LGR4 is a G protein-coupled receptor that functions as a co-receptor for R-spondins to potentiate canonical Wnt signaling, distinct from classical GPCRs as it does not activate heterotrimeric G-proteins 1. In the gastric epithelium, LGR4 specifically activates Wnt signaling in stem/progenitor cells of the isthmus, unlike LGR5 2. LGR4 regulates diverse developmental and homeostatic processes including bone remodeling through osteoblast-osteoclast communication 3, intestinal stem cell maintenance, spermatogenesis, and kidney development [UniProt]. Additionally, LGR4 suppresses innate immune responses by inhibiting TLR2/TLR4-mediated pro-inflammatory signaling [UniProt]. Disease relevance includes premature ovarian insufficiency, where LGR4 loss-of-function variants contribute to ovarian development defects 4, and osteoporosis associated with inactivating mutations 1. In cancer biology, elevated LGR4-Wnt signaling confers chemotherapy resistance in colorectal cancer by upregulating ferroptosis inhibitors 5, while RSPO2/RANKL-LGR4 signaling promotes breast cancer bone metastasis through osteoclast premetastatic niche formation 6. Post-myocardial infarction, macrophage LGR4 promotes inflammatory responses via AP-1 activation, impairing cardiac repair 7. Clinically, LGR4 represents an emerging therapeutic target across oncology, orthopedics, and cardiometabolic disease.