2. Academic Validation
  3. Lactate promotes cuproptosis in acute kidney injury by activating H3K18 lactylation-dependent upregulation of HSPA6 expression

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

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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