PPP2R1B encodes the PR65 scaffold subunit of protein phosphatase 2A (PP2A), coordinating assembly of the catalytic and regulatory B subunits 1. The protein functions as a scaffolding molecule enabling PP2A holoenzyme formation and activity 2. In metabolism, hepatic PPP2R1B is transcriptionally induced by IRF3 during obesity-induced inflammation, amplifying PP2A activity to dephosphorylate AMPKα and AKT, thereby suppressing hepatic glucose production and dysglycemia 1. Alternative splicing of PPP2R1B regulates its function; transcript-201 (retaining exons 2-3) enables full PP2A enzyme activity and Wnt/β-catenin signaling, promoting osteogenesis of mesenchymal stem cells 3. PPP2R1B serves as a tumor suppressor; somatic alterations occur in 8-15% of colorectal and lung cancers, with mutations in the PP2A-C binding domain impairing holoenzyme assembly and cell cycle regulation 245. PPP2R1B is essential for spermatogenesis, with homozygous deletion causing meiotic arrest; heterozygous mutations identified in azoospermia patients reduce protein stability through dysregulated ubiquitination 6. These findings establish PPP2R1B as a critical regulator of metabolism, cell cycle control, and reproduction with tumor-suppressive properties.