Fatty acid synthesis promotes mtDNA release via ETS1-mediated oligomerization of VDAC1 facilitating endothelial dysfunction in sepsis-induced lung injury

Abstract Sepsis involves endothelial cell dysfunction leading to the development of lung injury. Fatty acid synthesis contributes to the development of inflammatory injury in sepsis. However, the regulatory mechanisms of fatty acid synthesis-related endothelial activation remain unclear. In this study, we found that fatty acid synthesis in patients with sepsis was greatly disordered. Inhibition of fatty acid synthesis significantly alleviated sepsis-induced endothelial damage and lung injury both in vitro and in vivo. We further found that the release of mtDNA participated in fatty acid synthesis-related regulation of endothelial inflammatory and coagulation activation. Mechanistically, fatty acid synthesis promoted the oligomerization of voltage-dependent anion channel 1 (VDAC1) via ETS proto-oncogene 1 (ETS1)-mediated inhibition of VDAC1 ubiquitination, thereby leading to the increased release of mtDNA and subsequent activation of cGAS-STING signaling and pyroptosis in endothelial cells. Our findings revealed that fatty acid synthesis promoted endothelial dysfunction through mtDNA release, providing new insight into the therapeutic strategies for treating sepsis-associated lung injury.