uPAR/suPAR Signaling and Organ Crosstalk in Cardiovascular-Kidney-Metabolic Syndrome.

Cardiovascular-kidney-metabolic syndrome is driven by inflammatory mechanisms that propagate injury across organ boundaries, yet the molecular mediators converting systemic inflammation into end-organ damage remain incompletely defined. Across multiple prospective cohorts, suPAR (soluble urokinase plasminogen activator receptor) is associated with incident cardiovascular events, heart failure, diabetes, and kidney disease progression, and genetic and experimental studies support a causal role. How a glycosylphosphatidylinositol-anchored receptor without a transmembrane domain initiates intracellular signaling has remained a fundamental paradox. A membrane-tethered receptor, uPAR, addresses this paradox by assembling lateral signalosomes with coreceptors including αvβ3 integrin, the receptor for advanced glycation end-products, and receptor tyrosine kinases on myeloid, endothelial, and vascular smooth muscle cells, transducing signals that drive atherosclerotic plaque inflammation, vascular remodeling, and maladaptive fibrosis. Proteolytic and lipolytic cleavage of uPAR releases suPAR and its fragments into the circulation; a cleavage/release switch that converts locally scaffolded signaling into diffuse systemic agonist activity and links inflammation in 1 tissue to injury in distant organs. SuPAR activates podocyte αvβ3 integrin and receptor for advanced glycation end-products, now identified as an obligate coreceptor, triggering a Rac1/NOX2-Src-TRPC6 (transient receptor potential canonical channel 6) cascade that produces proteinuria and glomerulosclerosis. The D2D3 cleavage fragment drives insulin-dependent diabetes in transgenic mice through direct β-cell toxicity, an effect reversed by anti-uPAR antibody. This framework reframes the uPAR/suPAR axis not as a single biomarker but as a compartmentalized signaling system operating in distinct modes across cardiovascular-kidney-metabolic-relevant cell types. We map pharmacologically tractable intervention nodes spanning transcriptional suppression, suPAR neutralization, receptor interface disruption, and downstream kinase and channel inhibition, and propose that matching therapeutic strategy to the predominant signaling mode may enable disease-context-dependent precision approaches to cardiovascular-kidney-metabolic syndrome.