z-bio 2025-12-25 2909

　　Recently, the top international journal in the cardiovascular field, Circulation (IF=38.7), published online a major research result on the prevention and treatment of myocardial fibrosis and heart failure. This study, completed by a joint team from Harbin Medical University and Nanjing Medical University, systematically revealed the molecular mechanism of thiol-nitrosylation modification of pyruvate kinase 2 (PKM2) that drives myocardial fibrosis. It also found that Mitapivat, a drug for the treatment of hemolytic anemia, has new potential in the prevention and treatment of heart failure, providing innovative strategies for clinical intervention. Associate Professor Zhang Yan, School of Basic Medicine, Nanjing Medical University, is deeply involved in the research as the co-first author. His team's continued in-depth research in the field of cardiovascular disease molecular mechanisms and drug transformation has once again gained international recognition.

　　Myocardial fibrosis is the common pathological basis of multiple heart diseases such as hypertensive heart failure and ischemic heart disease, and is also a key link leading to the deterioration of cardiac function. Currently, there is a lack of effective clinical treatments that directly inhibit the activation of cardiac fibroblasts. Protein thiol-nitrosyl modification (SNO) is the core mechanism of nitric oxide signaling, and its functional imbalance plays a key role in the occurrence and development of various diseases. This study focused on this core pathway and clarified for the first time the driving role of SNO-PKM2 in cardiac fibrosis.

　　The research team found that PKM2 is specifically highly expressed in cardiac fibroblasts but not in adult mouse cardiomyocytes. This characteristic makes it an ideal target for targeted intervention. SNO-PKM2 levels were significantly increased in various animal models of myocardial fibrosis such as angiotensin II stimulation, aortic coarctation (TAC), acute myocardial infarction, and heart tissue of patients with heart failure. Through mass spectrometry analysis and point mutation technology, the team further confirmed that the key modification sites of PKM2 are cysteine 49 and 326 (Cys49/326). Inhibiting this modification can significantly improve the systolic and diastolic function of the mouse heart and reduce collagen deposition.

　　At the level of mechanism exploration, the study demonstrated for the first time that SNO-PKM2 promotes the activation of cardiac fibroblasts through the dual pathway of "metabolic reprogramming + mitochondrial fission": on the one hand, SNO modification inhibits PKM2 enzyme activity and shifts the glucose metabolism of fibroblasts to the pentose phosphate pathway, providing energy and material base for cell proliferation. On the other hand, the binding of modified PKM2 to gelsolin (GSN) is weakened, resulting in the enhanced binding of GSN to the mitochondrial fission protein DRP1, promoting the phosphorylation of DRP1 by recruiting CaMKII, triggering excessive mitochondrial fission and dysfunction, and ultimately promoting the transformation of fibroblasts into myofibroblasts. This discovery provides a new perspective on metabolic regulation for understanding the pathogenesis of heart failure.

　　What is more valuable for translation is that based on the above mechanism, the research team screened and found that Mitapivat, a commonly used clinical hemolytic anemia treatment drug, can activate PKM2 in a dose-dependent manner and effectively inhibit the activation of cardiac fibroblasts. In TAC and angiotensin II-induced heart failure models, Mitapivat significantly delayed the deterioration of cardiac function and showed good preventive and therapeutic effects. Considering that heart failure and anemia often promote each other, this drug may have the therapeutic advantage of "killing two birds with one stone" in anemia patients with underlying cardiac diseases, opening up an important direction for the new use of old drugs.

　　Professor Ji Yong, Professor Xie Liping (Nanjing Medical University) and Professor Han Yi (Harbin Medical University) are the co-corresponding authors of this study. The team has long been engaged in research on the relationship between protein thiol-nitrosyl modification and cardiovascular disease. It has established a systematic SNO detection platform and has successively discovered multiple key regulators of heart failure. The series of results were published in top journals such as Circulation and Circulation Research, providing a number of innovative theories and potential targets for the precise prevention and treatment of cardiovascular disease.

　　As the co-first author, Associate Professor Zhang Yan of Nanjing Medical University has long focused on research on the molecular mechanisms and drug prevention and treatment of cardiovascular diseases. She is a training target of the Jiangsu Association for Science and Technology’s Young Scientific and Technological Talents Project. She was also selected into Nanjing Medical University’s “Outstanding Young and Middle-aged Key Teachers” and “Young Top-notch Talents” talent programs, leading the Spark team of graduate tutors. The results published this time are her second high-level paper published in Circulation as the first author. Her previous research results have also won the top ten basic research papers on cardiovascular disease in China in 2021.