Consensus machine learning identifies cell death gene signature for carotid artery stenosis diagnosis

Carotid artery stenosis (CAS) is a major contributor to ischemic stroke, and molecular tools for its early detection remain limited. To address this need, we integrated one in-house RNA-seq cohort with eight public datasets comprising 696 samples, together with proteomic profiling, RT-qPCR, single-cell sequencing, and FYCO1 silencing experiments. From 1,258 curated cell death-related genes, candidates were filtered by logistic regression across cohorts, and ten machine learning algorithms were combined into 105 model configurations to derive a consensus diagnostic classifier. Fourteen genes showed consistent associations with CAS, and the machine learning-derived diagnostic signature (MLDS), consisting of IRF1, FYCO1, and FDFT1, demonstrated the highest cross-cohort performance. FYCO1 downregulation was validated in plaques and blood and supported by single-cell analysis, while functional assays indicated impaired autophagic flux and heightened inflammatory signaling. These findings highlight MLDS as a robust molecular tool that may enhance the precision diagnosis of CAS.