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.