Targeting p85β condensates by RNA therapy inhibits liver cancer progression

PI3K complex consists of catalytic subunit p110s and regulatory subunit p85s. Emerging evidence indicates that p110-free p85 subunits play pivotal roles in diverse biological processes, including cancer progression. In this study, we demonstrate the oncogenic function and underlying mechanism of p110-free p85β in hepatocellular carcinoma (HCC) development. PIK3R2/p85β is highly expressed in HCC tissues and correlates with worse overall survival of HCC patients. Nuclear p85β, but not its cytoplasmic counterpart, exhibits oncogenic activity. In the nucleus of HCC cells, p85β undergoes liquid-liquid phase separation (LLPS) and specifically accumulates in the fibrillar centers of nucleoli, where it drives HCC progression. Within the nucleolar compartment, p85β directly interacts with and stabilizes POLR1A, the catalytic core subunit of RNA polymerase I, thereby enhancing rRNA biosynthesis and maintaining HCC stemness. Furthermore, we develop an engineered circular RNA that encodes a peptide containing p110α ABD domain, which effectively suppresses HCC tumor growth by simultaneously disrupting p85β/POLR1A condensates and inhibiting PI3K/AKT signaling pathway. Our findings not only elucidate the critical role of p85β biomolecular condensates in HCC tumorigenesis but also establish a novel RNA-based therapeutic strategy for HCC intervention.