Myocardial fibrosis is a significant pathological basis of heart failure. Overactivation of the ERK1/2 and JNK1/2 signaling pathways of MAPK family members synergistically promotes the proliferation of myocardial fibroblasts and accelerates the development of myocardial fibrosis. In addition to some small molecule inhibitors and Western drugs, many Chinese medicines can also inhibit the activity of ERK1/2 and JNK1/2, thus slowing down the development of myocardial fibrosis, and are generally safe and effective. However, the specific biological mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis still need to be fully understood, and there is no systematic review of existing drugs and methods to inhibit them from improving myocardial fibrosis. This study aims to summarize the roles and cross-linking mechanisms of ERK1/2 and JNK1/2 signaling pathways in myocardial fibrosis and to systematically sort out the small-molecule inhibitors, Western drugs, traditional Chinese medicines, and non-pharmacological therapies that inhibit ERK1/2 and JNK1/2 to alleviate myocardial fibrosis. In the future, we hope to conduct more in-depth research from the perspective of precision-targeted therapy, using this as a basis for developing new drugs that provide new perspectives on the prevention and treatment of heart failure.

Pulmonary vascular remodeling is the critical structural alteration and pathological feature in pulmonary hypertension (PH) and involves changes in the intima, media and adventitia. Pulmonary vascular remodeling consists of the proliferation and phenotypic transformation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) of the middle membranous pulmonary artery, as well as complex interactions involving external layer pulmonary artery fibroblasts (PAFs) and extracellular matrix (ECM). Inflammatory mechanisms, apoptosis and other factors in the vascular wall are influenced by different mechanisms that likely act in concert to drive disease progression. This article reviews these pathological changes and highlights some pathogenetic mechanisms involved in the remodeling process.

Optimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine (TCM) formula for heart failure treatment. MAPK signaling pathway is the key driver of myocardial fibrosis in heart failure. However, the mechanism of ONSMP on myocardial fibrosis and MAPK signaling pathway remains unclear. To evaluate the effect of ONSMP against myocardial fibrosis in heart failure and the underlying mechanisms. Firstly, UHPLC-Q-Exactive-MS/MS was used to identify the active components in ONSMP. Secondly, a rat model of heart failure was established by ligating the left anterior descending branch of the coronary artery. After four weeks of intragastric administration of ONSMP, we used various classic tests, including echocardiography, exhaustive swimming, cardiopulmonary coefficient, heart failure markers, and cardiac pathological section, to assess the prescription's anti-myocardial fibrosis in heart failure properties. AGEs, Ang Ⅱ, VEGF, CTGF, and TGFβ levels in rat serum were quantified using ELISA. The positive expression of p-ERK1/2 and p-JNK1/2 of rat myocardium was determined immunohistochemical. The protein and mRNA levels of genes involved in the MAPK signaling pathway and myocardial fibrosis were measured using western blotting or real-time PCR. The main components of ONSMP that regulate the MAPK signaling pathway are isorhamnetin, kaempferol, quercetin, and tanshinone ⅡA. ONSMP ameliorated cardiac function and exercise tolerance and reduced cardiopulmonary coefficient, heart failure marker levels, and myocardial fibrosis in the heart failure rats. In addition, ONSMP diminished the serum MAPK pathway activator levels, positive expression level of p-ERK1/2 and p-JNK1/2, protein and mRNA levels of components of the MAPK signaling pathway in the myocardial tissue of heart failure rat, indicating that it inhibits MAPK signaling pathway. ONSMP delayed heart failure by inhibiting myocardial fibrosis via the MAPK signaling pathway.

Focusing on cardiomyocyte survival in the prevention and treatment of heart failure, ferroptosis and pyroptosis-two vital modes of cell death-have attracted intense interest. The immunomodulatory cGAS/STING axis, a currently prominent pathway, has also been found to mediate both ferroptosis and pyroptosis; however, the underlying mechanisms remain unclear. This review first traces the historical development of ferroptosis and pyroptosis, dissecting their distinctions, interconnections, and molecular biology. It then spotlights the cGAS/STING axis, elucidating the structural hallmarks of its core proteins, the cascade of signal activation and propagation, its self-amplifying feedback loop, and the precise routes through which it orchestrates ferroptosis and pyroptosis, while also revealing how these two death modalities in turn reinforce the pathway. Furthermore, we investigate the combined effects of ferroptosis and pyroptosis on cardiac structure and function, and rigorously evaluate emerging therapeutic strategies targeting the cGAS/STING axis, encompassing chemical drugs, bioactive natural compounds, small-molecule antagonists, genetic interventions, and exercise training. By integrating the axis's dual role in counteracting pyroptosis and ferroptosis, the review highlights the cGAS/STING pathway as a central target in heart failure management, offering insights to advance both theoretical frameworks and practical therapeutic avenues.