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

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.

This study aims to explore whether HDL/ApoA1 confers atheroprotection through regulating macrophage ferroptosis.

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.

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.

This study demonstrates that HDL/ApoA1 inhibits macrophage ferroptosis via the NRF2-SLC7A11-GSH pathway, thereby attenuating atherosclerosis.