Local lymphatic circulation disorder: A key promoter of tissue inflammation and organ fibrosis

The lymphatic system serves as a vital vascular network essential for maintaining fluid homeostasis, macromolecule and lipid transport, and modulating immune responses. While traditional research has predominantly focused on peripheral lymphedema and secondary fibrosis resulting from local lymphatic circulation disorders, accumulating evidence indicates that lymphatic dysfunction is a key driver of systemic inflammation and fibrotic remodeling across various solid organs. This review systematically elucidates the pathological basis of peripheral lymphatic circulation disorders, including lymphatic endothelial cell dysfunction, impaired vessel contractility, lymphatic muscle cell and valve abnormalities, and abnormal permeability. Furthermore, we synthesize the core mechanism linking lymphatic failure to tissue fibrosis, specifically highlighting the crosstalk between chronic immune activation, cytokine signaling, fibroblast activation, extracellular matrix deposition, and altered lymphangiogenesis. By mapping these universal pathogenic pathways onto organ-specific diseases, spanning cardiovascular, renal, pulmonary, and hepatic systems, as well as metabolic and tumor-associated microenvironments, we demonstrate how localized lymphatic deficits precipitate broader fibrotic consequences through shared mechanisms and organ-specific amplifying pathways. Finally, we highlight the interplay between immune cells and lymphatic vessels, emphasizing the need for targeted therapies that restore lymphatic integrity and functional drainage to halt progressive organ fibrosis.