IRAK4 is a serine/threonine kinase that initiates innate immune responses by integrating signaling downstream of Toll-like receptors (TLRs), IL-1R, and IL-18R 1. Upon TLR activation, IRAK4 is recruited by MYD88 to form the Myddosome complex, where it phosphorylates IRAK1 and Pellino proteins to activate downstream NF-κB signaling and inflammatory cytokine production 2. IRAK4 plays critical roles in multiple immune cell types including dendritic cells, keratinocytes, and granulocytes 1. Clinically, IRAK4 dysregulation contributes to several diseases. Gain-of-function MYD88 mutations in activated B-cell lymphoma depend on IRAK4 for cell survival 3. IRAK4 overexpression drives pathogenic inflammation in hidradenitis suppurativa and atopic dermatitis through TLR and IL-1 signaling 4. Similarly, IRAK4 activation contributes to psoriasis and allergic rhinitis pathogenesis 12. Conversely, microbial trimethylamine inhibits IRAK4 to ameliorate metabolic inflammation and improve glycemic control in obesity 5. Therapeutically, IRAK4 inhibitors and degraders represent promising approaches for autoimmune and inflammatory diseases 6. An IRAK4 degrader (KT-474) demonstrated clinical efficacy in phase 1 trials for hidradenitis suppurativa and atopic dermatitis with favorable safety profiles 47, with phase 2 trials now underway.