Methyl Caffeate Binds to IQGAP1 and Inhibits the Senescence-Associated Secretory Phenotype in Senescent Cells

The senescence-associated secretory phenotype (SASP) contributes to various age-related pathologies. Methyl caffeate exhibits strong SASP-inhibitory activity; however, its molecular targets and the precise mechanisms underlying its effects remain unclear. Therefore, in this study, we performed affinity chromatography using methyl caffeate-immobilized beads to identify its intracellular binding proteins. The functional roles of the identified target were validated via knockdown experiments, assessment of SASP factor (interleukin [IL]-6 and IL-8) expression at the mRNA and secretion levels, and analysis of nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was identified as a methyl caffeate-binding partner. IQGAP1 knockdown significantly reduced IL-6 and IL-8 expression levels, mimicking the effects of methyl caffeate treatment. Furthermore, IQGAP1 depletion suppressed nuclear factor-κB activation and p38 phosphorylation. Overall, this study identified IQGAP1 as a critical scaffold protein essential for SASP induction and a target of methyl caffeate. Our findings provide key insights into SASP regulation, facilitating the development of SASP-modulating therapeutics targeting specific IQGAP1 domains.