LC-MI-3 is an orally active and potent interleukin-1 receptor-associated kinase 4 ( IRAK4 ) PROTAC degrader, with a DC 50 of 47.3 nM. LC-MI-3 effectively inhibits the activation of downstream NF-κB signaling. LC-MI-3 can be used for the research of acute and chronic inflammatory skin. (Blue: VHL ligand, Black: linker, Pink: CRBN ligand ).