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Chronic proinflammatory signaling is a characteristic trait in myeloproliferative neoplasms (MPN), particularly myelofibrosis (MF). Aberrant inflammatory signaling, particularly from NF-κB pathway, exacerbates the progression of MPN. Previously, we identified a critical role of miR-146a, a negative regulator of the TLR/NF-κB axis, in MF development. MPN patients carrying the miR-146a rs2431697-TT genotype, associated with lower miR-146a expression levels, have a higher risk of progression to overt-MF from chronic-phase disease. Using miR-146a -/- (KO) mice, a MF-like model lacking MPN driver mutations, we here investigate whether pacritinib, a dual JAK/NF-κB pathways inhibitor (via JAK2/IRAK1, respectively), prevents the age-associated myelofibrotic phenotype of these mice. Young miR-146a -/- mice were treated either with or without pacritinib, for 3 or 6 months. Notably, pacritinib prevented the splenomegaly, reticulin fibrosis and osteosclerosis observed in untreated KO mice. Pacritinib also avoided the myeloproliferation, loss of splenic architecture, and extramedullary hematopoiesis observed in age-matched untreated KO mice. Pharmacological targeting of IRAK1/JAK2 attenuated the pro-inflammatory environment, preventing the increase of inflammatory cytokines, particularly CXCL1 and TNF-α, without inducing cytopenias but rather the opposite. Compared to age-matched untreated KO mice, treated mice showed higher platelet counts irrespective of treatment duration, and higher erythrocyte counts with the longer treatment. Additionally, pacritinib preventive treatment reduced COL1A1 production in an in vitro model mimicking JAK2-driven fibrosis. These findings highlight that dual inhibition of JAK2/IRAK1 with pacritinib, by delaying or attenuating the myelofibrotic progression, could be a potential modifier of the natural course of MPN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Francisca Ferrer-Marin reports a relationship with CTI BioPharma Corp, a Sobi company, that includes: funding grants (CFE/BI/72–19). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)