R-Spondin1 (NU-206) / Kyowa Kirin, Oruka Therapeutics - LARVOL DELTA

Establishment of mouse endometrial assembloids with luminal epithelial-like structures in vitro. (PubMed, Zool Res) - "Optimization of the GLO culture was achieved by fine-tuning the concentrations of Wnt3a and R-Spondin1, while stromal viability and functionality were enhanced by supplementation with hydrocortisone, L-ascorbic acid, and ITS-X. Compared to existing mEOs, analyses confirmed that ALI-mEnAOs closely mimic in vivo endometrial architecture, lineage composition, phase-specific gene expression signatures, and dynamic hormonal response. This model offers a physiologically relevant platform for mechanistic investigation of endometrial function and embryo implantation dynamics."

Journal • Preclinical • WNT3A

Deletion of Rspo1 or Rspo3 in the mesenchyme does not affect Wolffian duct maintenance or morphogenesis. (PubMed, MicroPubl Biol) - "Wolffian duct maintenance and morphogenesis was unaffected in either Rspo1 or Rspo3 conditional knockout mice. Our results indicate that mesenchymal Rspo1 or Rspo3 is dispensable for Wolffian duct development in mice."

Journal • RSPO1 • RSPO3 • SPON1

Oral Delivery of R-spondin1-Loaded Small Extracellular Vesicles Activates WNT Signalling Pathway to Accelerate Intestinal Injury Repair and Reverse Ageing. (PubMed, J Extracell Vesicles) - "Furthermore, evRSPO1 treatment induces ISCs proliferation and reverses the intestinal senescence phenotype in aged mice. Collectively, this study establishes evRSPO1 as a potential first-in-class, orally deliverable therapeutic that overcomes biological barriers to activate ISCs, enabling efficient intestinal tissue repair and rejuvenation."

Journal • RSPO1

A novel variant p.Y250C of FZD4 influences Norrine/β-catenin signaling pathway that associates with familial exudative vitreoretinopathy (FEVR). (PubMed, Sci Rep) - "Overexpression of mutant FZD4 and NDP or activation with agonist R-Spordin 1 (RSPO1) reduced downstream signaling proteins, including phosphorylated β-catenin (p-β-catenin), and vascular endothelial growth factor (VEGF-A)...Fzd4 exhibited broad tissue expression, and it was notably present during the early developmental stages of retinal and ocular formation in mice. The novel missense mutation c.A749G in the FZD4 gene may impair the Norrin/β-catenin signaling pathway and alter subcellular localization, thereby driving FEVR pathogenesis."

Journal • Dyslipidemia • Retinal Disorders • LDLR • NDP • RSPO1

Comparative RNA-Seq Analysis of Differentially Expressed Genes in the Testis and Ovary of Mudskipper, Boleophthalmus pectinirostris. (PubMed, Animals (Basel)) - "These DEGs were primarily associated with male (e.g., dmrt1, amh, amhr2) or female (e.g., bmp15, gdf9, rspo1) sex determination and differentiation, steroidogenesis (e.g., hsd17b1, hsd3b1, cyp17a1), and meiosis (e.g., cyp26b1, aldh1a2, piwil2). Functional enrichment analysis revealed that male upregulated DEGs were involved in spermatogenesis pathways such as calcium signaling, while female upregulated DEGs were associated with oogenesis pathways including oocyte meiosis and progesterone-mediated oocyte maturation...The amh gene produces two alternatively spliced isoforms that differ by a partial deletion in the second exon, both expressed in ovaries and testes. Collectively, this study provides the first comprehensive molecular framework of sex determination and differentiation in Gobiidae species, offering critical insights into the regulatory mechanisms of B. pectinirostris reproductive development."

