HDL/ApoA1 attenuates atherosclerosis by suppressing macrophage ferroptosis via NRF2-SLC7A11-GSH axis activation.

Abstract

BACKGROUND: Macrophage death modalities critically determine atherosclerotic plaque stability and progression. While high-density lipoprotein (HDL) and its major component apolipoprotein A1 (ApoA1) are known for their cholesterol reverse transport and atheroprotective effects, their role in regulating macrophage ferroptosis-an iron-dependent lipid peroxidation-driven cell death-is unexplored. OBJECTIVES: This study aims to explore whether HDL/ApoA1 confers atheroprotection through regulating macrophage ferroptosis. METHODS: The correlation between macrophage ferroptosis and plaque stability was first established using murine atherosclerosis models and human atherosclerotic specimens. The inhibitory effects of HDL/ApoA1 on macrophage ferroptosis were then validated using multiple pharmacological inducers. Integrated bioinformatic analysis combined with multi-level experimental approaches was employed to identify the underlying regulatory pathways. Finally, AAV-mediated overexpression and knockdown models in atherosclerotic mice were utilized for in vivo verification. RESULTS: Animal experiments showed that ferroptosis inhibitors improved plaque stability in ApoE-/- mice. Analysis of human specimens revealed iron deposition, macrophage infiltration, and lipid peroxidation in atherosclerotic plaques, with strong spatial colocalization of these features, suggesting a potential contribution of macrophage ferroptosis to atherosclerosis progression. In vitro, HDL/ApoA1 effectively counteracted RSL3/FAC-induced macrophage ferroptosis, as indicated by reduced LDH release, decreased ROS levels, diminished ferrous iron content, and improved mitochondrial morphology. Mechanistically, HDL/ApoA1 inhibited NRF2 ubiquitination and degradation, promoted its nuclear translocation, upregulated SLC7A11 expression and restored intracellular GSH levels. In vivo, ApoA1 overexpression alleviated RSL3-aggravated atherosclerotic lesions, whereas macrophage-specific Nrf2 knockdown or SLC7A11 inhibition abolished the protective effects of ApoA1. CONCLUSION: This study demonstrates that HDL/ApoA1 inhibits macrophage ferroptosis via the NRF2-SLC7A11-GSH pathway, thereby attenuating atherosclerosis.

Key Findings

• Macrophage ferroptosis contributes to atherosclerosis progression and plaque instability.
• HDL/ApoA1 suppresses macrophage ferroptosis by inhibiting NRF2 ubiquitination, promoting its nuclear translocation, and activating the NRF2-SLC7A11-GSH axis.
• Overexpression of ApoA1 alleviates atherosclerotic lesions aggravated by ferroptosis inducers, while macrophage-specific Nrf2 knockdown worsens disease.

Clinical Significance

Citation

Yi Yuting, Luo Yonghong, Deng Yongjieet al.. HDL/ApoA1 attenuates atherosclerosis by suppressing macrophage ferroptosis via NRF2-SLC7A11-GSH axis activation. Free radical biology & medicine. 2026-Jul-04.