ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1596655
This article is part of the Research TopicNew Drugs and Future Challenges in Drug Metabolism and TransportView all 20 articles
Mechanistic Insights into the PAI-1 Inhibitor PAItrap3: Enhancing Lipid Metabolism in Adipose Tissue of Diabetic db/db Mice
Provisionally accepted
- 1Fujian Medical University Union Hospital, Fuzhou, China
- 2State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry, Chinese Academy of Sciences (CAS), Beijing, Beijing Municipality, China
- 3Fujian Provincial Key Laboratory of Ecology-Toxicological Effects & Control for Emerging Contaminants, College of Environmental and Biological Engineering, Putian University, Putian, Fujian Province, China
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Objective: This study aimed to investigate the effects of PAItrap3, a novel PAI-1 inhibitor, on lipid metabolism, and autophagy pathways in diabetic mice.Methods: db/db diabetic mice were administered PAItrap3 (5.7mg/kg/day, IV) for 21 consecutive days, and its impact on metabolic, gene expression, and lipidomic profiles was assessed. Western blot analysis was performed to examine lipid metabolism-related proteins in white adipose tissue (FASN, HSL, CPT1A, ACADM) and autophagy markers (LC3B, P62, Parkin, PGC1α, PPARGC1B). Additionally, RNA-seq and targeted lipidomics were employed to analyze gene expression and lipid metabolic alterations.Results: PAItrap3 significantly reduced blood glucose and glycated hemoglobin levels while improving insulin sensitivity. In lipid metabolism, FASN and HSL levels were upregulated, whereas CPT1A and ACADM levels were downregulated in the DMP group. Regarding the autophagy pathway, PPARGC1B, LC3B, and PGC1α expression levels were increased, while P62 and Parkin levels were decreased. Lipidomics analysis revealed that triglycerides (TG) and diacylglycerols (DG) were generally downregulated, with TG (18:2/18:2/18:2) (0.96 [0.8491, 1]), LPI (18:0) (0.96 [0.8491, 1]), and MLCL (14:3/20:4/22:6) (0.96 [0.8491, 1]) identified as key metabolites.This study finds that PAItrap3 modulates lipid metabolism, energy homeostasis, and autophagy pathways, thereby improving metabolic dysfunction in diabetic mice. These findings highlight its potential therapeutic value for treating diabetes-associated lipid metabolic disorders.
Keywords: PAI-1 inhibitor, Lipid Metabolism, Autophagy, Energy Metabolism, Diabetes Mellitus
Received: 20 Mar 2025; Accepted: 26 May 2025.
Copyright: © 2025 Lijing, Linxi, zhouyangyang, Menhua, Liqin, Libin, Chen and Shuzhi. 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: Wang Lijing, Fujian Medical University Union Hospital, Fuzhou, China
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