ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression

•Knockdown of ACSL4 reduced proinflammatory cytokine production.•Knockdown of ACSL4 inhibited the activation of NF-κB signaling.•ACSL4 promoted neuroinflammation by reducing VGLL4 expression.•Knockdown of ACSL4 alters lipid metabolism.•ACSL4 knockdown attenuated LPS and MPTP-induced neuroinflammation in vivo. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme in polyunsaturated fatty acid (PUFA) metabolism. The role of ACSL4 in the lipopolysaccharide (LPS)-induced inflammation of microglia, and the effects of ACSL4-mediated inflammation on the progression of Parkinson’s disease (PD) are unknown. In this study, we found that ACSL4 expression was increased after LPS stimulation. Knocking down ACSL4 in microglia decreased proinflammatory cytokine production. Mechanistically, ACSL4 reduced vestigial-like family member 4(VGLL4) expression to promote NF-κB signal transduction; and ACSL4 regulated lipid composition after LPS stimulation. In addition, knocking down ACSL4 alleviated neuroinflammation in a systemic LPS model and acute l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) model. These data revealed ACSL4 to be a novel regulator that promotes microglia-mediated neuroinflammation by regulating VGLL4 expression and lipid metabolism.