Nucleolar stress facilitates islet β cell senescence via hijacking the DNA damage response pathways

Senescence is a crucial contributor to pancreatic β cell dysfunction during diabetes progression. Herein, we demonstrated that nucleolar stress, a stress event resulting from disrupted ribosomal RNA (rRNA) synthesis, drives β cell senescence. Senescent β cells exhibited altered nucleolar morphology and redistribution of the nucleolar protein nucleophosmin (NPM) <i>in vivo</i>. Exposure to nucleolar stress inducers CX-5461 and actinomycin D (ActD) resulted in senescence-associated β-gal staining (SA-β-gal) activity in cultured β cells. This was accompanied by upregulation of senescence markers p53, p21, and p16 and a senescence-associated secretory phenotype (SASP). Notably, nucleolar stress also induced γ-H2AX foci formation and Ataxia telangiectasia mutated (ATM) activation independently of DNA double-strand breaks (DSBs). Pharmacological inhibition of ATM with KU60019 strongly attenuated nucleolar stress-induced β cell senescence. Collectively, these findings identify nucleolar stress as a key upstream event in β cell senescence and highlight the γ-H2AX-ATM axis as a critical mediator of this process.