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

ABSTRACT: 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, lactylati

SUBMITTER: Yu H 

PROVIDER: S-EPMC12783763 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature