铁死亡是一种铁依赖性细胞死亡，会影响多种抗肿瘤方案的疗效，在癌症治疗中显示出巨大的潜力。蛋白激酶 D2 (PKD2) 在调节坏死和细胞凋亡中发挥着至关重要的作用。然而，PKD2 与铁死亡的关系仍不清楚。在本研究中，我们主要分析了PKD2在肺腺癌（LUAD）铁死亡和化疗中的作用。我们发现 PKD2 在 LUAD 中高表达，沉默 PKD2 可以促进erastin诱导的活性氧（ROS）、丙二醛（MDA）积累、细胞内铁含量和LUAD细胞死亡。从机制上讲，增强 PKD2 可以防止铁蛋白的自噬降解，而巴弗洛霉素 A1 可能会损害铁蛋白的自噬降解。我们进一步发现，PKD2 过表达会促进 LC3B-II、p62/SQSTM1 积累，并以不依赖 TFEB 的方式阻断自噬体-溶酶体融合，而巴弗洛霉素 A1 可能会损害这种融合。 Bafilomycin A1 刺激可减弱 PKD2 消除对铁死亡的促进作用。沉默铁蛋白重链 1 (FTH1) 可以逆转 PKD2 过表达对铁死亡的抵抗力。此外，体外和体内实验验证了 PKD2 促进 LUAD 细胞的增殖、迁移和侵袭。 PKD2 敲低或 CRT0066101 的药理学抑制可以通过铁死亡和细胞凋亡增强卡铂在 LUAD 中的疗效。总的来说，我们的研究表明，废除 PKD2 可以通过促进自噬体-溶酶体融合来加重铁蛋白自噬介导的铁死亡，并增强卡铂在 LUAD 中的疗效。靶向 PKD2 诱导铁死亡可能是 LUAD 治疗的一种有前景的策略。版权所有 © 2023。由 Elsevier B.V. 出版。

Ferroptosis is an iron-dependent cell death and affects efficacies of multiple antitumor regimens, showing a great potential in cancer therapy. Protein kinase D2 (PKD2) plays a crucial role in regulating necrosis and apoptosis. However, the relationship of PKD2 and ferroptosis is still elusive. In this study, we mainly analyzed the roles of PKD2 on ferroptosis and chemotherapy in lung adenocarcinoma (LUAD). We found PKD2 was highly expressed in LUAD and silencing PKD2 could promote erastin-induced reactive oxygen species (ROS), malondialdehyde (MDA) accumulation, intracellular iron content and LUAD cells death. Mechanistically, augmenting PKD2 could prevent autophagic degradation of ferritin, which could be impaired by bafilomycin A1. We further found that PKD2 overexpression would promote LC3B-II, p62/SQSTM1 accumulation and block autophagosome-lysosome fusion in a TFEB-independent manner, which could be impaired by bafilomycin A1. Bafilomycin A1 stimulation could weaken ferroptosis promotion by PKD2 abrogation. Silencing ferritin heavy chain-1 (FTH1) could reverse the resistance to ferroptosis by PKD2 overexpression. Additionally, in vitro and vivo experiments validated PKD2 promoted proliferation, migration and invasion of LUAD cells. PKD2 knockdown or pharmacological inhibition by CRT0066101 could enhance efficacy of carboplatin in LUAD via ferroptosis and apoptosis. Collectively, our study revealed that abrogation of PKD2 could aggravate ferritinophagy-mediated ferroptosis by promoting autophagosome-lysosome fusion and enhance efficacy of carboplatin in LUAD. Targeting PKD2 to induce ferroptosis may be a promising strategy for LUAD therapy.Copyright © 2023. Published by Elsevier B.V.