TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD

The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.

本研究聚焦于肺腺癌（lung adenocarcinoma, LUAD）——肺癌的主要类型。尽管诊断技术与分子疗法已取得诸多进展，但由于其五年生存率较低，临床治疗仍颇具挑战。本研究旨在探究跨膜蛋白TMEM164在肺腺癌铁死亡（ferroptosis）与抗肿瘤免疫中的作用，并评估其作为治疗靶点的潜力。本研究通过细胞实验（涵盖QPCR、WB、CCK-8、EdU、Transwell、流式细胞术、免疫共沉淀（CO-IP））与动物模型实验（包括苏木精-伊红（HE）染色、免疫组化（IHC）分析），探究了TMEM164表达与肺腺癌进展的关联，并重点关注其在铁死亡与自噬中的调控机制。研究结果显示，TMEM164在肺腺癌组织中表达下调，且与不良预后显著相关。上调TMEM164表达可显著抑制细胞增殖、迁移与侵袭，同时促进依赖ATG5（autophagy-related gene 5）完成自噬体形成的自噬过程，进而促进铁死亡。在小鼠模型中，高表达TMEM164联合抗PD-1（anti-PD-1）抗体疗法展现出协同抗肿瘤效应。上述研究结果凸显了TMEM164在肺腺癌发生发展中的关键作用，提示调控TMEM164表达可为肺腺癌治疗开辟全新途径。