Liraglutide affects mitochondrial function and histone acetylation through the NQO1/SIRT3 pathway in diabetic kidney disease

Liraglutide protected kidney cells and rat kidneys from diabetic kidney disease by restoring the NQO1/SIRT3 pathway. It lessened oxidative stress and cell death, repaired mitochondrial function and mitophagy, and reduced abnormal histone acetylation. Blocking NQO1/SIRT3 weakened or completely abolished these protective effects.

Journal article — In vitro and in vivo preclinical study. Population: HK-2 cells under glucolipotoxic conditions and DKD rat models. Interventions: Liraglutide.

Both in vitro and in vivo, the injury phenotype was induced and accompanied by downregulation of the NQO1/SIRT3 pathway; disrupting this pathway further exacerbated the injuries. Liraglutide treatment counteracted this phenotype, improving metabolic parameters, renal function, and histopathology. Liraglutide attenuated oxidative stress and apoptosis, restored mitochondrial function and mitophagy, and reduced histone hyperacetylation. These protective effects were consistently associated with restoration of NQO1/SIRT3 expression. Genetic or pharmacological disruption of the NQO1/SIRT3 axis attenuated liraglutide's efficacy, and combined inhibition completely abolished its effects.

Researchers working on Liraglutide would care because this paper positions the NQO1/SIRT3 pathway as a mechanistic mediator of liraglutide's renoprotective effects, linking glucose-independent benefits to mitochondrial homeostasis and epigenetic regulation. It does not establish human dosing, clinical efficacy, or whether the same pathway operates in patients.

Key findings

• In glucolipotoxic HK-2 cells and DKD rats, liraglutide counteracted oxidative stress, apoptosis, mitochondrial dysfunction, and histone hyperacetylation compared with untreated injury models.
• The DKD injury phenotype was accompanied by downregulation of the NQO1/SIRT3 pathway, and disrupting this pathway further exacerbated the injuries.
• Liraglutide improved blood glucose, blood insulin, blood lipids, renal function, and histopathology compared with untreated DKD models.
• Genetic or pharmacological disruption of NQO1/SIRT3 attenuated liraglutide's protective effects, and combined inhibition completely abolished them.
• Liraglutide's protective effects were consistently associated with restoration of NQO1/SIRT3 expression.

Limitations

• Preclinical cell and rat models only; human translation is not established.
• The abstract gives no sample size, dose, duration, or statistical comparisons, so effect size and precision are unknown.
• Mechanistic dependence was shown through artificial inhibition and silencing, which may not reflect clinical conditions.

The record

• Journal: Molecular and cellular biochemistry
• Published: 2026-08-03
• PMID: 42545560 — DOI: 10.1007/s11010-026-05670-3
• Funding: Gansu Joint Research Fund; Major Scientific and Technological Innovation Project of Health Industry in Gansu Province; Science and Technology planning project of Lanzhou City; National Natural Science Foundation of China
• Author countries: China

Peptide profiles: Liraglutide.

All indexed evidence: Liraglutide trials & papers.

Related studies: Glucagon-like peptide-1 receptor agonist-based regimens compared with metformin-based…, Hypertensive disorders of pregnancy and GLP-1 receptor agonist timing: a systematic…, Relationship Between GLP-1-Based Therapies and Periodontal Health: A Systematic Review…, GLP-1 receptor agonists in multiple sclerosis: a systematic review of preclinical and….