Abstract Background Coronary atherosclerotic heart disease poses a significant threat to global health, with its core pathological mechanism involving ferroptosis-mediated inflammatory infiltration of macrophages, which drives the progression of atherosclerosis (AS). A critical challenge in coronary artery disease (CAD) treatment lies in delaying AS plaque advancement and stabilizing vulnerable plaques. Purpose This study aimed to investigate the precise mechanisms by which TREM2 alleviates ferroptosis and to explore its therapeutic potential in delaying the progression of AS plaques and stabilizing vulnerable plaques. Methods Clinically, we analyzed soluble TREM2 levels in peripheral blood serum and TREM2 expression in peripheral blood monocytes from CAD patients, correlating these findings with imaging characteristics of culprit lesions. Single-cell RNA sequencing was employed to characterize the TREM2low macrophage subpopulation. Using ferroptosis agonist Erastin and inhibitor deferoxamine mesylate in cellular and mouse models, we validated TREM2's role in ferroptosis regulation.. TREM2-/- mice were generated and subjected to AAV-PCSK9-induced atherosclerosis modeling to assess the interplay between TREM2 alleviated plaque formation by inhibiting ferroptosis. Ferroptosis-associated lipid metabolism was profiled via metabolomics and spatial metabolomic analyses. Mechanistically, mass spectrometry, AlphaFold3 structural predictions, and CO-IP assays following FLAG-tagged TREM2 overexpression were utilized to elucidate TREM2's regulation of FTH1/NCOA4 interactions. Results Clinical data revealed elevated TREM2hi macrophage prevalence in stable plaques compared to their significant reduction in vulnerable plaques. Single-cell analysis identified TREM2low macrophages as ferroptosis-susceptible. Both pharmacological induction and inhibition of ferroptosis in vitro and in vivo confirmed TREM2's regulatory role. Metabolomic profiling demonstrated disrupted ferroptosis-associated metabolites (glutathione and arachidonic acid) in TREM2-/- mice. Atherosclerotic murine models, peritoneal macrophage assays, and spatial metabolomics collectively demonstrated TREM2-mediated plaque burden mitigation through ferroptosis suppression. Mechanistically, TREM2 competitively binds FTH1, disrupting FTH1/NCOA4-driven ferritinophagy and thereby inhibiting ferroptosis. Conclusion Combining clinical observations with multi-omics analyses, this study demonstrates that TREM2 inhibits FTH1/NCOA4-mediated ferritinophagy, thereby suppressing ferroptosis and attenuating the progression of atherosclerosis. These findings highlight TREM2 as a critical regulator of iron metabolism and a promising therapeutic target for stabilizing advanced AS plaques.
Zhu et al. (Sat,) studied this question.