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Background: House dust mite is the most frequent trigger of allergic asthma, with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the nucleotide-binding oligomerisation domain 1 (NOD1)/receptor-interacting serine/threonine protein kinase 2 (RIPK2) signalling pathway as a relevant contributor to murine house dust mite-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using a house dust mite-induced asthma model in wild-type and humanised NOD1 mice harbouring an asthma-associated risk allele, and its relevance using air-liquid interface epithelial cultures from asthma patients., Methods: A RIPK2 inhibitor was administered intranasally either preventively or therapeutically in a murine house dust mite-induced asthma model. Airway hyperresponsiveness, bronchoalveolar lavage composition, cytokine/chemokine expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices. Furthermore, the inhibitor was tested on air-liquid interface epithelial cultures from asthma patients and controls., Results: While local preventive administration of the RIPK2 inhibitor reduced airway hyperresponsiveness, eosinophilia, mucus production, T-helper type 2 cytokines and interleukin 33 (IL-33) in wild-type mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in humanised NOD1 mice. Results in precision-cut lung slices emphasised an early role of thymic stromal lymphopoietin and IL-33 in the NOD1-dependent response to house dust mite, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor downregulated thymic stromal lymphopoietin and chemokines in house dust mite-stimulated epithelial cultures from asthma patients., Conclusion: These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in house dust mite-induced asthma., Competing Interests: Conflict of interest: All authors report support for the present study from Inserm and grants from Institut Pasteur (PTR (18-16)) and ANR (18-CE14-0020). M. Chamaillard reports grants from CoPOC grant entitled RIFFLE from Inserm-Transfert. M. Chamaillard, I. Gomperts Boneca, M. Fanton d'Andon, S. Ait Yahlia, D. Alvarez-Simon and A. Tsicopoulos report a patent filed on 11 October 2023 (Nber EP23306767.7). I. Gomperts Boneca and M. Fanton d'Andon report support for the present study from Laboratoire d'Excellence “Integrative Biology of Emerging Infectious Diseases” (ANR-10-LABX-62-IBEID)., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)