{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336445/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336445"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Androgen Receptor-Driven RASSF3 Upregulation Promotes CKD Progression by Inhibiting Gαs/Gq Activity to Mediate Metabolic Reprogramming [DT]","description":"Male sex is a risk factor for Chronic Kidney Disease (CKD), but the underlying mechanism is not yet clear. Given the well-established central role of TGF-β in CKD, we hypothesize it reprograms AR’s transcriptional network, shifting AR’s kidney function from healthy to pathogenic. Transcriptomic profiling identified RASSF3 as a critical downstream target of DHT and TGF-β1, upregulated in kidneys from male CKD patients and mice but not females. Tubule-specific Rassf3 knockout in mice prolonged survival and protected against CKD models, whereas its overexpression exerted opposite effects. Mechanistically, RASSF3 binds Gα subunits Gq and Gαs, accelerating their GTP-to-GDP transition (active to inactive) to suppress their activity—an interaction that drives kidney tubule metabolic reprogramming and exacerbates kidney injury and CKD progression. GTPase-deficient Gq/Gαs mutants or Gq/Gαs knockout abolished RASSF3-mediated metabolic reprogramming, confirming dependence on Gq/Gαs GTPase activity. AR transcriptionally upregulates RASSF3 via interaction with SP1 (a TGF-β downstream target). Importantly, δ-tocopherol binds RASSF3’s Ras-associating domain, inhibiting its activity and alleviating CKD. Our study uncovers the molecular basis of AR-driven CKD sexual dimorphism, elucidates mechanisms linking AR to kidney metabolic dysregulation, and identifies RASSF3 as a novel CKD therapeutic target.","dates":{"publication":"2026/07/02"},"accession":"GSE336445","cross_references":{"GSM":["GSM9835477","GSM9835476","GSM9835469","GSM9835481","GSM9835480","GSM9835474","GSM9835472","GSM9835471"],"GPL":["24676"],"GSE":["336445"],"taxon":["Homo sapiens"]}}