根据世界卫生组织2022年癌症统计，肺癌位居十大死因之列，其中肺腺癌是最常见的类型。尽管肺癌治疗取得了重大进展，但许多临床限制仍然存在，这主要是由于耐药性的发展。本研究探讨了培美曲塞对人肺腺癌耐药机制的影响及其与孕酮受体膜成分 1 (PGRMC1) 表达的关系。鉴于KRAS突变型肺腺癌细胞系（例如A549）表现出较高的叶酸合成活性，因此选择结构与叶酸相似的培美曲塞作为治疗药物。本研究使用肺腺癌细胞系（A549）并建立了耐药肺腺癌细胞系（A549/PEM）。研究结果表明，A549/PEM 细胞中 PGRMC1 表达升高。据推测，PGRMC1 通过血红素结合调节铁的吸收，从而导致铁相关细胞死亡途径的偏好（铁死亡）。我们的研究结果表明，具有高 PGRMC1 水平的耐药肺腺癌细胞表现出细胞膜抗氧化活性升高，并且对铁依赖性细胞死亡途径的依赖增加。这表明 PGRMC1 与培美曲塞诱导的铁依赖性细胞死亡之间存在相关性。我们的研究有助于开发更有效的治疗策略，以改善肺腺癌患者的预后，特别是那些面临耐药性挑战的患者。版权所有 © 2024 Elsevier B.V. 保留所有权利。

According to the 2022 cancer statistics of the World Health Organization, lung cancer ranks among the top ten causes of death, with lung adenocarcinoma being the most prevalent type. Despite significant advancements in lung cancer therapeutics, many clinical limitations remain, primarily due to the development of drug resistance. The present study investigated the effects of pemetrexed on the drug resistance mechanisms in human lung adenocarcinoma and its association with progesterone receptor membrane component 1 (PGRMC1) expression. Given that KRAS-mutant lung adenocarcinoma cell lines (e.g., A549) exhibit a high folate synthesis activity, pemetrexed, which is structurally similar to folate, was selected as the therapeutic drug. The present study used a lung adenocarcinoma cell line (A549) and established a drug-resistant lung adenocarcinoma cell line (A549/PEM). The findings demonstrated that PGRMC1 expression was elevated in the A549/PEM cells. It has been hypothesized that PGRMC1 regulates iron absorption through heme binding, resulting in a preference for iron-related cell death pathways (ferroptosis). Our findings indicate that drug-resistant lung adenocarcinoma cells with high PGRMC1 levels exhibit elevated antioxidant activity on the cell membrane and increased reliance on iron-dependent cell death pathways. This suggests a correlation between PGRMC1 and pemetrexed-induced iron-dependent cell death. Our study contributes to the development of more effective therapeutic strategies to improve the prognosis of patients with lung adenocarcinoma, particularly those facing drug resistance challenges.Copyright © 2024 Elsevier B.V. All rights reserved.