Journal • Ophthalmology • ALDH1A2 • AMHR2 • CYP17A1 • DMRT1 • HSD3B1 • RSPO1

Whole-Genome Methylation Analysis of Female, Male, and Neomale Northern Pike (Esox lucius). (PubMed, Animals (Basel)) - "Furthermore, we identified four key differentially methylated candidate genes (Rspo1, hsd11b2, CYP27A1 and smad3) associated with sex determination and differentiation processes in E. lucius. Finally, by integrating GO and KEGG enrichment analyses, we explored the role of epigenetic modification regulatory networks in the sex determination and differentiation of E. lucius and identified multiple metabolic pathways related to sex determination and differentiation processes (Notch signaling pathway, Wnt signaling pathway and Ovarian steroidogenesis). This study thereby lays a foundation for subsequent functional verification."

Journal • CYP27A1 • RSPO1 • SMAD3

Identification of a novel RSPO1-NUMT insertion in a LUAD patient cohort and the challenges and insights into NUMT detection highlighting the importance of reference genomes and population databases. (PubMed, Transl Lung Cancer Res) - "Our findings also highlight technical challenges in NUMT detection across genome builds and databases, with significant discrepancies observed between reference genomes and population frequency estimates. We propose that this homozygous RSPO1-NUMT insertion may represent a previously unrecognized predisposing factor for LUAD development and progression through modulation of RSPO1 expression and subsequent WNT pathway activation, potentially influencing tumor vascularization, drug response, and disease progression."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RSPO1

Construction of a Duck Intestinal Organoid Culture System: From Crypt Isolation to Medium Optimization. (PubMed, Animals (Basel)) - "Media supplemented with CHIR99021 and LDN193189 (CL) supported growth comparable to that of media with EGF, Noggin, and R-spondin 1 (ENR). Duckling serum and specific factors, such as SB203580 and retinol, further improved organoid formation and promoted differentiation. While long-term passaging and expansion remain technically challenging, this work provides the first duck intestinal organoid model and lays the foundation for future applications in avian intestinal research, including nutrition, disease modeling, and intervention strategies."

Journal • Developmental Disorders • RSPO1 • SPON1

N-carbamylglutamate supplementation improves laying performance of layers by regulating hypothalamic-pituitary-ovarian axis. (PubMed, Front Vet Sci) - "Of particular interest, the expression of specific genes involved in the HPO axis, such as FSHB and GNRH1 in the hypothalamus, DHH and GNRHR in the pituitary, and RSPO1, ZP3, GSTA3, C14orf39, HOXA10, and IRX5 in the ovary, was significantly regulated by NCG supplementation. These findings were further validated by quantitative real-time polymerase chain reaction, which confirmed the expression profiles of the aforementioned genes observed in the RNA-seq results. Overall, these findings provide valuable insights into the endocrine mechanisms underlying the improvement of laying performance in layers through NCG supplementation."

Journal • FSHB • GSTP1 • HOXA10 • IRX5 • RSPO1

Dual-ligand engineered exosome regulates WNT signaling activation to promote liver repair and regeneration. (PubMed, Nat Commun) - "Remarkably, exoWNT3A/RSPO1 could accelerate liver repair and regeneration under various conditions, including acute and chronic injuries and aging-associated phenotypes. Collectively, our work revealed the broad therapeutic effects of WNT signaling activation in the liver through the dual-ligand-carrying exosomes."

Journal • PPARA • RSPO1 • SPON1 • WNT3A

Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. (PubMed, Elife) - "RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8...We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling in human cells, which may provide new insights into regenerative medicine and cancer therapy."

Journal • Oncology • Targeted Protein Degradation • FZD5 • RNF43 • RSPO1 • SPON1 • ZNRF3

Case Report: Genomic insights and personalized treatment in dual primary esophageal squamous cell carcinoma and gastric adenocarcinoma. (PubMed, Front Oncol) - "ESCC exhibited amplifications of MCL1, RECQL4, NKX2-1, PARP10, RSPO1, MUCL, and WTIP, while GAC showed deletions of APC and PRKG1, along with amplifications of ARRDC1 and NRARP. The patient achieved stable disease without recurrence following chemoradiotherapy and Sintilimab immunotherapy. This case underscores the role of genetic alterations in dual primary cancers and demonstrates the feasibility of precision treatment."

