Pharmacological blockade of p65 palmitoylation modulates NF-κB transcriptional activity

Nuclear factor kappa B (NF-κB) regulates inflammation and immunity and is frequently dysregulated in autoimmune diseases, inflammatory disorders, and cancers. Cytokines and pathogens activate NF-κB transcription factors, and nutrients and metabolites, including fatty acids, also modulate its activation, though the underlying mechanisms remain unclear. Here, we report that RelA (p65), a major component of the NF-κB transcription complex, is autopalmitoylated at cysteine 197 and 206. Palmitoylation of p65 enhances its nuclear localization and p65-p50 complex formation, thereby increasing NF-κB transcriptional activities. We further show that licochalcone D, a small-molecule anti-inflammatory compound, directly inhibits RelA/p65 autopalmitoylation, suggesting it may act through an additional mechanism. These results indicate that fatty acid metabolism can directly regulate NF-κB activity through p65 palmitoylation and suggest that targeting p65 autopalmitoylation may be a therapeutic strategy for diseases with dysregulated NF-κB signaling.