Cyclosporine A provokes paraptosis-like cell death in senescent cells by triggering endoplasmic reticulum stress

Senescent cells, defined by irreversible cell cycle arrest, exhibit a senescence-associated secretory phenotype (SASP) characterized by the secretion of proinflammatory mediators. The accumulation of senescent cells within tissues promotes chronic inflammation and contributes to the onset and progression of various age-related pathologies. Therefore, the selective elimination of senescent cells, termed senolysis, has emerged as a promising therapeutic strategy for mitigating a broad spectrum of age-related disorders, including tumors. However, most currently available senolytic drugs target antiapoptotic pathways activated in senescent cells, and their clinical utility is limited by dose-dependent toxicity. Accordingly, there is an urgent need to develop alternative senolytic approaches. Here, we show that cyclosporine A (CsA), a widely used clinical immunosuppressant, exerts an alternative senolytic effect by triggering paraptosis-like cell death in senescent cells. We demonstrate that CsA activates JNK signaling, elevates reactive oxygen species (ROS) production, and triggers the apoptosis signal-regulating kinase 1 (ASK1)–p38 mitogen-activated protein kinase (MAPK) pathway, thereby amplifying SASP factor expression. Senescent cells inherently exhibit chronic adaptive endoplasmic reticulum (ER) stress responses and heightened ER functional demands because of their extensive secretory activity. Consequently, further disruption of this fragile ER homeostasis by CsA-induced SASP overactivation renders senescent cells prone to paraptosis-like cell death. Importantly, CsA treatment eliminates senescent hepatic stellate cells in the livers of obese mice, thereby preventing the development of obesity-associated hepatocellular carcinoma. These findings establish ER stress-induced paraptosis-like cell death as a novel senolysis strategy, offering a promising senotherapy for eliminating senescent cells and mitigating senescence-associated tumorigenesis.