Quercetin-4'-O-β-D-glucopyranoside inhibits ferroptosis though SIRT5-mediated desuccinylation of TFR1 in diabetic nephropathy
Abstract
Diabetic nephropathy (DN) is a severe complication of diabetes, marked by podocyte injury and renal dysfunction. Quercetin-4'-O-β-D-glucopyranoside (QODG), a flavonoid glycoside, has demonstrated renal protective effects. Succinylation, a post-translational modification, plays a critical role in cellular metabolism and disease progression. This study aimed to explore whether QODG alleviates DN by modulating SIRT5-mediated desuccinylation. Mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) with or without QODG treatment. Cell viability was measured using the cell counting kit-8 assay. Ferroptosis was assessed via commercial kits detecting lipid peroxidation and iron accumulation. Protein expression of ferroptosis- and succinylation-related markers was evaluated by Western blot. Immunoprecipitation combined with Western blot was used to detect succinylation levels of ferroptosis-related proteins. The interaction between SIRT5 and transferrin receptor 1 (TFR1) was examined by co-immunoprecipitation and proximity ligation assay assays. Additionally, an in vivo DN model was established in mice using high-fat diet and streptozotocin administration. High glucose induced ferroptosis in MPC5 cells, as indicated by increased lipid peroxidation, iron accumulation, and dysregulation of ferroptosis-related proteins. These effects were mitigated by QODG treatment. Mechanistically, QODG upregulated SIRT5 expression, which promoted desuccinylation of TFR1 at lysine 626…
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