Mechanism of ferroptosis in heart failure: The role of the RAGE/TLR4-JNK1/2 pathway in cardiomyocyte ferroptosis and intervention strategies

Abstract

The ferroptosis of cardiomyocytes has been recognized as the core pathological mechanism of heart failure. During the evolution of cardiovascular diseases, the accumulation of angiotensin II and advanced glycation end products can lead to the excessive activation of the RAGE/TLR4-JNK1/2 pathway, which subsequently triggers ferritinophagy, clockophagy, and enhanced p53 activity, ultimately leading to cardiomyocyte ferroptosis. It is evident that deeply unraveling the specific mechanisms in this field and comprehensively evaluating potential drugs and therapeutic strategies targeting this pathway is crucial for improving the status of cardiomyocyte ferroptosis. However, our current understanding of this pathway's specific molecular biological mechanisms in the process of cardiomyocyte ferroptosis remains limited. In light of this, this paper first comprehensively reviews the historical context of ferroptosis research, compares the similarities and differences between ferroptosis and other standard modes of cell death, elucidates the core mechanisms of ferroptosis and its close connection with heart failure, aiming to establish a basic cognitive framework for readers on ferroptosis and its role in heart failure. Subsequently, the paper delves into the pivotal role of the RAGE/TLR4-JNK1/2 pathway in cardiomyocyte ferroptosis and its intricate molecular biological regulatory network. Furthermore, it systematically integrates various therapeutic approaches aimed at inhibiting RAGE, TLR4, and JNK1/2 activity to alleviate cardiomyocyte ferroptosis, encompassing RNA interference technology, gene knockout techniques, small molecule inhibitors, natural active ingredients, as well as traditional Chinese and Western medicines, with the ultimate goal of forging new avenues and strategies for the prevention and treatment of heart failure.