Beyond cardiac fibroblasts: research advances on understanding and targeting intercellular communication networks in cardiac fibrosis.

Cardiac fibrosis is pivotal in the progression of various cardiovascular diseases, ultimately leading to heart failure. Traditionally, research has focused on the activation and transformation of cardiac fibroblasts. However, the heart's complexity, involving multiple cell types, means fibrosis is not driven by a single cell type but by a network of intercellular communication. This network includes signaling mediators from the pericardial space, a crucial regulatory compartment for intercellular cross-talk. This article reviews recent advances that surpass the traditional single-cell approach, providing an in-depth analysis of the complex networks involved in myocardial fibrosis. These networks encompass cardiomyocytes, endothelial cells, and immune cells like macrophages and T cells, which interact through paracrine signaling, direct cell-cell contact, and extracellular vesicle-mediated mechanisms. The review delves into the molecular mechanisms of these communication modes, clarifying the functional outcomes of each signaling pathway in fibrosis initiation and persistence. It also summarizes the phenotypic changes and functional impairments caused by abnormal intercellular crosstalk, such as excessive extracellular matrix deposition, myocardial stiffness, electrical signal disturbances, and cardiac contractile dysfunction. Additionally, the review examines the latest therapeutic strategies and potential intervention targets, focusing on specific cytokines, signaling pathways, or vesicular delivery systems. It discusses the translational value of preclinical findings, the limitations of single-target interventions, and the need for multi-target combined strategies. The article concludes with insights into core regulatory nodes and future optimization directions for anti-fibrotic therapy. This exploration aims to provide new theoretical foundations and directions for developing precise and effective anti-fibrotic therapies.