity, and immunologic risk. Ultimately, integrating mechanistic insight with clinical precision will be key to translating senescence-targeted strategies into effective therapies for COPD.