IRAK1/NF-κB signaling in MPN

Current understanding

IRAK1 (interleukin-1 receptor-associated kinase 1) couples Toll-like receptor and IL-1R signaling to NF-κB-driven inflammatory transcription, providing a JAK-STAT-independent pro-inflammatory and pro-fibrotic axis in MPN. Pacritinib’s off-target IRAK1 inhibition is the leading clinical-stage hypothesis that combined JAK2 + IRAK1 blockade may suppress both clonal proliferation and the NF-κB-mediated cytokine/fibrosis program, distinguishing it mechanistically from ruxolitinib and fedratinib.

Evidence log

• 2026-09-16 — Canakinumab or emavusertib for anemia in lower-risk MDS: results of the CANFIRE and LUCAS phase 2, open-label, multicenter trials.: Phase-2 LUCAS trial of emavusertib (IRAK4 inhibitor) in lower-risk MDS/MDS-MPN was terminated early without erythroid response, providing negative clinical evidence that upstream IRAK4 blockade — one step above IRAK1/NF-κB — is insufficient to reverse ineffective erythropoiesis in this population. (novelty: 3)
• 2026-08-18 — Immune and cytokine landscape differs between cytopenic and proliferative phenotypes in primary myelofibrosis.: cross-connection with asxl1-mutations: NF-κB inflammatory activation characterizes ASXL1-enriched cytopenic PMF, suggesting IRAK1/NF-κB-directed therapies (e.g., pacritinib) may be mechanistically matched to this phenotype. (novelty: 3)
• 2026-08-01 — Inflammatory Network Architecture Across Bone Marrow Failure: An Immune-Genetic Continuum.: cross-connection with jak-stat-signaling: Review identifies JAK-STAT and NF-κB as the two conserved transcriptional hubs downstream of the TNF-α/IFN-γ/IL-6 inflammatory core across bone marrow failure syndromes. (novelty: 3)
• 2026-06-23 — Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms.: cross-connection with galectin-1-tlr4-nfkb-monocyte-inflammation-mpn: Both converge on monocyte NF-κB-driven cytokine output, suggesting LGALS1–TLR4 and IRAK1 represent parallel upstream feeders of the same inflammatory hub. (novelty: 5)
• 2026-02-06 — Pacritinib For Bone Marrow Fibrosis In Patients With Myelofibrosis Who Have Thrombocytopenia: cross-connection with jak-stat-signaling: Pacritinib’s dual JAK2/IRAK1 inhibition links canonical JAK-STAT proliferative signaling to the parallel IRAK1/NF-κB inflammatory axis, suggesting these pathways co-sustain MF biology and may require combined blockade. (novelty: 4)

Open questions

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