Loo Tze Mun, Zhou Xiangyu, Tanaka Yoko, Sugawara Sho, Yamauchi Shota, Kawasaki Hiroko, Matsuoka Yuta, Sugiura Yuki, Sakuma Shinya, Yamanishi Yoko, Yotsumoto Satoshi, Dodo Kosuke, Shirasaki Yoshitaka, Kamatani Takashi, Takahashi Akiko
Division of Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nat Commun. 2025 Jul 29;16(1):6617. doi: 10.1038/s41467-025-61894-9.
Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
衰老细胞以不可逆的细胞周期停滞和炎症因子分泌为特征，会引发各种与年龄相关的病症。衰老细胞对铁死亡（一种铁依赖性细胞死亡形式）具有抗性；然而，其潜在机制仍不清楚。在此，我们发现溶酶体酸度对于胱氨酸剥夺诱导的脂质过氧化和铁死亡至关重要。在衰老细胞中，溶酶体碱化会导致亚铁离子异常滞留在溶酶体中，从而产生对铁死亡的抗性。用V-ATPase激活剂EN6处理可恢复衰老细胞中的溶酶体酸度和铁死亡敏感性。在胰腺癌细胞系中观察到了类似的涉及溶酶体碱化的铁死亡抗性机制。EN6处理可预防异种移植和Kras突变小鼠模型中的胰腺癌发展。我们的研究结果揭示了溶酶体功能障碍与铁死亡调节之间的联系，为治疗与年龄相关的疾病提供了一种治疗策略。
