Pharmacological inhibition of STING-mediated GPX4 autophagic degradation by 4-octyl itaconate ameliorates sepsis-induced acute kidney injury.

Abstract

The precise pathogenic mechanisms underlying sepsis-induced acute kidney injury (AKI) remain elusive. Emerging evidence suggests a link between tubular ferroptosis and the pathogenesis of AKI, though the regulatory pathways are not fully understood. Stimulator of interferon genes (STING), previously recognized as a pivotal mediator of innate immunity via DNA-sensing pathways, is increasingly associated with lipid peroxidation, a hallmark of ferroptosis, and 4-octyl itaconate (4-OI) has been shown to inhibit STING activation, exerting anti-inflammatory effects. This study investigates the protective mechanisms of 4-OI in sepsis-AKI. Following cecal ligation and puncture (CLP), inflammation, oxidative stress, and ferroptosis levels in kidney tissue increased. Both 4-OI and ferrostatin-1 (Fer-1) mitigated renal ferroptosis, exerting anti-inflammatory and antioxidant stress effects, and improved renal function. Consistently, in vitro experiments demonstrated that 4-OI reduced ferroptosis in human renal proximal tubule (HK-2) cells induced by lipopolysaccharide (LPS). Mechanistically, 4-OI suppressed LPS-induced activation of the STING pathway and reduced levels of inflammatory cytokines in a manner independent of NF-E2-related factor 2 (Nrf2). Additionally, 4-OI inhibited STING transcription through the activation of Nrf2. These dual actions effectively suppressed LPS-induced STING pathway activation, thereby inhibiting STING-mediated autophagic degradation of glutathione peroxidase 4 (GPX4), reducing reactive oxygen species (ROS) accumulation, and alleviating ferroptosis. In summary, 4-OI is a promising therapeutic candidate, functioning both as a STING inhibitor and a ferroptosis inhibitor, with potential applications in the treatment of sepsis.