2. Academic Validation
  3. Targeting FoxO1-STX17-mediated autophagic flux: Quercetin's therapeutic mechanism in diabetic nephropathy

Targeting FoxO1-STX17-mediated autophagic flux: Quercetin's therapeutic mechanism in diabetic nephropathy

  • Eur J Pharmacol. 2025 Dec 5:1008:178309. doi: 10.1016/j.ejphar.2025.178309.
Baoluo Hou 1,  Yachun Li 2,  Jingyi Tang 1,  Xiaoxue Cao 1,  Shujiao Zhang 1,  Yuzi Cai 1,  Jing Guo 3,  Junyu Xi 1,  Dongyi Wang 1,  Wei Jing Liu 4,  Hongmei Lu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China.
  • 2 Shanxi Provincial Hospital of Chinese Medicine, Xi'an, 710000, China.
  • 3 Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China; Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
  • 4 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China. Electronic address: [email protected].
  • 5 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China; Renal Research Institution of Beijing University of Chinese Medicine, Beijing, 100700, China. Electronic address: [email protected].
PMID: 41207350 DOI: 10.1016/j.ejphar.2025.178309
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 quercetin as a promising therapeutic candidate for DN.

Keywords

Autophagic stress; Autophagosome-lysosome fusion; Diabetic nephropathy; FoxO1; Quercetin.

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