Undisclosed GPR161 modulator therapeutic / Omeros - LARVOL DELTA

Oncogenic GPR161 Drives Melanoma Proliferation and Metabolic Activity through TXNIP Inhibition. (PubMed, J Microbiol Biotechnol) - "Together, our findings revealed that GPR161 promotes melanoma malignancy by linking STAT3 activation to TXNIP suppression and metabolic enhancement. This study identified GPR161 as a potential biomarker and therapeutic target in melanoma."

Journal • Diabetes • Melanoma • Oncology • Solid Tumor • STAT3 • TXNIP

Trisomy 21 alters ciliary localization of Sonic Hedgehog signaling proteins. (PubMed, bioRxiv) - "Trisomy (T21) impedes primary cilia assembly and function.T21 causes diminished ciliary Smoothened (SMO) levels and activation.T21 alters the localization of other SHH-associated proteins.Increased cilia maturation time equilibrates localization of SHH-associated ciliary proteins."

Journal • Developmental Disorders • Genetic Disorders

Integrated Analysis of ATAC-Seq and RNA-Seq Reveals the Signal Transduction Regulation of the Molting Cycle in the Muscle of Chinese Mitten Crab (Eriocheir sinensis). (PubMed, Biomolecules) - "Further structural analysis and RT-qPCR validation identified eight GPCRs involved in molting regulation: GRM7 and moody were specific to the post-molt_vs_inter-molt stage; Kpna6, ADRB2, and SSTR2 were unique to the pre-molt_vs_molt stage; FMRFaR and gpr161 functioned in both post-molt_vs_inter-molt and pre-molt_vs_molt stages; and mth2 was active in both post-molt_vs_inter-molt and molt_vs_post-molt stages. These findings improve the understanding of molting regulation and provide potential targets for further genetic improvement in E. sinensis."

Journal • ADRB2 • KPNA6 • SSTR2

Dissection of Gαs and Hedgehog Signaling Crosstalk Reveals Therapeutic Opportunities to Target Hedgehog-Dependent Tumors. (PubMed, Cancer Res) - "Tumors from Gαs pathway inactivation were independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as SMO-independent oncogenic Hedgehog signaling models. Finally, activation of the Gαs-coupled adenosine 2B receptor with BAY60-6583 counteracted oncogenic SMO, reducing Hedgehog signaling and tumor growth. Together, these findings offer a potential therapeutic strategy for BCC."

Journal • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

GPR161-GLI3 repressor signaling at cilia directs apical constriction and cell fate during cranial neural tube closure. (PubMed, Development) - "These results reveal metamere-specific, cilia-dependent hedgehog repression thresholds in control of spatially restricted gene expression and dynamic cell behavior during cranial closure. Targeted interventions increasing hedgehog repression could ameliorate regional cranial defects."

Journal • CNS Disorders • GLI2 • GLI3

Identifying the biomarkers associated with G protein-coupled receptors of parkinson's disease. (PubMed, Sci Rep) - "Finally, six drugs, such as sorafenib, 10 proteins, such as ARRB1 and ARRB2, and 15 miRNAs, such as hsa-miR-140-5p were found to be associated with biomarkers. NTSR1 and GPR161 were identified as novel biomarkers associated with GPCRs in PD. These might serve as potential therapeutic targets and provide new ideas for disease prevention, diagnosis, and treatment of PD."

Biomarker • IO biomarker • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • ARRB1 • MIR140 • PD-1

Determining the Role of GPR161 in PKD (KIDNEY WEEK 2025) - "Studies on testing whether non-self-activatable variants of GPR161 can rescue the ciliary cAMP and cystogenesis in Inpp5e/Gpr161 dko IMCD3 cells are ongoing, as well as the animal studies. Conclusion Our current results suggest an intriguing possibility that GPR161 via self-activation constitutively produces the basal level of cAMP in primary cilia, which may elevate the ciliary cAMP to a level that triggers cystogenesis when PKD mutations cause abnormal increase of GPR161 or weaken certain counteracting mechanisms in cilia."

Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Integrating Network Analysis and Machine Learning Identifies Key Autism Spectrum Disorder Genes Linked to Immune Dysregulation and Therapeutic Targets. (PubMed, Genes (Basel)) - "This study effectively bridges the basic transcriptomic discoveries and clinical applications in ASD research. The findings contribute to a better understanding of the etiology of ASD and provide potential therapeutic leads. Future research could focus on validating these potential drugs in clinical studies, as well as further exploring the biological functions of the identified genes to develop more targeted and effective treatments for ASD."

