Abstract
Recurrent ischemic stroke represents a major unmet clinical challenge, contributing significantly to the global burden of neurological disability and mortality. Despite widespread implementation of guideline-recommended secondary prevention strategies-including antiplatelet therapy, lipid management, and blood pressure control-a substantial proportion of stroke survivors experience subsequent ischemic events (GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Neurology. 2021;20(10):795-820.). This persistent residual risk suggests that current clinical paradigms fail to capture the complex, heterogeneous biological dysregulation driving the recurrent disease state (Hankey in Lancet Neurol 13:178-194, 2014). Ischemic stroke is fundamentally a catastrophic metabolic crisis, involving rapid bioenergetic failure, profound oxidative stress, and prolonged inflammatory cascades (Dirnagl et al. in Trends Neurosci 22:391-397, 1999). Mass spectrometry (MS)-based metabolomics has emerged as a premier technological platform in preclinical and exploratory clinical research, capable of simultaneously quantifying hundreds to thousands of endogenous small-molecule metabolites (Nicholson and Lindon in Nature 455:1054-1056, 2008). By providing a functional readout of cellular phenotypes, MS metabolomics offers a unique window into the dynamic biochemical alterations that precede, accompany, and follow ischemic injury. This review provides a comprehensive synthesis of recent advances in applying MS-based approaches to dissect the pathophysiology of recurrent ischemic stroke. We critically examine strong evidence implicating core metabolic disruptions, including the "sphingolipid rheostat" and blood-brain barrier integrity, the shift toward pro-inflammatory lipid mediators in the inflammation-thrombosis axis, mitochondrial tricarboxylic acid cycle dysfunction, and the complex interplay between gut microbiota-derived metabolites and host vascular health. Furthermore, we explore the emerging field of pharmacometabolomics, detailing how MS profiling is providing mechanistic insights into resistance to standard antiplatelet therapies, particularly involving clopidogrel bioactivation pathways and arachidonic acid shunting in aspirin-treated patients. The potential of metabolomics to elucidate the biological mechanisms of complementary therapies, such as acupuncture, is also reviewed with critical appraisal. Finally, we provide a realistic and sobering assessment of the current translational gap. We highlight that while MS metabolomics offers unparalleled pathophysiological insights, significant technical and validation hurdles-including standardization of protocols, absolute quantification challenges, and the need for large-scale, diverse cohort studies-must be overcome before these metabolic signatures can be translated into viable clinical tools for personalized risk stratification and prevention of recurrent stroke (Wishart in Physiol Rev 99:1819-1875, 2019).