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LDHA induces beta cell dedifferentiation in diabetes through metabolic and epigenetic reprogramming

Xirui Li1,2, Haoqiang Gong2, Can Xiong2

  • 1Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Diabetologia
|December 11, 2025
PubMed
Abstract

Insights

Lactate dehydrogenase A (LDHA) inhibition preserves pancreatic beta cell identity and function, offering a potential new treatment for diabetes. This study reveals LDHA

Area of Science:

  • Metabolic and Epigenetic Regulation in Diabetes
  • Pancreatic Beta Cell Biology
  • Molecular Mechanisms of Diabetes

Background:

  • Pancreatic beta cell dedifferentiation is a key factor in diabetes, reducing beta cell mass and function.
  • Understanding the molecular mechanisms of beta cell dedifferentiation is crucial for developing effective diabetes treatments.
  • Interventional targets are needed to prevent or reverse beta cell dedifferentiation.

Purpose of the Study:

  • To investigate the role of Lactate dehydrogenase A (LDHA) in pancreatic beta cell dedifferentiation.
  • To explore LDHA inhibition as a potential therapeutic strategy for diabetes.
  • To elucidate the molecular mechanisms linking LDHA, epigenetic modifications, and beta cell dysfunction.

Main Methods:

  • Analysis of LDHA expression and activity in human diabetic islets and mouse models (db/db and HFD-induced).
  • Assessment of LDHA inhibition effects on beta cell function and identity in diabetic mice.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to study LDHA's impact on histone lactylation and gene expression.

Main Results:

  • LDHA inhibition preserved beta cell identity, delayed disease progression in impaired fasting glucose, and improved glucose homeostasis in diabetic models.
  • LDHA activation increased histone H3 lysine 9 lactylation (H3K9la) at key beta cell dedifferentiation marker genes (Sox9, Hes1, Aldh1a3).
  • Increased H3K9la facilitated transcription of dedifferentiation markers, leading to impaired beta cell function and glucose homeostasis.

Conclusions:

  • LDHA plays a critical role in metabolic and epigenetic reprogramming driving beta cell dedifferentiation in diabetes.
  • LDHA-mediated histone lactylation is a key mechanism linking metabolic changes to beta cell dysfunction.
  • Inhibition of LDHA represents a promising novel therapeutic strategy for managing and treating diabetes.
Keywords:
Beta cell dedifferentiationDiabetesEpigenetic reprogrammingHistone lactylationLDHA

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