Targeting FoxO1-STX17-mediated autophagic flux: Quercetin's therapeutic mechanism in diabetic nephropathy
Abstract
BACKGROUND: Diabetic nephropathy (DN) involves autophagic stress from defective lysosomal clearance. Quercetin, a flavonol, shows therapeutic potential but its mechanism remains unclear.
OBJECTIVE: Investigate quercetin's role in DN via FoxO1-STX17-mediated autophagosome-lysosome fusion.
METHODS: DN was induced in C57BL/6J mice (uninephrectomy + streptozotocin [50 mg/kg]). Quercetin (150 mg/kg/day) or valsartan (40 mg/kg/day) was administered for 12 weeks. Renal function, histopathology, and autophagy markers (p62, LC3-II, STX17) were evaluated. Quercetin metabolites were identified via UPLC-HRMS. Network pharmacology, molecular docking, dynamics (MD), and biolayer interferometry (BLI) validated targets. Advanced glycation end products (AGE) (100 μg/mL)-stimulated podocytes, Bafilomycin (Baf)-A1-treated and FoxO1-silenced podocytes were used for mechanistic validation.
RESULTS: In vivo, quercetin ameliorated renal injury and restored autophagic flux without affecting upstream autophagy initiation. Ten quercetin-derived metabolites were identified in serum. Bioinformatics analysis nominated FoxO1 as a key regulator of quercetin-modulated autophagy. In vitro, quercetin protected podocytes and promoted autophagosome-lysosome fusion, effects that were reversed by Baf-A1 and replicated in FoxO1-silenced cells.
CONCLUSION: Quercetin alleviates DN by targeting FoxO1 to restore STX17-dependent autophagosome-lysosome fusion, thereby resolving autophagic stress. These findings support…
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