Interleukin-1β as a central driver of inflammation: Mechanistic insight into activation, receptor signaling, and therapeutic inhibition.

Interleukin-1β (IL-1β) is a major pro-inflammatory cytokine that links innate immune sensing, inflammasome activation, and downstream inflammatory signaling. Dysregulated production or signaling of IL-1β contributes to a broad range of disorders, including monogenic autoinflammatory syndromes, rheumatic diseases, cardiovascular and metabolic disorders, and neurodegenerative conditions. Consequently, the IL-1β/interleukin-1 receptor type I (IL-1RI) signaling axis has emerged as an important therapeutic target in inflammatory and immune-mediated diseases. This review discusses the key molecular mechanisms governing IL-1β biosynthesis, inflammasome-mediated activation, receptor recognition, and downstream signal transduction. It also highlights the experimentally validated receptor-binding hotspots, molecular determinants governing ligand recognition, receptor activation, and assembly of the signaling-competent IL-1β/IL-1RI/IL-1RAcP complex, followed by a description of modern computational approaches, including molecular docking, molecular dynamics simulations, pharmacophore modelling, QSAR, virtual screening, and artificial intelligence-assisted drug discovery. The emerging therapeutic strategies, including FDA-approved biologics, natural product-derived modulators, synthetic small-molecule inhibitors, drug-repurposing approaches, and recent advances in structure-based computational drug discovery, are also described. By bridging fundamental cytokine biology with translational therapeutics and structure-guided drug design, this review provides a contemporary perspective on IL-1β signaling and highlights future opportunities for the development of precision immunotherapies targeting IL-1β.