FASN contributes to the pathogenesis of lupus by promoting TLR-mediated activation of macrophages and dendritic cells

•FASN is highly expressed in monocytes and DCs of SLE patients, correlating with disease severity;•FASN promotes TLRs-mediated activation of BMDMs and BMDCs;•Knockdown or inhibition of FASN alleviates lupus mice by reducing macrophages and DCs activation;•Targeting FASN may be a promising approach for the treatment of SLE. Hyper-activations of monocytes/macrophages and dendritic cells (DCs) contribute to the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE). Fatty acid synthase (FASN) is essential for the de novo synthesis of long-chain fatty acids, which play a key role in controlling the activation, differentiation, and function of immune cells. However, the role of FASN in regulating the activations of monocytes/macrophages and DCs has not been studied. In this study, we investigated the involvement of the FASN in modulating the activations of macrophages and DCs, as well as the pathogenesis of SLE. Importantly, we observed a significant upregulation of FASN expression in monocytes and DCs from patients with SLE. This increase is strongly correlated with disease severity and activation status of the immune cells. Furthermore, overexpression of FASN significantly boosts the TLR4/7/9–mediated activation of macrophages and DCs, while knockdown of FASN markedly inhibits this activation. Notably, knockdown of FASN alleviates TLR7 agonist imiquimod (IMQ)-induced lupus in mice and the activation of macrophages and DCs. It makes more sense that pharmaceutical targeting of FASN by using TVB-2640 significantly alleviates IMQ-induced lupus in mice and the activation of macrophages and DCs, as well as in spontaneous lupus MRL/lpr mice. Thus, FASN contributes to the TLRs-mediated activation of macrophages and DCs, as well as the pathogenesis of SLE. More importantly, FASN inhibitor TVB-2640 is expected to be an effective drug in the treatment of SLE.