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

## TL;DR

This study shows that alpha-linolenic acid helps prevent heart damage in diabetes by reducing a type of cell death called ferroptosis.

## Contribution

The study is the first to show that ALA alleviates DCM by modulating the AMPK-STAT3 pathway to inhibit ferroptosis.

## Key findings

- ALA significantly alleviates cardiac dysfunction and prevents ferroptosis in diabetic models.
- ALA inhibits NCOA4-mediated ferritinophagy and reduces mitochondrial iron overload and ROS accumulation.
- ALA enhances the SLC7A11-GPX4 antioxidant axis to reduce lipid peroxidation.

## Abstract

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.