Bai Wenxue, Zhang Shengding, Hua Lijuan, Wang Dongyuan, Guo Mengyao, Wang Xuezhao, Zhou Ying, Cao Yong, Wang Qi, Zhang Ni, Xue Bin, Xie Min
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Respir Res. 2025 May 30;26(1):204. doi: 10.1186/s12931-025-03285-8.
Sirolimus, the therapy choice for lymphangioleiomyomatosis (LAM), displayed cytostatic but not cytocidal action, with disease recurrence after withdrawal. The aim of this study is to identify novel potential biomarkers and therapeutic strategies for LAM patients.
TMT-labeling proteomics was utilized for screening the differentially expressed proteins (DEPs) in the plasma of 10 LAM patients and 6 controls. Plasma levels of transferrin (TRF), ferritin (FRT) and beta2-microglobulin (B2M) were validated in a cohort of 30 LAM patients and 20 controls. The diagnostic efficacy of TRF with/without VEGF-D was assessed using ROC curve analysis. The therapeutic effects of a ferroptosis inducer artesunate (ART) were evaluated both in vitro Tsc2 - / - MEFs cells and in xenograft LAM models.
Proteomics analysis revealed 132 DEPs between LAM patients and controls, which primarily enriched in the regulation of iron ion transport. LAM patients had decreased TRF, elevated FRT and B2M levels compared with controls in the confirmation cohort (p = 0.0386, p = 0.0327 and p = 0.0155, respectively) which independent with VEGF-D level or rapamycin therapy. TRF positively correlated with both FEV% predicted (r = 0.4486, p = 0.0251) and DLCO% predicted (r = 0.4018, p = 0.0516) of LAM patients. The combination of TRF and VEGF-D showed superior diagnostic value compared to individual indicator. ART induced the ferroptosis and inhibited the growth in Tsc2 - / - MEFs cells. In LAM animal models, ART exerted anti-tumor effects without obvious adverse effect.
LAM patients exhibit abnormal iron metabolism independent of VEGF-D level. Ferroptosis inducer ART holds promise as a therapeutic novel approach for treating LAM.
西罗莫司是淋巴管平滑肌瘤病（LAM）的治疗选择，具有细胞抑制作用而非细胞杀伤作用，停药后疾病会复发。本研究的目的是为LAM患者确定新的潜在生物标志物和治疗策略。
采用TMT标记蛋白质组学技术筛选10例LAM患者和6例对照者血浆中的差异表达蛋白（DEP）。在30例LAM患者和20例对照者的队列中验证了转铁蛋白（TRF）、铁蛋白（FRT）和β2-微球蛋白（B2M）的血浆水平。使用ROC曲线分析评估TRF联合或不联合VEGF-D的诊断效能。在体外Tsc2 - / - MEF细胞和异种移植LAM模型中评估铁死亡诱导剂青蒿琥酯（ART）的治疗效果。
蛋白质组学分析显示LAM患者和对照者之间有132个DEP，主要富集于铁离子转运的调节。在验证队列中，与对照者相比，LAM患者的TRF降低，FRT和B2M水平升高（分别为p = 0.0386、p = 0.0327和p = 0.0155），这与VEGF-D水平或雷帕霉素治疗无关。TRF与LAM患者的预测FEV%（r = 0.4486，p = 0.0251）和预测DLCO%（r = 0.4018，p = 0.0516）均呈正相关。与单个指标相比，TRF和VEGF-D的联合显示出更高的诊断价值。ART诱导Tsc2 - / - MEF细胞发生铁死亡并抑制其生长。在LAM动物模型中，ART发挥了抗肿瘤作用且无明显不良反应。
LAM患者表现出独立于VEGF-D水平的铁代谢异常。铁死亡诱导剂ART有望成为治疗LAM的一种新的治疗方法。
