Metabolic-epigenetic reprogramming of airway fibroblasts by K + N therapy suppresses IL-33 and ameliorates allergic asthma.

BACKGROUND: Allergic asthma is a prevalent Th2-driven chronic inflammatory airway disease. While lung fibroblasts and fibroblast-derived IL-33 critically regulate airway inflammation, the fibroblast-specific role of IL-33 and the therapeutic mechanism of the immune regulatory small-molecule KQS1 and nicotinamide (K + N) remain poorly understood. METHODS: We utilized fibroblast-specific Il33 conditional knockout mice in an ovalbumin-induced allergic asthma model. We characterized baseline fibroblast physiology, K + N therapeutic efficacy, and the underlying metabolic and epigenetic mechanisms. Partial shRNA-mediated knockdown of Il33 was performed to rule out therapeutic floor effects, and primary human airway fibroblasts from healthy donors and patients with asthma were used for translational validation. RESULTS: Fibroblast-specific Il33 deletion did not alter homeostatic fibroblast physiology but significantly attenuated allergen-induced asthmatic pathology. The therapeutic benefits of K + N-including reduced airway hyperresponsiveness, inflammation, and goblet cell hyperplasia-were completely abrogated in fibroblast-specific Il33 knockout mice, demonstrating strict dependency on fibroblast IL-33. Mechanistically, K + N retained the capacity to elevate NAD/α-KG ratios and reduce Il33 locus H3K27ac enrichment even in IL-33-deficient fibroblasts, uncoupling K + N's upstream metabolic/epigenetic reprogramming from its downstream IL-33-mediated anti-asthmatic effects. Partial Il33 knockdown confirmed IL-33 as a non-redundant target. In human asthmatic fibroblasts, K + N rescued dysregulated NAD-glycolysis metabolism and suppressed elevated IL33 and IL13 expression via conserved reduction of IL33 promoter H3K27ac enrichment. CONCLUSION: This study identifies a conserved fibroblast-intrinsic NAD-epigenetic-IL-33 axis. K + N-driven metabolic and epigenetic reprogramming relies on intact fibroblast IL-33 to exert its anti-asthmatic functions, highlighting this axis as a promising translational therapeutic target for allergic asthma.