Journal • Autism Spectrum Disorder • Genetic Disorders • GABRE • NLRP3 • TFAP2A

Transcriptional Consequences of MeCP2 Knockdown and Overexpression in Mouse Primary Cortical Neurons. (PubMed, Int J Mol Sci) - "Among these, RTT-associated candidates such as Plcb1, Gpr161, Mknk2, Rgcc, and Abhd6 were linked to disrupted synaptic signaling and neurogenesis, while ASD-associated genes, including Aim2, Mcm6, Pcdhb9, and Cbs, implicated neuroinflammation and metabolic stress. These findings establish a compact and mechanistically informative set of MeCP2-responsive genes, which enhance our understanding of transcriptional dysregulation in RTT and ASD and nominate molecular markers for future functional validation and therapeutic exploration."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Inflammation • Movement Disorders • Psychiatry • MCM6 • MKNK2

Exploring the Potential of FLASH Proton Therapy in Medulloblastoma: Insights from Cerebellar and Tumor Organoids (ASTRO 2025) - "For medulloblastoma organoids, GPR161 knockout iPS cells were generated via gene editing to replicate the induction of SHH-type medulloblastoma... This study elucidated the differential cellular responses of cerebellar and medulloblastoma organoids to UHDR proton irradiation. The results suggest that FLASH proton therapy may contribute to reducing toxicity in normal cerebellar tissue while maintaining its efficacy against medulloblastoma."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CASP3 • FGF2 • MYCN • PAX6

Identification of novel interacting proteins of FUZ and GPR161. (PubMed, bioRxiv) - "Among the identified proteins, we prioritized FKBP8 and confirmed its biochemical interactions with both FUZ and GPR161 exclusively. In summary, our proteomic profiling uncovered the protein network of FUZ and GPR161, revealing their individual and cooperative functions in multiple cellular processes."

Journal

Compound heterozygous ROBO1 gene variants in a neonate with congenital hypopituitarism, dysmorphic features and midline abnormalities: a case report and review of the literature. (PubMed, J Pediatr Endocrinol Metab) - "This case, together with accumulating evidence, supports ROBO1 as a potential causative gene for CH. ROBO1 should be considered during genetic evaluation of patients with CH and midline abnormalities. The co-occurrence of NOTCH3 and GPR161 variants raises the possibility of an oligogenic or multigenic etiology. The cross-talk between ROBO/SLIT and NOTCH signaling pathways may contribute to the complex phenotype observed and warrants further functional investigation."

Journal • Endocrine Disorders • Growth Hormone Deficiency • NOTCH3 • ROBO1

GPR161 mechanosensitivity at the primary cilium drives neuronal saltatory migration. (PubMed, Sci Adv) - "We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a critical role of mechanosensation in neuronal migration, regulating the rhythmicity of migration, in concert with the externalization/internalization dynamics of the primary cilium."

Journal

Skeletal ciliopathy variants of dynein-2 DYNC2LI1 subunit impair osteogenic differentiation of mesenchymal stem cells. (PubMed, J Cell Sci) - "Dync2li1-knockout cells expressing disease-causing DYNC2LI1 variants demonstrated defects in the retrograde ciliary protein trafficking, including Hedgehog pathway GPCRs, Smoothened and GPR161...By contrast, osteogenic differentiation via BMP signaling was derepressed in Dync2li1-knockout cells. This suggests that skeletal ciliopathies caused by DYNC2LI1 variants could be attributable in part to impaired osteogenic differentiation due to defects in Hedgehog signaling, resulting from defects in retrograde ciliary protein trafficking."

Journal • GLI3

β-Arrestin mediates the export of ciliary GPR161 but not Smoothened together with the BBSome and IFT machinery. (PubMed, J Cell Sci) - "We here propose that phosphorylated GPR161 recruits β-arrestins, converting them into their activated conformation. Activated β-arrestins then interact with the BBSome, which connects them to the IFT machinery to facilitate GPR161 export."

Journal • Bardet–Biedl Syndrome • Inherited Retinal Dystrophy • Ophthalmology • ARRB1

Differences in neuronal ciliation rate and ciliary content revealed by systematic imaging-based analysis of hiPSC-derived models across protocols. (PubMed, Front Cell Dev Biol) - "Interestingly, we found that while GPR161 signal almost completely disappeared from cilia upon Sonic hedgehog (SHH) stimulation in NSCs and immature neurons, this was not the case in more mature neurons, suggesting a possible developmental time window for cilia-dependent SHH signaling. Taken together, our results provide a systematic description of cilia in hiPSC-derived neuronal cells generated with different protocols, underscoring the importance of selecting the optimal model system and controls for investigating primary cilia in hiPSC-derived neuronal cells."

