---
title: "Puerarin reduces type 2 diabetes–linked ferroptosis by targeting AKT1 and upregulating GPX4"
id: "pubmed-42054876"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42054876"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42054876/"
doi: "10.1016/j.bioorg.2026.109915"
published_at: "2026-08-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Puerarin reduces type 2 diabetes–linked ferroptosis by targeting AKT1 and upregulating GPX4
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42054876
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42054876/)
- **DOI:** [10.1016/j.bioorg.2026.109915](https://doi.org/10.1016%2Fj.bioorg.2026.109915)
- **Published At:** 2026-08-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study investigated how **puerarin** affects type 2 diabetes mellitus (T2DM) progression through modulation of **ferroptosis**, a regulated, iron-dependent form of cell death driven by lipid peroxidation and oxidative stress. - Researchers integrated **network pharmacology**, **proteomics**, and experimental validation to identify potential puerarin targets in T2DM and to explore molecular mechanisms. - In vitro, palmitic acid–induced oxidative stress triggered ferroptosis in mouse pancreatic β-cells (MIN6); puerarin intervention altered markers consistent with reduced ferroptosis. - Oxidative stress and ferroptosis-related biomarkers measured included **ROS**, malondialdehyde (MDA), manganese-dependent superoxide dismutase (Mn-SOD), glutathione (GSH), iron ions, mitochondrial morphology, insulin, GPX4, COX2, and ACSL4. - Mechanistic experiments used AKT1 overexpression and knockdown models and NRF2 inhibitors, with Western blot analysis to track pathway changes. - Findings indicate puerarin upregulates **AKT1**, increases phosphorylation of GSK3β, and raises expression of **NRF2**, which together correlate with elevated **GPX4** expression and suppression of ferroptosis. - The proteomics/network pharmacology approach identified AKT1 as a key target of puerarin in the context of T2DM; this integrated approach and the mechanistic link to the AKT/GSK3β/NRF2/GPX4 axis are presented as novel contributions. - The study reports that puerarin may mitigate oxidative stress damage in T2DM by promoting glutathione metabolism via upregulation of **GPX4**, thereby reducing ferroptosis. - Details on in vivo efficacy, clinical translation, dosing, and long-term effects were not reported in the abstract of the source article.
## Clinical Analysis & Structured Key Points
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Epub 2026 Apr 24. # Puerarin alleviates type 2 diabetes by targeting AKT1 to inhibit ferroptosis: Integrating network pharmacology, proteomics and experimental validation [Yulin Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Xiaojie Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+X&cauthor_id=42054876)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-2 "College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530299, PR China."), [Tian Lin](https://pubmed.ncbi.nlm.nih.gov/?term=Lin+T&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Ziwei Lei](https://pubmed.ncbi.nlm.nih.gov/?term=Lei+Z&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Junlin Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Hai Kuang](https://pubmed.ncbi.nlm.nih.gov/?term=Kuang+H&cauthor_id=42054876)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-3 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China. Electronic address: kuanghai@hotmail.com."), [Xiaohui Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+X&cauthor_id=42054876)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-4 "Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China. Electronic address: 1056112307@qq.com."), [Tao Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+T&cauthor_id=42054876)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#full-view-affiliation-5 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China; Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, Guangxi 530021, PR China. Electronic address: kqliangtao@126.com.") Affiliations Expand ### Affiliations * 1 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China. * 2 College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530299, PR China. * 3 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China. Electronic address: kuanghai@hotmail.com. * 4 Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China. Electronic address: 1056112307@qq.com. * 5 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China; Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, Guangxi 530021, PR China. Electronic address: kqliangtao@126.com. * PMID: **42054876** * DOI: [ 10.1016/j.bioorg.2026.109915 ](https://doi.org/10.1016/j.bioorg.2026.109915) Free article Item in Clipboard # Puerarin alleviates type 2 diabetes by targeting AKT1 to inhibit ferroptosis: Integrating network pharmacology, proteomics and experimental validation Yulin Chen et al. Bioorg Chem. 2026. Free article Show details Display options Display options Format Abstract PubMed PMID Bioorg Chem Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bioorg+Chem%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Bioorg+Chem%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42054876/) . 