Fatty acid metabolism in ischemic stroke: multi-omics biomarker discovery and therapeutic potential of GPR84.

Abstract

Objective: Ischemic stroke (IS), a leading cause of global disability and premature mortality, results from cerebral artery occlusion and subsequent ischemic necrosis. Fatty acid metabolism (FAM) plays a crucial role in energy supply and oxidative damage associated with IS, yet reliable biomarkers and targeted therapies remain elusive, necessitating systematic investigation.

Methods: We integrated peripheral blood transcriptomes (GSE22255 and GSE58294) to identify FAM-related differentially expressed genes (FRDEGs). Consensus clustering of FRDEG expression classified IS subtypes. Weighted gene co-expression network analysis constructed subtype-specific modules. Biomarkers were screened using generalized linear models, least absolute shrinkage and selection operator, support vector machine, and random forest, validated by an independent cohort (GSE16561) and real-time quantitative PCR (RT-qPCR). A diagnostic nomogram was established, and immune infiltration was assessed. Single-cell RNA sequencing (GSE174574) mapped cellular expression, while Connectivity Map analysis and molecular docking predicted potential drugs.

Results: We identified 14 FRDEGs enriched in the tumor necrosis factor, interleukin-17, and nuclear factor-κB pathways. IS patients were classified into two subtypes. VIM, G0S2, and GPR84 emerged as diagnostic biomarkers, with the nomogram demonstrating high efficacy. RT-qPCR validation confirmed their significant upregulation in the peripheral blood of IS patients. Further analysis showed associations with immune infiltration and distinct single-cell expression patterns. Canertinib and flecainide were identified as high-affinity ligands for GPR84.

Conclusion: This study highlights the role of FAM in IS, identifies VIM, G0S2, and GPR84 as novel diagnostic biomarkers, and positions GPR84 as a therapeutic target, thereby advancing precision diagnosis and treatment.