RSPO3 (R-spondin 3) is a secreted protein that functions as a key activator of Wnt signaling pathways through binding to LGR4-6 receptors. RSPO3 regulates multiple physiological processes including hepatocyte zonation, vascular endothelial function, and tissue regeneration. In the liver, hepatic stellate cell-derived RSPO3 controls hepatocyte zonation and liver size through Wnt signaling modulation, with decreased RSPO3 expression associated with liver disease progression 1. RSPO3 plays dual roles in vascular biology: it promotes endothelial regeneration after inflammatory injury through LGR4-dependent activation of β-catenin and integrin-linked kinase signaling pathways 2, while paradoxically impairing endothelial barrier function by disrupting adherens junctions and synergizing with pro-inflammatory IL-1β 3. In cardiac tissue, the RSPO3-LGR6 axis protects against myocardial ischemia-reperfusion injury by suppressing necroptosis through Wnt pathway activation 4. RSPO3 also contributes to prostate regeneration through paracrine signaling 5. Clinically, RSPO3 has been identified as a potential therapeutic target for inflammatory bowel disease through Mendelian randomization studies 6, and plasma RSPO3 levels correlate with endothelial injury markers in septic patients 2.