ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Diabetes: Molecular Mechanisms
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1594897
Impact of Per-and Polyfluoroalkyl Substances on Diabetic Kidney Disease
Provisionally accepted
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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This study aims to elucidate the mechanistic role of Per-and Polyfluoroalkyl Substances (PFAS) in the pathogenesis and progression of diabetic kidney disease (DKD).This study systematically evaluated the toxicity profiles of PFAS compounds utilizing PubChem, ProTox 3.0, and ChEMBL databases. Potential PFAS-related targets were predicted through SwissTargetPrediction and SuperPred platforms. Gene targets associated with DKD were compiled from the GeneCards and OMIM databases.Intersection analysis of PFAS and DKD-related targets was performed to identify candidate genes. A protein-protein interaction network was constructed using STRING to delineate hub targets. Functional enrichment analyses were subsequently conducted via DAVID to elucidate underlying biological processes and pathways. Validation of hub targets encompassed immunohistochemical staining, single-cell expression profiling, subcellular localization assays, and gene expression analyses using external datasets from the Human Protein Atlas (HPA) and Gene Expression Omnibus (GEO).Furthermore, correlations between immune cell infiltration and gene set enrichment analysis (GSEA) were performed to investigate potential mechanistic links. Finally, molecular docking simulations of PFAS compounds with hub proteins were executed using Discovery Studio and CDOCKER to predict binding interactions.A total of 424 PFAS-associated targets were identified, alongside 9,999 potential toxic targets related to DKD. KEGG pathway enrichment analysis revealed that PFAS toxicity in DKD is implicated in critical signaling pathways, including nitrogen metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, endocrine resistance, insulin resistance, and AMP-activated protein kinase (AMPK) signaling.Hub targets identified comprised MMP9, BCL2, CYP3A43, ACE, HNF4A, HSP90AA1, AGTR1, MMP2, AGTR2, and HMGCR. GSEA further indicated that these hub targets may contribute to immune-mediated renal injury. Molecular docking simulations substantiated strong binding affinities between PFAS compounds and the identified hub proteins, supporting their potential mechanistic involvement.This study provides a theoretical framework for elucidating the toxic targets and underlying mechanisms through which PFAS contribute to the pathogenesis of DKD.
Keywords: Per-and polyfluoroalkyl substances, Network toxicology, Diabetic, molecular docking, Diabetic kidney disease
Received: 18 Mar 2025; Accepted: 11 Aug 2025.
Copyright: © 2025 Song, Huang, Zhou and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jiangyi Yu, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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