IO biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • Squamous Cell Carcinoma • ACKR3 • MCL1 • PARP10 • RECQL4 • RSPO1

R-Spondin1 regulates fate of enteric neural progenitors via differential LGR4/5/6-expression in mice and humans. (PubMed, Cell Mol Gastroenterol Hepatol) - "LGR-receptor expression therefore might represent a previously unknown mechanism influencing the fate decision of ENS-progenitor cells between proliferation and neuronal differentiation. Thus, our study is essential for our understanding of regenerative aspects of the postnatal ENS in health and disease."

Journal • Preclinical • LGR4 • LGR5 • LGR6 • RSPO1

Cryo-EM structure of the full-length LGR4-RSPOs complex and a targeting nanobody for anti-obesity therapy. (PubMed, Nat Commun) - "Notably, we develop an inhibitory nanobody (NB21) that blocks the binding of RSPO1/2 to LGR4, and we also determine the structure of the LGR4-NB21 complex...Furthermore, LGR4 deficiency abolishes the effects of NB21-mFc in boosting the browning program and subsequent weight reduction. In summary, our study unveils structural insights into the LGR4-RSPOs and LGR4-NB21 complexes, paving the way for the development of an LGR4-targeting nanobody for weight loss."

Journal • Genetic Disorders • Obesity • LGR4 • RSPO1 • RSPO2

Plasma neurology-related proteins associated with cognition are modulated by lifestyle in adults. (PubMed, EBioMedicine) - "This study identified protein signatures that are associated with CD and observed that a weight loss, energy-reduced Mediterranean diet, and physical activity may influence the relationship between these protein signatures and cognitive outcomes in older adults with MetS. However, further research is needed to confirm these findings and clarify causal relationships."

IO biomarker • Journal • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • CD200 • CD38 • CRP • IL6 • RSPO1 • VWC2

Temporal dynamics of macrophage activation during Salmonella enterica serovar Typhi infection: An integrated transcriptomic and metabolomic analysis. (PubMed, Virulence) - "CCM analysis identified critical genes (e.g. RGS4, KIF18A, RSPO1) exhibiting strong causal relationships with metabolic alterations, underscoring the tight integration between immune and metabolic responses. This study provides a comprehensive, time-resolved view of S. Typhi infection, highlighting dynamic immune activation and metabolic reprogramming in macrophages. These findings advance our understanding of host-pathogen interactions."

Journal • Infectious Disease • Inflammation • KIF18A • RGS4 • RSPO1

Characterization of DMRT1 variants for testis determination and differentiation in emu. (PubMed, Cytogenet Genome Res) - "These findings suggest that while molecular sex differentiation mechanisms are largely conserved between Palaeognathae and Neognathae, they differ in parts. In particular, early RSPO1 expression may initiate ovarian differentiation prior to testis determination by DMRT1. The presence of emu-specific DMRT1 variants further indicates possible species-specific mechanisms in testis development."

Journal • CYP19A1 • DMRT1 • FOXL2 • RSPO1 • SOX9

Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer. (PubMed, Oncotarget) - "This study investigates the R-spondin family of genes (RSPO1/2/3/4), a group of secreted proteins that act as Wnt regulators, and their subsequent role in advanced prostate cancer (PC)...Conversely, this was not observed when CTNNB1 was overexpressed in the same models. These findings highlight that, in PC, RSPO2 functions as a unique member of the R-spondin family by promoting genes and signaling pathways associated with aggressive PC, and RSPO2 amplifications are associated with poor outcomes in PC patients."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • APC • AR • CTNNB1 • RSPO1 • RSPO2 • SPON1 • TWIST1 • ZEB1 • ZEB2

Enhancing Long-Term Survival and Self-Renewal of Primary Hepatocytes via Rapid Spheroid Formation Using Rocker System through Co-Culturing with HUVEC Over-Expressing RSPO1. (PubMed, Tissue Eng Regen Med) - "Large-scale cultured hepatocyte + R-HUVEC spheroids address in vitro challenges of scale, yield, and functional sustainability, promising advances in liver therapeutics and drug development."

