Immunoferroptosis: a novel mechanism and promising therapeutic strategy in lung transplantation.

肺移植是终末期肺部疾病患者的最后手段。肺移植受者从这一过程中受益，健康状况得到改善。不幸的是，在所有实体器官移植中，肺移植的长期存活率最差。尽管外科技术、供体选择、肺保存和免疫抑制治疗已经取得了进步，但肺移植后的中位生存期仅略有增加，成人仅为6.7年。对于移植后存活超过一年的肺移植受者来说，长期生存的最大威胁是慢性肺移植功能障碍(CLAD)的发生和发展，包括三种表型：毛细支气管炎闭塞综合征(BOS)、中性粒细胞可逆性同种异体移植功能障碍和限制性同种异体移植综合征，每种表型都以气道阻塞或限制为特征，并且在很大程度上对免疫抑制没有反应。在所描述的各种细胞死亡途径中，铁下垂是一种依赖ROS的细胞死亡形式，与两个主要的生化特征有关，即铁积累和脂质过氧化，导致半胱氨酸酶和坏死体不依赖的细胞死亡。缺血再灌注损伤(IRI)是发生慢性肺移植排斥反应的危险因素之一，最近的研究将IRI的严重程度与铁性下垂现象联系起来。然而，在慢性排斥肺中诱导铁链细胞死亡及其对BOS发展的贡献的分子机制及其作为迫切需要的治疗靶点的潜力尚不清楚。在这里，我们的目的是阐明免疫铁眼炎作为主要细胞死亡机制在慢性排斥肺移植中协调包膜和BOS发展中的作用，并描述它们作为BOS生物标志物在患者中提高早期诊断的潜力。Alexey Dashkevich博士作为临床医生和AliÖnder Yildirim博士作为基础研究人员的共同应用应该加强BASE研究结果对临床相关问题的影响。

Lung transplantation is the last resort for patients with end-stage lung diseases. The lung transplant recipients benefit from this procedure with health improvement. Unfortunately, lung transplantation displays the worst long-term survival in all solid organ transplantation. Although surgical technique, donor selection, lung preservation, and immunosuppressive therapies have been advanced, the median survival after lung transplantation has increased only slightly, to just 6.7 years in adults. The greatest threat to long-term survival for lung recipients who have survived more than one year post-transplantation is the onset and progression of chronic lung allograft dysfunction (CLAD), which includes three phenotypes: bronchiolitis obliterans syndrome (BOS), neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome, and each of them is characterized either by airway obstruction or restriction, and is largely unresponsive to immunosuppression.Among various cell death pathways described, ferroptosis is a ROS-dependent form of cell death associated with two main biochemical characteristics, namely iron accumulation and lipid peroxidation, leading to caspase- and necrosome-independent cell death. Ischemia-reperfusion injury (IRI) is one of the risk factors for developing chronic lung allograft rejection and recent publications are linking the severity of IRI with the phenomenon of ferroptosis. However, the molecular mechanisms underlying the induction of ferroptotic cell death in the chronically rejecting lung and its contribution to BOS development remains unknown along with its potential as a much-needed therapeutic target. Here, we aim to elucidate the contribution of specific mechanisms of immunoferroptotis as the primary cell death in orchestrating CLAD and BOS development in the chronically rejecting lung allografts and to delineate their potential as BOS biomarkers in patient to improve an early diagnosis.The mutual application of Dr. Alexey Dashkevich as a clinician and Dr. Ali Önder Yildirim as a basic researcher should enforce the implication of the bench findings to the clinically relevant questions.