碱中毒是一种受调节的细胞死亡形式，其特征是溶酶体功能障碍和细胞内 pH 值碱化。使用小分子化合物 JTC801 药理学诱导碱中毒已成为各种类型癌症，特别是胰腺导管腺癌 (PDAC) 中一种有前景的抗癌策略。在这项研究中，我们研究了一种新机制，通过巨胞饮作用（一种涉及细胞外物质摄取的内吞过程）促进人 PDAC 细胞对碱中毒的抵抗力。通过脂质代谢组学分析和功能研究，我们证明脂肪酸（例如油酸）对碱中毒的抑制并不依赖于内源合成途径，而是依赖于巨胞饮作用促进的外源摄取。因此，通过药理学方法（例如使用 EIPA 或 EHoP-016）或遗传干预（例如 RAC1 敲除）靶向巨胞饮作用可有效增强 JTC801 诱导的人 PDAC 细胞碱中毒。这些发现提供了令人信服的证据，表明巨胞饮作用的调节可以增加癌细胞对碱中毒诱导剂的敏感性。© 作者 2024。由牛津大学出版社出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限均可通过我们网站文章页面上的“权限”链接通过我们的 RightsLink 服务获得 - 欲了解更多信息，请联系journals.permissions@oup.com。

Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g., using EIPA or EHoP-016) or genetic interventions (e.g., RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.