STING Aggravates Ferroptosis in Septic Acute Kidney Injury by Promoting Ubiquitin–Proteasome–Dependent Degradation of FSP1

Sepsis-associated acute kidney injury (SA-AKI) is a common and life-threatening complication of sepsis. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays an important role in the pathogenesis of SA-AKI. However, the role of STING in regulating ferroptosis during SA-AKI and the underlying molecular mechanism remain unclear. A mouse model of SA-AKI was established by cecal ligation and puncture (CLP). Ferrostatin-1 (Fer-1) was used to evaluate the role of ferroptosis in SA-AKI. STING knockout mice and the STING inhibitor H-151 were used to assess the effects of STING on renal injury and ferroptosis. The involvement of FSP1 was examined using the FSP1 inhibitor iFSP1. Direct STING activation was further evaluated using cGAMP under non-septic conditions. In vitro, HK-2 cells were stimulated with lipopolysaccharide (LPS) to establish a cellular injury model. STING silencing, cGAMP-mediated STING activation, and treatment with MG132, chloroquine (CQ), and cycloheximide (CHX) were used to investigate the molecular mechanisms by which STING regulates FSP1 protein stability. Fer-1 alleviated CLP-induced renal dysfunction and tubular injury and reduced oxidative stress and ferroptosis. STING deficiency markedly attenuated SA-AKI and was associated with increased GPX4 and FSP1 expression and reduced lipid peroxidation. iFSP1 partially reversed the protective effects of STING deficiency. Consistently, STING silencing reduced LPS-induced oxidative stress and ferroptosis in HK-2 cells, whereas iFSP1 partially weakened these effects. Direct activation of STING by cGAMP in non-septic mice activated STING signaling and significantly reduced renal FSP1 protein expression. Mechanistically, STING activation reduced FSP1 protein levels without significantly affecting FSP1 mRNA expression. MG132, but not CQ, restored FSP1 expression, while CHX chase assays showed accelerated FSP1 protein turnover following STING activation. STING activation also increased FSP1 ubiquitination, supporting ubiquitin–proteasome-dependent degradation of FSP1. Pharmacological inhibition of STING with H-151 preserved FSP1 expression, suppressed ferroptosis, and ameliorated SA-AKI, whereas iFSP1 partially reversed these protective effects. STING contributes to ferroptosis and renal injury in SA-AKI, at least in part, by promoting ubiquitin–proteasome-dependent degradation of FSP1. Targeting the STING/FSP1 axis may provide a potential therapeutic approach for SA-AKI.