IL-1R1/NLRP3 signaling in the MDS/aged-associated mouse influences MSC dysfunction, BMME aging, skewing hematopoietic lineage differentiation, and promoting MDS clonal expansion. Targeting IL-1R1/IL-18 with IRAK4 inhibitor (PF06650833) and NLRP3 inhibitor (MCC950) reverses these phenotypes, restoring BM niche functionality.