Reprogramming Iron Metabolism via the RIG-I/c-Myc/FTH Axis Mitigates Renal Ischemia-Reperfusion Injury

<b><i>Aims:</i></b> Iron metabolism disorders are critical in the pathogenesis of acute kidney ischemia-reperfusion injury (IRI). However, the molecular mechanisms driving these disturbances remain poorly understood. <b><i>Results:</i></b> In IRI mouse kidneys, pathological alterations, iron metabolism disruptions, and functional impairments were observed. Retinoic acid-inducible gene-I (RIG-I), transcription factor c-Myc, and ferritin heavy chain (FTH) exhibited elevated expression and colocalization in tubular epithelial cells, accompanied by decreased glutathione peroxidase 4 (GPX4) level and evidence of ferroptosis. Further <i>in vitro</i> studies revealed that RIG-I promoted c-Myc activation. The latter demonstrated its positive regulation of FTH transcription by chromatin immunoprecipitation assays and c-Myc siRNA experiments. Interestingly, FTH overexpression resulted in elevated levels of RIG-I, transferrin receptor, ferroportin, and nuclear receptor coactivator 4. Ultimately, the c-Myc inhibitor 10058-F4 reversed all adverse alterations and demonstrated a protective role in IRI mouse kidneys and mouse kidney tubule cells subjected to the ferroptosis inducer erastin, RIG-I agonist, or hypoxia/reoxygenation. This reversal was reflected in improved renal morphology and function, balanced iron metabolism, increased GPX4 level, decreased 4-hydroxynonenal level, reduced inflammatory cell infiltration, interleukin-1 beta release, and kidney injury molecule 1 expression. <b><i>Innovation:</i></b> This study proposes a novel mechanism in which c-Myc is activated by elevated RIG-I in IRI kidneys and positively regulates FTH transcription, therefore involving iron metabolism disorders. <b><i>Conclusions:</i></b> The RIG-I, c-Myc, and FTH disrupt iron homeostasis, and the c-Myc inhibition stabilizes iron metabolism and mitigates oxidative stress, suggesting a potential therapeutic target in IRI. <i>Antioxid. Redox Signal.</i> 43, 622-636. [Figure: see text].