Ischemic stroke and comorbidities: Impact on recovery and the role of genetics and epigenetics

Ischemic stroke (IS) remains a leading cause of long-term disability and mortality worldwide, with recovery outcomes shaped by the interplay between acute vascular injury, pre-existing comorbidities, and individual molecular profiles. Common risk factors-such as diabetes mellitus, atrial fibrillation, hypertension, and dyslipidemia-not only increase stroke susceptibility but also impair neurovascular repair by perpetuating systemic inflammation, endothelial dysfunction, and impaired neuroplasticity. Aging remains an underexplored determinant of epigenetic remodeling in stroke. Beyond these clinical determinants, genetic and epigenetic mechanisms contribute substantially to stroke heterogeneity. Genome-wide association studies (GWAS) have identified loci such as HDAC9, PATJ, PTCH1, and ABO that modulate inflammation, oxidative stress, and vascular remodeling. Complementary epigenetic pathways, including DNA methylation, histone acetylation, and circular RNAs (circRNAs), dynamically regulate gene expression in response to ischemia and comorbid influences, encoding a persistent "molecular memory" that shapes both injury and repair. Functional studies reveal that circRNAs orchestrate apoptosis, angiogenesis, and synaptic remodeling, while selective DNMT and HDAC inhibition can restore neurovascular integrity in experimental models. Recent multi-omics and longitudinal approaches demonstrate that these molecular signatures evolve across acute, subacute, and chronic phases of recovery, yet clinical translation remains limited. Aging and chronic comorbidities further modify epigenetic programs, reducing repair capacity. Although genotype-guided antiplatelet therapy illustrates the feasibility of personalized stroke care, broader genomics- and epigenetics-informed interventions require rigorous validation. This review integrates current knowledge on the interplay between vascular comorbidities, genetic predisposition, and epigenetic regulation in shaping stroke recovery. Understanding these interactions is essential for developing precision medicine approaches that enhance functional outcomes and reduce recurrence in stroke survivors.Integrating multi-omics profiling with comorbidity stratification, functional validation, and longitudinal biomarker tracking will be pivotal to achieving actionable precision medicine and improving outcomes in stroke survivors.