{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRSPO1 is a secreted protein that potently amplifies canonical and non‐canonical Wnt signaling by modulating the cell–surface composition of Wnt receptors. Mechanistically, RSPO1 binds to distinct domains on transmembrane proteins—such as the E3 ubiquitin ligases ZNRF3/RNF43 and the leucine‐rich repeat receptors LGR4/5—as well as to other structural motifs, thereby inhibiting receptor turnover and recruiting intracellular mediators like IQGAP1. In addition, proper N‐glycosylation is required for its efficient folding and secretion. 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It further synergizes with Wnt ligands to induce osteoblastic differentiation in both human and murine models and to rescue liver dysfunction by expanding liver stem cells, while also modulating hepatic stellate cell activation in fibrogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of sexual development, RSPO1 plays a decisive role in ovarian determination. It acts as an amplifier of beta‐catenin signaling within the bipotential gonad to oppose testis formation. Mutations in RSPO1 are linked to syndromes of 46,XX sex reversal, often accompanied by palmoplantar hyperkeratosis and predisposition to squamous cell carcinomas, underscoring its importance in gonadal as well as extra‐gonadal developmental pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRSPO1 is also implicated in cancer progression and stem cell maintenance within malignancies. Its overexpression or altered function contributes to enhanced Wnt signaling, which in turn promotes tumor cell proliferation, chemoresistance, and cancer stem cell survival in various settings including ovarian, gastric, glioma, and colorectal cancers. Moreover, innovative drug delivery systems targeting RSPO1‐responsive receptors on cancer stem cells have been developed, highlighting its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in developmental and neoplastic contexts, RSPO1 participates in metabolic regulation and even ocular development. Genetic studies have associated RSPO1 variants with altered ocular axial length and high myopia, while its overactivity in adipose tissues suppresses thermogenesis and predisposes to obesity. 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