STING1 exacerbates iodinated contrast-induced acute kidney injury by promoting ferroptosis through chaperone-mediated autophagic degradation of FTH1

Iodinated contrast-induced acute kidney injury (CI-AKI) is a common clinical complication with poor prognostic outcomes, yet its molecular mechanisms remain incompletely understood. Ferroptosis, a regulated form of cell death driven by iron overload and lipid peroxidation, has been implicated in CI-AKI. However, its involvement and precise regulation in CI-AKI remain unclear. Here, we identify STING1 (stimulator of interferon response cGAMP interactor 1) as a key mediator of ferroptosis in renal proximal tubular cells (RPTCs). We demonstrate that iodinated contrast media (ICM) activate STING1, triggering ferroptosis. Using proximal tubule-specific <i>sting1</i> knockout mice and primary RPTCs, we show that <i>Sting1</i> deficiency mitigates ferroptosis and alleviates CI-AKI. Mechanistically, STING1 interacts with HSPA8/HSC70 (heat shock protein family A (Hsp70) member 8) in patients with acute tubular necrosis and experimental CI-AKI models, facilitating the chaperone-mediated autophagic degradation of FTH1 (ferritin heavy chain 1) and GPX4 (glutathione peroxidase 4). Notably, inhibition of chaperone-mediated autophagy (CMA) via LAMP2A (lysosomal associated membrane protein 2A) knockdown inhibits FTH1 and GPX4 degradation, and attenuates ferroptosis. These findings uncover a novel STING1-driven mechanism linking CMA to ferroptosis in CI-AKI and highlight the STING1 pathway as a potential therapeutic target for contrast-induced renal injury.<b>Abbreviations:</b> 3-MA: 3-methyladenine; AIFM2/FSP1: AIF family member 2, ferroptosis suppressor; CLBD: cytoplasmic ligand-binding domain; CGAS: cyclic GMP-AMP synthase; CI-AKI: contrast-induced acute kidney injury; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTT: C-terminal tail; DHE: dihydroethidium; FTH1: ferritin heavy chain 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPX4: glutathione peroxidase 4; GSH/GSSG: glutathione/glutathione oxidized; KO: knockout; HK-2 cell: human renal proximal tubular epithelial cell; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IRI: ischemia-reperfusion injury; KFERQ: CMA recognition pentapeptide; LAMP2A: lysosomal associated membrane protein 2A; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PT: proximal tubule; RPTCs: renal proximal tubule cells; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TMD: transmembrane domain; WT: wild-type.