Cardiovascular disease (CVD) is a serious global health issue with high mortality rates worldwide. Despite the numerous advancements in the study of CVD pathogenesis in recent years, further summarization and elaboration of specific molecular pathways are required. An extensive body of research has been conducted to elucidate the association between the MAPK signaling pathway, which is present in all eukaryotic organisms, and the pathogenesis of cardiovascular disease. This review aims to provide a comprehensive summary of the research conducted on MAPK and CVD over the past five years. The primary focus is on four specific diseases: heart failure, atherosclerosis, myocardial ischemia–reperfusion injury, and cardiac hypertrophy. The review will also address the pathophysiological mechanisms of MAPK in cardiovascular diseases, with the objective of proposing novel clinical treatment strategies for CVD.

Cardiovascular and cerebrovascular diseases, encompassing cardiac arrhythmias, atherosclerosis, and ischaemic stroke, remain the foremost causes of death and long-term disability globally. Despite improved outcomes with conventional therapy, substantial residual risk persists, providing the impetus for gene-based intervention. KCNQ1/KCNH2 suppression-and-replacement, SCN5A base editing, and structural protein restoration via PKP2 and TMEM43 have each demonstrated capacity to re-establish electrophysiological stability in arrhythmia models. For atherosclerosis, RNA-based agents, notably inclisiran, alongside in vivo editing strategies such as VERVE-101, offer durable lipid reduction and attenuation of vascular inflammation. In ischaemic stroke, cGAS–STING silencing, AAV-NeuroD1-mediated neuronal reprogramming, and delivery of neurotrophic factors, including VEGF and BDNF, extend the therapeutic window well beyond reperfusion. Collectively, these approaches position gene therapy as a meaningful complement to standard care, capable of addressing root molecular pathology rather than downstream consequences. This review synthesises current mechanistic understanding, translational obstacles, and emerging directions across these three disease domains, arguing that, delivery and safety challenges notwithstanding, gene therapy stands to substantially reshape how cardiovascular and cerebrovascular diseases are prevented and treated.