Progress on the role of mixed lineage kinase 3 in cardiovascular diseases

Despite great changes in the spectrum of human diseases, cardiovascular diseases (CVDs) have been the leading cause of human death worldwide for more than 20 years. According to a report from the World Health Organization, an estimated 17.9 million people die of CVDs every year, accounting for 32% of total deaths worldwide. Developing countries are those with the greatest loss of healthy life years. China is the largest developing country in the world, and deaths from CVDs in China have ranked first among total causes of death for urban and rural residents for many years. According to the latest Annual Report on Cardiovascular Health and Diseases in China (2021), the number of patients with CVDs in China has reached 330 million, which has brought a heavy disease burden to the national economy and medical system. Therefore, further exploration of the potential pathogenesis and possible therapeutic targets of CVDs is of great significance for disease prevention and human health promotion. Mixed lineage kinase 3 (MLK3, also known as MAP3K11) is a member of the mitogen-activated protein kinase (MAPK) family. It is an important molecule in the cell life cycle and regulates many critical pathophysiological processes such as cell proliferation, differentiation, apoptosis, and energy metabolism through c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways. In addition, it is involved in the initiation and development processes of numerous types of tumors in the digestive system, nervous system, reproductive system, and some other physiological systems. It is noteworthy that recent studies suggest that MLK3 is also closely associated with CVDs, and plays a significant role in the pathophysiological processes of CVDs such as heart failure, myocardial hypoxic injury, and sepsis-induced cardiomyopathy. It has been found that MLK3 is likely to be involved in the initiation and development of these diseases through activation of the inflammatory response, damage from reactive oxygen species, induction of cell apoptosis, and through its influence on metabolic and energy homeostasis. However, the role of MLK3 in different CVDs differs; in recent studies, some of its effects are controversial and need to be further verified. Overall, MLK3 is likely to be a potential therapeutic target for CVDs. Here, we provide a general overview and summarize related signaling pathways of MLK3 in the physiological state, while elucidating the mechanisms of MLK3 in common CVDs based on the latest research results. This provides a baseline for broadening research and exploring preventive and therapeutic ideas in CVDs.