Li Jiaxin, Liu Han, Shan Zhitao, Zhong Kezhuo, Liang Qun
The First Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, China.
University College London, London, United Kingdom.
Front Med (Lausanne). 2025 Aug 15;12:1615264. doi: 10.3389/fmed.2025.1615264. eCollection 2025.
Sepsis remains a life-threatening condition worldwide, causing significant morbidity and mortality across diverse patient populations. Among the various organs adversely affected by sepsis, the lung is particularly vulnerable, often succumbing to acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). Recent basic and translational research has highlighted the importance of multiple regulated cell death (RCD) pathways beyond traditional apoptosis in the pathogenesis of septic lung injury. Three such RCDs, termed ferroptosis, cuproptosis, and disulfidptosis, are increasingly studied for their relevance to critical illnesses. Ferroptosis involves iron-driven lipid peroxidation, cuproptosis depends on copper ion imbalance and mitochondrial protein aggregation, and disulfidptosis emerges from dysregulated sulfide metabolism leading to excessive disulfide bond formation. This review provides an extensive discussion of these RCD pathways within the context of sepsis-induced lung injury. We begin by summarizing the current state of knowledge in septic lung injury, emphasizing inflammatory, immunological, and oxidative stress mechanisms. We then provide a detailed overview of ferroptosis, cuproptosis, and disulfidptosis, illustrating their molecular underpinnings and how they intersect with established sepsis pathways, such as tumor necrosis factor (TNF), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) signaling cascades. We also discuss emerging findings on the crosstalk among these RCD modes, potential biomarkers for early detection, and therapeutic targets for modulating these pathways. Although many of these findings remain in the early stages of translational research, they collectively underscore the complexity of septic lung injury and offer new directions for improving clinical management. Future investigations, bolstered by integrative "omics" approaches, refined animal models, and well-designed clinical trials, will be pivotal to fully realize the diagnostic and therapeutic potential of ferroptosis, cuproptosis, and disulfidptosis in sepsis. We further propose a "redox stress-metal homeostasis-sulfur metabolism" triangular network, centered on Nrf2's dual regulation of iron/copper transporters and glutathione synthesis, as a unifying framework for RCD modulation in sepsis. A signaling interaction diagram highlights actionable targets for combinatorial therapies.
脓毒症在全球范围内仍然是一种危及生命的病症，在不同患者群体中导致显著的发病率和死亡率。在受脓毒症不利影响的各种器官中，肺尤其脆弱，常常会发展为急性肺损伤（ALI）或其更严重的形式——急性呼吸窘迫综合征（ARDS）。最近的基础研究和转化研究强调了除传统凋亡之外的多种调节性细胞死亡（RCD）途径在脓毒症性肺损伤发病机制中的重要性。三种这样的RCD，即铁死亡、铜死亡和二硫死亡，因其与危重症的相关性而受到越来越多的研究。铁死亡涉及铁驱动的脂质过氧化，铜死亡取决于铜离子失衡和线粒体蛋白聚集，而二硫死亡则源于硫化物代谢失调导致二硫键过度形成。本综述在脓毒症诱导的肺损伤背景下对这些RCD途径进行了广泛讨论。我们首先总结脓毒症性肺损伤的当前知识状态，强调炎症、免疫和氧化应激机制。然后，我们详细概述铁死亡、铜死亡和二硫死亡，阐明它们的分子基础以及它们如何与已确立的脓毒症途径（如肿瘤坏死因子（TNF）、核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号级联）相互作用。我们还讨论了这些RCD模式之间相互作用的新发现、早期检测的潜在生物标志物以及调节这些途径的治疗靶点。尽管这些发现中的许多仍处于转化研究的早期阶段，但它们共同强调了脓毒症性肺损伤的复杂性，并为改善临床管理提供了新方向。未来通过综合“组学”方法、优化动物模型和精心设计的临床试验进行的研究，对于充分实现铁死亡、铜死亡和二硫死亡在脓毒症中的诊断和治疗潜力至关重要。我们进一步提出一个以Nrf2对铁/铜转运蛋白和谷胱甘肽合成的双重调节为中心的“氧化还原应激-金属稳态-硫代谢”三角网络，作为脓毒症中RCD调节的统一框架。一个信号相互作用图突出了联合治疗的可操作靶点。
