Mitoxyperiosis Defines a Monocyte-driven Inflammatory Endotype in Ischemic Stroke: Multi-cohort Transcriptomic and...

Mitoxyperiosis is a recently identified form of regulated cell death driven by mitochondrial oxidative membrane rupture, but its role in ischemic stroke remains unknown. We investigated whether mitoxyperiosis-associated transcriptional activity identifies an inflammatory endotype and computationally prioritized candidate regulators. We analyzed peripheral-blood transcriptomes from GSE16561 (39 patients, 24 controls). Molecular subtypes were evaluated in GSE37587 (34 patients with paired Baseline and Follow-Up samples) and GSE58294 (23 patients sampled at 3, 5, and 24 h). CITE-seq data from GSE285659 (74,714 cells) were used for cellular localization. After adjustment for age and sex, 11 of 38 mitoxyperiosis-related genes were upregulated in ischemic stroke, and the pathway score was higher than in controls (P = 0.038; unadjusted Cohen's d = 0.80). Consensus clustering identified Mito-high (n = 12) and Mito-low (n = 27) subtypes (d = 2.51). Mito-high showed higher pyroptosis, ferroptosis, and necroptosis signature scores and lower expression of 11 of 12 differentially expressed immune checkpoints. All 50 subtype-associated genes were directionally concordant in GSE37587. In GSE58294, the inter-subtype effect size increased from 3 to 24 h (d = 0.83 to 1.20). Mito-high cells comprised 0.32% of profiled cells, of which 92.8% were monocytes. Connectivity mapping and target-pathway correlation analyses prioritized EZH2 and HDAC2 as candidate regulators. Mitoxyperiosis-associated transcriptional activity characterizes a monocyte-enriched inflammatory endotype in ischemic stroke. The Mito-high/Mito-low classification provides a molecular framework for investigating subtype-associated immune features and candidate epigenetic regulators.