Nucleophosmin 1 lactylation in graft kidney induces ferroptotic trigger waves that exacerbate delayed graft function

作者：Haitao Yu, Hubin Yin, Yuhua Mei, Xuesong Bai, Chunlin Zhang, Zhenwei Feng, Li Mao, Haonan Chen, Simin Liang, Xin Gou, Wenlong Zhong, Weiyang He, Jie Li, Tianxin Lin, Xinyuan Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-66991-3 · 被引用次数：10 · 研究领域：Ferroptosis and cancer prognosis、Clusterin in disease pathology、Immune cells in cancer

Ferroptotic waves aggravate kidney ischemia-reperfusion injury and drive delayed graft function (DGF). We demonstrate that elevated glycolysis and lactate production in graft kidney correlate with ferroptosis and functional impairment. A signaling axis composed of the long non-coding RNA IGIP-5, microRNA 670-3p, and lactate dehydrogenase A promotes lactate secretion from injured tubular cells, inducing lactylation and ferroptosis in neighboring cells and triggering ferroptotic waves. Lactylome profiling identifies that nucleophosmin 1 (NPM1), an epigenetic regulator, is lactylated at lysine 257 by the lactyltransferase AARS1. Suppressing NPM1 lactylation-via K257 mutation, AARS1 knockout, or taurochenodeoxycholic acid-upregulates SLC7A11 and inhibits ferroptosis. Mechanistically, lactylation stabilizes NPM1 by reducing MDM2-mediated ubiquitination and strengthens SLC7A11 repression, disrupting cystine metabolism. In mouse allografts, blocking lactate shuttle-mediated NPM1 lactylation prevents ferroptotic propagation and ameliorates graft function. Additionally, we develop an early prediction model for DGF using postoperative urinary lactate concentrations. These findings reveal a metabolic-epigenetic axis driving ferroptotic propagation and propose NPM1 lactylation as a therapeutic target for DGF.