MARK4, also known as microtubule-affinity regulating kinase 4, is a member of the AMPK-related kinase family. It is involved in multiple biological processes, regulating cell division, proliferation, migration, and the cell cycle. It participates in pathways such as the MAPK/ERK signaling pathway and is associated with microtubule detyrosination, which is crucial for cardiomyocyte contractility. Genetic models, especially KO mouse models, are valuable for studying its functions [1,5].

In a mouse model of myocardial infarction, MARK4 deficiency limits the reduction in left ventricular ejection fraction without affecting infarct size or cardiac remodeling, suggesting its role in regulating cardiac inotropy through microtubule detyrosination [1]. In a tauopathy mouse model, Mark4 ablation ameliorates tau pathology, improving mortality and memory, accompanied by reduced neurodegeneration and astrogliosis [2]. In STZ-induced diabetic cardiomyopathy mice, AAV9-shMARK4-mediated decreased MARK4 expression alleviates diabetic myocardial damage, reduces oxidative stress and apoptosis, and promotes myocardial lipid oxidation metabolism by downregulating ACSL4 [3]. In atherosclerotic Ldlr-deficient mice, Mark4-deficiency in bone marrow cells reduces lesion size and NLRP3 inflammasome-related cytokine levels [4]. In gastric cancer, MARK4 promotes the malignant phenotype through the MAPK/ERK signaling pathway, and its up-regulation is associated with poor prognosis [5].

In conclusion, MARK4 plays essential roles in multiple biological processes and disease conditions. Gene-knockout mouse models have revealed its significance in cardiac function, neurodegenerative diseases, diabetic cardiomyopathy, atherosclerosis, and gastric cancer. Understanding MARK4's functions provides potential therapeutic targets for these diseases.