Work

Lactate promotes cuproptosis in acute kidney injury by activating H3K18 lactylation-dependent upregulation of HSPA6 expression

Year: 2026

Type: article

Abstract: AIMS: The present study aims to investigate the role and mechanism of lactate-induced histone lactylation in regulating cuproptosis during renal IRI. MATERIALS AND METHODS: We employed both in vivo (mouse IRI) and in vitro (HK-2 cell oxygen-glucose deprivation/reperfusion, OGD/R) models. Multi-omics analyses (proteomics, CUT&Tag, RNA-seq) were integrated with molecular techniques (Western blot, transmission electron microscopy, biochemical assays, ChIP-qPCR, RT-qPCR) to examine histone lactylation and cuproptosis. KEY FINDINGS: Renal IRI led to significant lactate accumulation and a global increase in histone lactylation, with the H3K18 site being most prominently modified. Proteomics indicated significant enrichment of cuproptosis-related pathways, alongside copper dysmetabolism, mitochondrial damage, and elevated oxidative stress. Inhibition of lactate dehydrogenase (LDHA) reduced H3K18la levels and alleviated cuproptosis. Integrated multi-omics analysis identified HSPA6 (heat shock protein family A member 6) as a direct downstream target of H3K18la, linked to MAPK (mitogen-activated protein kinase) signaling. Lactate stimulation or inhibition reciprocally regulated HSPA6 expression via H3K18la, confirmed by ChIP-qPCR. Knockdown of HSPA6 effectively suppressed OGD/R-induced cuproptosis. SIGNIFICANCE: The present study unveils a previously unidentified epigenetic pathway in AKI, whereby lactate-driven H3K18 lactylation transcriptionally activates HSPA6, consequently promoting cuproptosis and exacerbating renal damage. The "lactate-H3K18la-HSPA6" axis has been identified as a promising new target for therapeutic intervention in AKI.

Source: Life Sciences

DOI: 10.1016/j.lfs.2026.124244