Journal Article

α-Linolenic Acid Alleviates Diabetic Cardiomyopathy by Activating AMPK-STAT3 Pathway to Inhibit Ferritinophagy and Enhance SLC7A11-GPX4 Antioxidant Axis

Yang, Jianhong, Bai, Xue, Zhang, Ziqian, Du, Qian

2025

Overview

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, in which ferroptosis is a key pathogenic mechanism. This study examines how alpha-linolenic acid (ALA), a plant-derived omega-3 polyunsaturated fatty acid, protects against damage from ferroptosis in DCM. Using an in vitro model of H9C2 cardiomyocytes treated with high glucose/palmitate, combined with a high-fat diet and mouse model of low-dose streptozotocin (STZ)-induced diabetes, this research demonstrates for the first time that ALA significantly alleviates cardiac dysfunction and prevents ferroptosis. Mechanistically, ALA inhibits STAT3 phosphorylation by activating the AMPK signaling pathway, thereby reducing NCOA4-mediated ferritinophagy and mitigating mitochondrial iron overload and reactive oxygen species accumulation. It also enhances the function of the SLC7A11/GSH/GPX4 axis, reducing lipid peroxidation (LPO)-induced ferroptosis. Collectively, these findings indicate that ALA protects against diabetic cardiomyopathy by coordinating the regulation of ferritinophagy and antioxidant defense through the AMPK-STAT3 pathway, offering a potential therapeutic strategy for disease management.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: alpha-Linolenic Acid - pharmacology / Amino Acid Transport System y+ - metabolism / AMP-Activated Protein Kinases - metabolism / AMPK-STAT3 signaling pathway / Analysis / Animals / Antioxidants / Antioxidants - metabolism / Autophagy / Cardiomyocytes / Cardiomyopathy / Cell death / Cell Line / Development and progression / Diabetes / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - metabolism / Diabetic Cardiomyopathies - drug therapy / Diabetic Cardiomyopathies - etiology / Diabetic Cardiomyopathies - metabolism / Diabetic Cardiomyopathies - pathology / diabetic cardiomyopathy / Diet therapy / Fatty acids / ferritinophagy / Ferroptosis / Ferroptosis - drug effects / Genes / Glutathione / Health aspects / Heart diseases / Heart failure / Hypertension / Linolenic acids / Lipid peroxidation / Lipid Peroxidation - drug effects / Lipids / Male / Mice / Mortality / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Omega-3 fatty acids / Oxidative stress / Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism / Phosphorylation / Prevention / Protein expression / Proteins / Rats / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal Transduction - drug effects / SLC7A11/GSH/GPX4 axis / STAT3 Transcription Factor - metabolism / Type 2 diabetes / α-linolenic acid