Journal • ARL13B

Dissection of Gαs and Hedgehog signaling crosstalk reveals therapeutic opportunities to target adenosine receptor 2b in Hedgehog-dependent tumors. (PubMed, bioRxiv) - "Tumors from Gαs pathway inactivation are independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as an SMO-independent oncogenic Hedgehog signaling model. Finally, we demonstrate that activation of the Gαs-coupled adenosine 2B receptor counteracts oncogenic SMO, reducing Hedgehog signaling and tumor formation and offering a potential therapeutic strategy for BCC."

Journal • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

Genomic landscape of medulloblastoma subtypes in an Asian cohort. (PubMed, Transl Cancer Res) - "All germline variants of the ten susceptibility genes of interest (APC, BRCA2, PTCH1, PTCH2, ELP1, SUFU, CTNNB1, SMARCA4, GPR161, and TP53) were annotated and validated...This study provides valuable insights into the genetic landscape of MB in an Asian cohort, emphasizing the importance of population-specific research. The subtype-specific germline variant landscape identified in this study contributes to the understanding of MB and its genetic underpinnings in Asian populations, potentially guiding future research and therapeutic strategies."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • APC • BRCA2 • CTNNB1 • PTCH1 • PTCH2 • SMARCA4 • TP53

BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis. (PubMed, EMBO Rep) - "Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity."

Journal • Bardet–Biedl Syndrome • Inherited Retinal Dystrophy • Ophthalmology • CDC42

Obesity Associated Proteins Dynamically Localize to Cilia in the Mouse Brain (OBESITY WEEK 2024) - "For example, some GPCRs (SSTR3 and GPR161) appear to be removed from cilia in a ligand dependent manner in cells... Certain ciliary proteins appear to dynamically localize under different physiological conditions in vivo, while others appear to remain relatively static in their cilia localization. Alternatively, a subset of cilia may be dynamic and are not revealed in our analysis. A better understanding of the subcellular localization dynamics of ciliary signaling proteins could reveal new mechanisms regulating behavior and energy homeostasis."

Preclinical • Genetic Disorders • Obesity • ARL13B

Determining the Pathogenic Mechanism Underlying Childhood ADPKD Caused by a Monoallelic Pathogenic Variant in NEK8 (KIDNEY WEEK 2024) - "Although the ciliary level of GPR161 remained unchanged, SAG induced less accumulation of Smoothened and Gli3 in NEK8R45W cilia than WT, indicating a weaker activation of the Hedgehog (Hh) signaling... We further study the characteristics of the monoallelic NEK8 p.Arg45Trp and determined that the kinase activity of NEK8 in cilia is necessary for the ciliary trafficking of the PC complex, activation of Hh signaling, and epithelial morphogenesis. These signaling pathways may collectively contribute to the establishment and maintenance of renal tubule structures. Understanding the crosstalk between these pathways via studying the role of NEK8R45W may reveal potential drug targets for the treatment of ADPKD in children."

Clinical • Autosomal Dominant Polycystic Kidney Disease • Nephrology • Polycystic Kidney Disease • Renal Disease • GLI3 • PKD1 • PRKD1

Linkage between Fuz and Gpr161 genes regulates sonic hedgehog signaling during mouse neural tube development. (PubMed, Development) - "The Fuz protein biochemically interacts with Gpr161, and Fuz regulates Gpr161-mediated ciliary localization, a process that might utilize β-arrestin 2. Our study characterizes a previously unappreciated Gpr161-Fuz axis that regulates Shh signaling during mouse neural tube development."

Journal • Preclinical • ARRB1

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors. (PubMed, Front Oncol) - "Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma...Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • APC • PTCH1 • TP53

In vivo and in vitro anti-inflammation of Rhapontici Radix extract on mastitis via TMEM59 and GPR161. (PubMed, J Ethnopharmacol) - "ICAB is a prominent antioxidant in RRE. RRE and ICAB reduce mammary inflammation via MAPK and NF-κB pathways and the interaction between TMEM59 and GPR161 mediates the control of ICAB in NF-κB signaling."

Journal • Preclinical • Inflammation • IL1B • IL6 • MAPK8 • TNFA

The evolutionary impact of childhood cancer on the human gene pool. (PubMed, Nat Commun) - "For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool."

Journal • Oncology • Pediatrics • MSH2 • SDHA