Fig. 2

Inflammatory signaling pathways involved in MDS and associated therapeutic targets. S100A8/A9 bind to TLR4 and CD33 and initiate the assembly of the NLRP3 inflammasome. The binding of S100A8/A9 to TLR4 also activates NF-kB through IRAK1/TRAF6/NF-κB signaling pathway, which results in the production of proinflammatory cytokines (pro-IL-1β and pro-IL-18). S100A8/A9 promote NOX activation, leading to excessive production of ROS and the subsequent activation of NLPR3 and inflammasome assembly. Inflammasomes recruit ASCs to form complexes that facilitate the conversion of pro-caspase-1 to caspase-1. Mature and activated caspase-1 cleaves pro-IL-1β and pro-IL-18 into their bioactive forms, which induce pyroptosis. TLR: toll-like receptor; TIRAP: toll-interleukin-1 receptor domain-containing adaptor protein; IRAK: interleukin receptor-associated kinase; TRAF: tumor necrosis factor receptor-associated factor; IκK: inhibitor of κB kinase; NF-κB: nuclear factor kappa B; NLRP3: nucleotide-binding domain and leucine-rich repeat pattern recognition receptor; ASC: apoptosis-associated speck-like protein containing a caspase-recruitment domain; GSDMD: gasdermin D; NOX: nicotinamide-adenine dinucleotide phosphate oxidase; ROS: reactive oxygen species; Ub: ubiquitin; TGF-β: transforming factor-β; IL: interleukin