Polystyrene nanoplastics induce ovarian granulosa cell senescence via autophagy suppression

Polystyrene nanoplastics (PS-NPs) pose escalating threats to female reproductive health, yet their impact on ovarian granulosa cell senescence remains poorly understood. This study investigates the mechanisms by which 50 nm PS-NPs induce senescence in human ovarian granulosa KGN cells. Exposure to PS-NPs (50-250 μg/mL) triggered concentration-dependent cellular senescence in KGN cells, as evidenced by increased senescence-associated β-galactosidase (SA-β-gal) activity, suppressed Lamin B1 expression, and enhanced activation of the P53/P16 signaling axis. PS-NPs also triggered both a senescence-associated secretory phenotype (SASP) and senescence-associated mitochondrial dysfunction (SAMD), marked by upregulated pro-inflammatory cytokines (IL-6, IL-8, IL-1β) and increased reactive oxygen species (ROS) levels coupled with mitochondrial membrane potential (ΔΨm) disruption. Mechanistically, we demonstrated that PS-NP-induced senescence in KGN cells is mediated by autophagy suppression. Autophagy modulation experiments revealed that rapamycin (an autophagy activator) reversed PS-NP-triggered senescence, SASP and SAMD, whereas 3-methyladenine (3-MA, an autophagy inhibitor) exacerbated these effects. These results establish autophagy suppression as a critical mediator of PS-NP-induced granulosa cell senescence and highlight the therapeutic potential of autophagy enhancement to mitigate PS-NPs-associated reproductive toxicity. Our study provides novel insights into the molecular pathways linking environmental nanoplastics to premature ovarian aging, underscoring the urgent need for strategies to address nanoplastics exposure in reproductive health.