GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336344/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336344GEOGSEfalseAndrogen Receptor-Driven RASSF3 Upregulation Promotes CKD Progression by Inhibiting Gαs/Gq Activity to Mediate Metabolic Reprogramming [R3]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.2026/07/02GSE336344GSM9833102GSM9833105GSM9833106GSM9833103GSM9833104GSM983310724676336344Homo sapiens