IFN-γ-Associated Signaling Networks in Interstitial Lung Disease Associated With Sjögren's Disease

Sjögren's disease (SD) is a chronic systemic autoimmune disorder that can affect multiple organ systems. Interstitial lung disease (ILD) is a clinically significant pulmonary manifestation of SD and is associated with impaired quality of life and increased mortality. Interferon-γ (IFN-γ), a major effector cytokine of Th1 immunity, has been implicated in immune dysregulation and chronic inflammation; however, its contribution to SD-associated ILD (SD-ILD) and its relationship with fibrotic remodeling remain incompletely understood.

This pathway-oriented narrative review synthesized evidence identified through a structured and iterative search of PubMed, Embase, and Web of Science, updated through August 2026. Priority was given to direct evidence from SD-ILD. When disease-specific evidence was limited, mechanistic findings from SD without characterized ILD, related connective tissue disease-associated ILDs, fibrotic lung diseases, and experimental models were considered and interpreted as indirect or extrapolated evidence.

Available evidence supports a conceptual network in which IFN-γ may function as a potential signaling node interacting with JAK/STAT, PI3K/AKT, NF-κB, MAPK, WNT/β-catenin, and IDO-kynurenine-AhR pathways. These pathways may contribute at different levels to immune-cell activation, inflammatory amplification, immunometabolic regulation, epithelial injury, fibroblast activation, and fibrotic remodeling. Evidence is strongest for the biological relevance of IFN-γ-JAK/STAT signaling, whereas support for PI3K/AKT, NF-κB, and MAPK is more indirect, and the relevance of WNT/β-catenin and particularly IDO-Kyn-AhR to SD-ILD remains less well established.

The proposed IFN-γ-associated network should be regarded as a conceptual mechanistic framework rather than a fully validated signaling hierarchy in SD-ILD. Distinguishing direct disease-specific evidence from mechanistic extrapolation highlights important knowledge gaps and provides a rationale for future investigation of pathway-informed biomarkers and stage-specific therapeutic strategies. Prospective SD-ILD studies integrating longitudinal clinical data with spatial and single-cell approaches are needed to validate these relationships and clarify their translational relevance.