# Slc7a11‐Mediated Cystine/Glutamate Antiport Reprograms Macrophage Polarization and Ameliorates Atherosclerosis

## TL;DR

This study shows that the Slc7a11 protein helps reprogram macrophages to reduce inflammation and atherosclerosis, offering a new therapeutic approach for heart disease.

## Contribution

The study reveals that Slc7a11-mediated amino acid metabolism can reprogram macrophages and serve as a novel therapeutic strategy for atherosclerosis.

## Key findings

- Slc7a11 overexpression in macrophages reduces atherosclerotic lesions and increases plaque stability.
- Slc7a11 inhibits M1 macrophage polarization and promotes M2 polarization through glutathione synthesis.
- Targeting Slc7a11 with ferrostatin-1 enhances antioxidant capacity and ameliorates atherosclerosis.

## Abstract

Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cystine/glutamate antiporter Slc7a11 was upregulated by oxidized low‐density lipoprotein, and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage‐specific Slc7a11 overexpression in ApoE null mice (ApoE–

/–
Slc7a11MOE
) attenuated atherosclerotic lesions and increased the plaque stability under a 16‐week western diet. ApoE–

/–
Slc7a11MOE
displayed unchanged blood lipids, decreased inflammatory cytokines, and increased antioxidant capacity. Mechanistically, Slc7a11‐mediated cystine uptake and glutathione synthesis inhibited the classically activated macrophage (M1) polarization via reducing Stat1 phosphorylation, and promoted alternatively activated macrophage (M2) polarization via enhancing Stat6 phosphorylation. Macrophage‐targeting lipid nanoparticles loading with ferrostatin‐1, an antioxidant reagent, promotes Slc7a11‐mediated glutathione synthesis, also enhanced plaque stability and ameliorated the progression of atherosclerosis. These findings reveal a critical role of Slc7a11 in the phenotypic switch of macrophage and indicate that Slc7a11‐mediated amino acid metabolism could be utilized as a novel therapeutic strategy in the prevention of ASCVDs.

Slc7a11‐mediated cystine uptake and glutathione synthesis inhibits M1 macrophage polarization by reducing Stat1 phosphorylation and markers expressions and promotes M2 macrophage polarization by enhancing Stat6 phosphorylation and markers expressions. Conversely, glutamate treatment or glutathione depletion reverses this macrophage phenotype. Macrophage‐specific Slc7a11 overexpression or macrophage‐targeting lipid nanoparticles loading with ferrostatin‐1 promotes M2 macrophage polarization and attenuates the development of atherosclerosis.