2026-10-06T05:22:55Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33871351 2026-09-17T04:50:36Z category_696 portal_316 item_type_3 month_year_09_2026

Table 12_MGST3 defines a mitochondrial-health-associated M2 macrophage state in atherosclerosis: integrative multi-omics, single-cell mediation, and functional validation.xlsx Qiong-Chao Zou (13134275) Yong-Hong Yi (6819023) Jin He (341320) Jing-Jing Rong (686403) Hong-Wei Pan (4870633) Peng-Fei Zheng (1559962) Genetic Immunology atherosclerosis M2 macrophage mendelian randomization MGST3 mitochondrial health single-cell mediation Abstract Background<p>Mitochondrial dysfunction is increasingly recognized as a driver of maladaptive macrophage polarization in atherosclerosis (AS), but the mitochondrial genes that shape disease-relevant macrophage states remain poorly defined.</p>Methods<p>We integrated weighted gene co-expression network analysis (WGCNA), machine learning, two-sample Mendelian randomization (two-sample MR), bulk transcriptomics, single-cell analysis, disease-level validation, single-cell mediation, and in vitro perturbation to identify macrophage-relevant mitochondrial regulators in AS.</p>Results<p>Eight candidate genes were consistently prioritized by WGCNA and machine learning; among them, microsomal glutathione S-transferase 3 (MGST3) showed the strongest protective genetic signal. Two-sample MR supported a protective association between genetically predicted MGST3 expression and coronary artery disease/coronary heart disease risk (training set OR = 0.989, 95% CI 0.978-0.999, P = 0.042; test set OR = 0.977, 95% CI 0.960-0.995, P = 0.013). Human carotid plaque validation confirmed reduced MGST3 at both mRNA and protein levels in AS lesions. Notably, despite this whole-plaque downregulation, single-cell and disease-level analyses revealed an expanded MGST3-high M2-like macrophage state in AS, suggesting a compensatory protective macrophage program within diseased plaques. MGST3-high M2-like cells displayed an OXPHOS-oriented, antioxidant, and less inflammatory transcriptional state, acted as an active signaling population, and showed higher composite MitoHealth scores. Single-cell mediation analysis further indicated that MitoHealth statistically links higher MGST3 expression to lower inflammatory activity, lower M1-like polarization, and lower atherogenic macrophage programming. In M2-polarized macrophages, MGST3 knockdown reduced M2-associated and mitochondrial/antioxidant transcripts while increasing pro-inflammatory transcripts, providing transcript-level functional support. PheWAS analysis detected no significant phenotype associations at the predefined threshold.</p>Conclusions<p>These findings define MGST3 as a marker of a mitochondrial-health-associated M2-like macrophage state that appears expanded within AS plaques despite reduced whole-plaque MGST3 expression. The MGST3-MitoHealth axis may represent a compensatory macrophage program linked to mitochondrial preservation and lower pro-atherogenic activation, warranting further diagnostic and therapeutic investigation in AS.</p> 2026-09-17T04:50:36Z Dataset Dataset 10.3389/fimmu.2026.1864957.s004 https://figshare.com/articles/dataset/Table_12_MGST3_defines_a_mitochondrial-health-associated_M2_macrophage_state_in_atherosclerosis_integrative_multi-omics_single-cell_mediation_and_functional_validation_xlsx/33871351 CC BY 4.0