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

  • Life Sci. 2026 Mar 15:389:124244. doi: 10.1016/j.lfs.2026.124244.
Mingxing Sui  1 ,  Jiazhao Fu  1 ,  Yuhong Li  1 ,  Junhao Yu  1 ,  Hanlan Lu  1 ,  Li Zeng  1 ,  Yanhua Li  2 ,  Wenyu Zhao  3
Affiliations
  • 1. Department of Organ Transplantation, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, 200433, Shanghai, China.
  • 2. Department of Organ Transplantation, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, 200433, Shanghai, China. Electronic address: [email protected].
  • 3. Department of Organ Transplantation, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, 200433, Shanghai, China. Electronic address: [email protected].
PMID: 41616844 DOI: 10.1016/j.lfs.2026.124244
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.

Keywords
Acute kidney injury; Cuproptosis; Histone lactylation; Lactate.
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