# Parkin–ACSL4 axis in ferroptosis regulation: a narrative review on therapeutic insights from exercise in aging cardiomyocytes

**Authors:** Negin Kordi, Behnam Bagherzadeh-Rahmani, Rezvan KheirAndish, Raheleh Rezaali, Brent R. Stockwell

PMC · DOI: 10.1038/s44324-025-00092-z · 2026-01-06

## TL;DR

This review explores how aerobic exercise may protect aging heart cells by regulating ferroptosis through the Parkin–ACSL4 pathway.

## Contribution

The paper highlights the novel role of the Parkin–ACSL4 axis in exercise-induced protection against ferroptosis in aging cardiomyocytes.

## Key findings

- Parkin reduces lipid peroxidation and ROS by ubiquitinating ACSL4.
- Exercise activates PINK1/Parkin mitophagy and hepcidin to improve mitochondrial resilience.
- Aerobic exercise may offer non-pharmacological cardiac protection against ferroptosis.

## Abstract

Ferroptosis, iron-dependent regulated cell death, drives age-related cardiac dysfunction. This review examines aerobic exercise modulation of ferroptosis in aging cardiomyocytes via Parkin–ACSL4 axis. Parkin promotes ACSL4 ubiquitination/degradation, reducing lipid peroxidation and ROS. Exercise activates PINK1/Parkin mitophagy and hepcidin, enhancing mitochondrial resilience and iron homeostasis. Despite promising preclinical evidence, molecular mechanisms remain unclear. Aerobic exercise offers non-pharmacological cardiac protection against ferroptosis in aging.

## Linked entities

- **Genes:** park (parkin) [NCBI Gene 40336], ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182], PINK1 (PTEN induced kinase 1) [NCBI Gene 65018]

## Full-text entities

- **Genes:** PRKN (parkin RBR E3 ubiquitin protein ligase) [NCBI Gene 5071] {aka AR-JP, LPRS2, PARK2, PDJ}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, HAMP (hepcidin antimicrobial peptide) [NCBI Gene 57817] {aka HEPC, HFE2B, LEAP1, PLTR}, ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182] {aka ACS4, FACL4, LACS4, MRX63, MRX68, XLID63}
- **Diseases:** cardiac dysfunction (MESH:D006331)
- **Chemicals:** ROS (-), lipid (MESH:D008055), iron (MESH:D007501)

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12775483/full.md

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Source: https://tomesphere.com/paper/PMC12775483