Journal • RSPO1 • SPON1

Advancing fatty liver research in dairy cows: Development of a bovine liver organoid model. (PubMed, J Dairy Sci) - "Aiming to enhance disease modeling and drug screening for fatty liver disease, a bovine liver organoid model was developed using R-spondin-1 conditioned medium...Treatment with 5 natural compounds (silymarin, gastrodin, cordycepin, curcumin, and polydatin) and a positive control (atorvastatin) showed significantly reduced inflammation and lipid accumulation in the bovine liver organoid...Collectively, the application of organoid technology exhibits its potential in simulating disease mechanisms and evaluating therapeutic interventions, notably reducing the need for live animal experiments. Our study establishes a bovine liver organoid model and validates its effectiveness as a tool for advancing disease research and pharmaceutical development."

Journal • Hepatology • Inflammation • RSPO1 • SPON1

High Dietary Phosphorus Impairs Bone Microarchitecture and Induces Alterations in the LGR4-R-Spondins Axis in Rats with Normal Renal Function. (PubMed, Nutrients) - " These findings highlight the detrimental impact of excessive dietary phosphorus on skeletal health, even without renal impairment, and suggest that components of this pathway, particularly RSPO1 and RSPO4, could serve as potential biomarkers of bone deterioration. The widespread consumption of phosphorus-rich processed foods underscores the importance of nutritional education to mitigate these skeletal risks in industrialized populations."

Journal • Preclinical • Renal Disease • LGR4 • RSPO1 • TNFRSF11A • TNFRSF11B

In vitro plasticity between ureteric epithelial and distal nephron identity and maturity is controlled by extracellular signals. (PubMed, bioRxiv) - "Subsequent addition of RSPO1 induced patterning of distalizsed nephrons, including distal convoluted tubule and thick ascending limb of loop of Henle but lacking proximal segments or glomeruli...The same epithelium seeded as single cells in Matrigel formed epithelial spheroids and adopted a RET+ ureteric tip identity. This in vitro continuum between nephric duct, ureteric epithelium and distal nephron illustrates the role of the microenvironment in cellular identity."

Journal • Preclinical • RSPO1

Ontogeny of RSPO1, FOXL2, and RUNX1 during ovarian differentiation in the marsupial tammar wallaby. (PubMed, Dev Dyn) - "RSPO1, FOXL2, and RUNX1 are highly conserved in the vertebrate ovary-determining pathway and were expressed in the tammar wallaby in a manner consistent with their role in the ovarian differentiation of eutherian mammals."

Journal • FOXL2 • RSPO1 • RUNX1

From Spheroid to Sprouting: Microenvironmental Modulation Boosts Hair Follicle Organoid Morphogenesis in 3D Culture. (PubMed, Cell Biol Int) - "Furthermore, RSPO1 not only potentiates Wnt/β-catenin-mediated organoid patterning but also coordinates a signaling triad involving PI3K-Akt, Rap1 and NF-κB to drive synchronized hair follicle sprouting and stratified pilogenic differentiation. Our 3D organoid-based expansion strategy enables definitive treatment of alopecia through in vitro hair follicle expansion, achieving functional hair neogenesis in patients with baldness."

Journal • Alopecia • Immunology • CTNNB1 • RSPO1

Phylogenetic Insights into the Evolutionary History of the RSPO Gene Family in Metazoa. (PubMed, Genes (Basel)) - "Gene family clustering and phylogenetic analysis identified four major subtypes of the family (RSPO1-RSPO4) and clarified their distribution of copy number in different species...Further conservative analysis of amino acids and alignment of tertiary protein structure revealed the potential functional sites for each subgroup. The results provide insight into the phylogenetic relationships and evolutionary patterns of conserved motifs of RSPO family genes in animal kingdoms, which will guide further studies on the biological functions of RSPO in other non-model species."

Journal • RSPO1 • RSPO3