The Role of Endothelin‐1 in Autoimmune Diseases: Mechanistic Insights and Therapeutic Targets

ABSTRACT Endothelin‐1 (ET‐1), a central mediator within the endothelin peptide family, is predominantly synthesized in vascular endothelial and smooth muscle cells. Its expression is observed across a diverse range of tissues and cellular populations. ET‐1 is a critically important endogenous vasoconstrictor, crucial for the maintenance of fundamental vascular tone and overall cardiovascular homeostasis. Beyond its vascular effects, ET‐1 establishes complex crosstalk with immune cells activating critical intracellular signaling pathways such as NF‐κB, MAPK, and PI3K through receptor‐mediated mechanisms. These interactions contribute to vasoconstriction, angiogenesis, inflammatory responses, tissue injury, and cell proliferation. Accumulating evidence demonstrates that ET‐1 exerts important regulatory functions in immune cell infiltration, cytokine release, and inflammatory cell proliferation. Autoimmune diseases (ADs), a group of chronic disorders driven by aberrant immune attacks against self‐tissues, affect various conditions including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, and organ fibrosis, as well as certain malignancies. Recent studies indicate that ET‐1 plays a crucial role in the initiation and progression of ADs. For example, in systemic sclerosis and systemic lupus erythematosus, ET‐1 promotes vascular remodeling and endothelial dysfunction by stimulating angiogenic factor secretion via receptor‐dependent pathways. In type 1 diabetes, persistent hyperglycemia and oxidative stress activate the ET‐1 system, thereby inducing endothelial impairment and microvascular complications. In rheumatoid arthritis, ET‐1 activates immune cell infiltration, drives vascular dysfunction and the release of inflammatory cytokines, and promotes structural joint damage including synovial hyperplasia and tissue destruction, thus forming a persistent inflammatory loop. Overall, ET‐1 functions not only as a central regulator of vascular homeostasis but also as a key mediator in the pathogenesis of ADs and cancer. Elucidating the therapeutic potential of ET‐1 as an immunomodulatory target may provide novel strategies for disease diagnosis and treatment. This review summarizes the structural and biological features of the ET protein family, the mechanisms of ET‐1‐immune cell interactions, ET‐1‐related signaling pathways, and recent advances regarding ET‐1 in ADs.