LCN2 drives ferroptosis-associated ischemia–reperfusion injury after renal transplantation: integrated machine learning and in vivo validation

作者：Zhiwei Wu, Bowen Yu, Qing He, Changhao Huang · 发表于：APOPTOSIS · 年份：2025 · DOI：10.1007/s10495-025-02182-1 · 被引用次数：3 · 研究领域：Ferroptosis and cancer prognosis、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Cancer-related molecular mechanisms research

Renal ischemia–reperfusion injury (IRI) remains a critical obstacle to optimal renal transplant outcomes, driving acute graft dysfunction and long-term allograft failure. While ferroptosis—an iron-dependent form of cell death—has been linked to IRI pathogenesis, the role of lipocalin-2 (LCN2), a regulator of iron homeostasis and inflammation, in transplant-related renal IRI remains uncharacterized. Six murine IRI transcriptomic datasets (83 samples) were integrated using weighted gene co-expression network analysis (WGCNA) and differential expression profiling to screen for IRI-associated hub genes. Findings were validated in two human transplant cohorts (212 samples) via 113 machine learning algorithms, including logistic regression, random forest, and ensemble models. Single-cell RNA sequencing (GSE237429) was used to map gene expression to specific renal cell populations, while a murine warm IRI model evaluated the effects of LCN2 inhibition (ZINC00640089) on tubular injury, ferroptosis markers (MDA, GSH, Fe²⁺), and inflammatory cytokines (IL-6, TNF-α) across mild (50-minute) and severe (80-minute) ischemia subgroups. WGCNA identified 36 hub genes, with LCN2 emerging as a key node in ferroptosis and immune regulation pathways. A six-gene machine learning model, including LCN2, CLU, and SOX9, demonstrated robust predictive accuracy for IRI (AUC = 0.93). Single-cell analysis revealed elevated LCN2 expression in neutrophils and macrophages in IRI kidneys, correlated with incr...