2026 Aug 5:177:109915. doi: 10.1016/j.bioorg.2026.109915. Epub 2026 Apr 24. ### Authors [Yulin Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Xiaojie Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+X&cauthor_id=42054876)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-2 "College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530299, PR China."), [Tian Lin](https://pubmed.ncbi.nlm.nih.gov/?term=Lin+T&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Ziwei Lei](https://pubmed.ncbi.nlm.nih.gov/?term=Lei+Z&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Junlin Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42054876)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-1 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China."), [Hai Kuang](https://pubmed.ncbi.nlm.nih.gov/?term=Kuang+H&cauthor_id=42054876)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-3 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China. Electronic address: kuanghai@hotmail.com."), [Xiaohui Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+X&cauthor_id=42054876)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-4 "Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China. Electronic address: 1056112307@qq.com."), [Tao Liang](https://pubmed.ncbi.nlm.nih.gov/?term=Liang+T&cauthor_id=42054876)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42054876/#short-view-affiliation-5 "College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China; Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, Guangxi 530021, PR China. Electronic address: kqliangtao@126.com.") ### Affiliations * 1 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China. * 2 College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning 530299, PR China. * 3 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China. Electronic address: kuanghai@hotmail.com. * 4 Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China. Electronic address: 1056112307@qq.com. * 5 College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, PR China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, Guangxi 530021, PR China; Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, Guangxi 530021, PR China. Electronic address: kqliangtao@126.com. * PMID: **42054876** * DOI: [ 10.1016/j.bioorg.2026.109915 ](https://doi.org/10.1016/j.bioorg.2026.109915) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract The progression of type 2 diabetes mellitus (T2DM) is closely linked to oxidative stress-induced damage. Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Its underlying mechanism involves an imbalance between reactive oxygen species (ROS) accumulation and cellular antioxidant defense, ultimately resulting in cell death. While puerarin has been shown to exhibit antioxidant properties, its ability to ameliorate T2DM via the ferroptosis pathway remains unclear. In this study, we combined network pharmacology, proteomics, and experimental validation to investigate the regulatory mechanisms of puerarin. Potential targets of puerarin in T2DM were identified using network pharmacology and proteomics. Oxidative stress markers-including ROS, malondialdehyde (MDA), manganese-dependent superoxide dismutase (Mn-SOD), and glutathione (GSH)-as well as insulin levels and ferroptosis-related markers such as glutathione peroxidase 4 (GPX4), cyclooxygenase-2 (COX2), and acyl-CoA synthetase long-chain family member 4 (ACSL4) were measured to assess the effect of puerarin on ferroptosis. Protein kinase B (AKT1) overexpression and knockdown models, together with nuclear factor erythroid 2-related factor 2 (NRF2) inhibitors, were used alongside Western blot analysis to investigate the pathway through which puerarin regulates ferroptosis. Results showed that palmitic acid-induced oxidative stress triggered ferroptosis in mouse pancreatic β-cells (MIN6). Under puerarin intervention, ferroptosis biomarkers including ROS, MDA, Mn-SOD, iron ions, and GSH, as well as mitochondrial morphology, were significantly altered. Mechanistic studies revealed that puerarin upregulates AKT1, leading to enhanced phosphorylation of GSK3β and increased expression of NRF2. Consequently, expression of GPX4, a key enzyme in glutathione metabolism, was elevated, thereby suppressing ferroptosis. This study is the first to identify targets of puerarin in T2DM through an integrated network pharmacology and proteomics approach. It demonstrates that puerarin may upregulate GPX4 via the AKT/GSK3β/NRF2 pathway, thereby mitigating oxidative stress damage and reducing ferroptosis, offering novel mechanistic insight for diabetes treatment. **Keywords:** Ferroptosis; Molecular docking; Proteomics; Puerarin; Type 2 diabetes mellitus. Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ Total flavones from Abelmoschus manihot (L.) Medik. [Malvaceae] extract ameliorates diabetic liver injury: association with ferroptosis suppression and the PI3K/AKT/Nrf2 pathway. ](https://pubmed.ncbi.nlm.nih.gov/41690038/) Lv C, Hou J, Sun H, Su W, Li Z, Wu Y, Wang L, Wei X, Anwaar S, Mou F, Wei D, Wang H, Xie Y, Yang Q, Yin M.Lv C, et al.Phytomedicine. 2026 Apr;153:157940. doi: 10.1016/j.phymed.2026.157940. Epub 2026 Feb 8.Phytomedicine. 2026.PMID: 41690038 * [ Vaccarin Ameliorates Renal Fibrosis by Inhibiting Ferroptosis via Nrf2/SLC7A11/GPX4 Signaling Pathway. ](https://pubmed.ncbi.nlm.nih.gov/40066086/) Cui M, Xu Q, Duan L, Lu J, Hu J.Cui M, et al.Drug Des Devel Ther. 2025 Mar 6;19:1609-1626. doi: 10.2147/DDDT.S509357. eCollection 2025.Drug Des Devel Ther. 2025.PMID: 40066086Free PMC article. * [ Artemisia keiskeana Miq. alleviates oxidative stress and ferroptosis in APAP-induced liver injury by mediating Nrf2/GPX4/NF-κB signaling pathway through ESR1. ](https://pubmed.ncbi.nlm.nih.gov/41151450/) Zhang Y, Lu Q, Yan Y, Zhang J, Liu T, Yu L, Fan Q, Wei K.Zhang Y, et al.Phytomedicine. 2025 Nov 25;148:157436. doi: 10.1016/j.phymed.2025.157436. Epub 2025 Oct 20.Phytomedicine. 2025.PMID: 41151450 * [ Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3β/NRF2/GPX4 axis. ](https://pubmed.ncbi.nlm.nih.gov/38056149/) Huang W, Wen F, Yang P, Li Y, Li Q, Shu P.Huang W, et al.Phytomedicine. 2024 Jan;123:155220. doi: 10.1016/j.phymed.2023.155220. Epub 2023 Nov 18.Phytomedicine. 2024.PMID: 38056149 * [ Formononetin, a bioactive isoflavonoid constituent from Astragalus membranaceus (Fisch.) Bunge, ameliorates type 1 diabetes mellitus via activation of Keap1/Nrf2 signaling pathway: An integrated study supported by network pharmacology and experimental validation. ](https://pubmed.ncbi.nlm.nih.gov/38104880/) Chen H, Lou Y, Lin S, Tan X, Zheng Y, Yu H, Jiang R, Wei Y, Huang H, Qi X, Zhang R, Liu Z, Wu J.Chen H, et al.J Ethnopharmacol. 2024 Mar 25;322:117576. doi: 10.1016/j.jep.2023.117576. Epub 2023 Dec 15.J Ethnopharmacol. 2024.PMID: 38104880 [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42054876) ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pu
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