Recently, the research team led by Prof. Chen Yuguo and Xu Feng at Qilu Hospital of Shandong University published an article online in Circulation entitled “The Aldehyde Dehydrogenase 2 rs671 Variant Enhances Platelet Activation and Arterial Thrombosis.” They confirmed that the Aldh2 gene variant leads to excessive platelet activation and arterial thrombosis, and revealed the specific molecular mechanism. Prof. Chen Yuguo and Prof. Xu Feng and Prof. Pan Chang at Qilu Hospital of Shandong University served as co-corresponding authors of this study. Dr. Sun Song, a postdoctoral fellow at Qilu Hospital of Shandong University, is the first author. Shandong University is credited as the first and corresponding author institution.

Inhibiting arterial thrombosis is crucial for reducing the incidence and mortality of cardiovascular and cerebrovascular diseases. Precision therapy can further improve patient outcomes compared to traditional treatment; however, there is currently a lack of scientific evidence tailored to the unique genetic background of the Chinese population. The Aldh2 rs671 variant occurs in up to 30%-50% of the Chinese population and is the most common genetic variant among Southeast Asian populations. Many researchers, including our team, have identified Aldh2 gene variants as independent risk factors for coronary artery diseases such as atherosclerosis and myocardial infarction. Nevertheless, the relationship between ALDH2 and arterial thrombosis remains unknown.

To investigate this, the team generated ALDH2^E506Kpoint-mutant mice and platelet-specific Aldh2 knockout mice. They observed that both the Aldh2 variant and deficiency promote excessive platelet activation and exacerbate arterial thrombosis. Using proteomics, mass spectrometry, and molecular biology approaches, the researchers further uncovered the mechanism: ALDH2 dysfunction facilitates the accumulation of toxic aldehydes and reactive oxygen species, which in turn enhances platelet activation. Additionally, they found that Aldh2 deficiency inhibits ubiquitination at the ACAD10 K567/K599 sites and promotes its mitophagy, thereby aggravating thrombosis through platelet hyperactivation.

In myocardial infarction, microvascular occlusion can occur in peri-infarct tissue following ischemia, leading to infarct expansion and progressive cardiac dysfunction. Using a mouse model of myocardial infarction, the team demonstrated that platelet-specific Aldh2 deletion accelerates ischemia-induced microthrombus formation, enlarges infarct size, and worsens cardiac dysfunction—effects that were reversed by silencing platelet ACAD10 expression. Finally, clinical data revealed that myocardial infarction patients carrying the Aldh2 variant exhibit higher levels of platelet activation and thrombotic markers, confirming the association between this genetic variant and arterial thrombosis in humans.

This study, starting with the key genetic variant Aldh2 rs671 and focusing on toxic aldehyde accumulation and ACAD10 K567/K599 ubiquitination, broadens the understanding of platelet activation and arterial thrombosis. It explores the value of the key molecule ACAD10 ubiquitination sites K567 and K599 as potential drug targets, while also providing a scientific basis for precision anti-thrombotic therapy in patients with acute coronary syndrome complicated by Aldh2 rs671 variant.

This work was supported by grants from the National Natural Science Foundation of China, Noncommunicable Chronic Diseases-National Science and Technology Major Project, the National Key R&D Program of China, the Key R&D Program of Shandong Province, Natural Science Foundation of Shandong Province, China Postdoctoral Science Foundation.