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Background <p>Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactylation has emerged as an important metabolic–epigenetic regulatory mechanism in diabetic tissues. Alanyl-tRNA synthetase 1 (AARS1) has recently been identified as a lactyltransferase, but whether and how AARS1-mediated lactylation contributes to tubular stress responses and DKD progression remains unclear.</p> Methods <p>Kidney-specific <i>Aars1</i> knockout mice and β-alanine treatment were used in streptozotocin-induced and <i>db/db</i> diabetic mouse models. Human proximal tubular epithelial cells cultured under high-glucose conditions, including CRISPR/Cas9-mediated <i>AARS1</i> knockout cells, were used for mechanistic studies. AARS1-dependent transcriptional programs were analyzed by CUT and Tag, ChIP assays, and luciferase reporter assays.</p> Results <p>AARS1 was upregulated in diabetic kidneys and directly lactylated Akt and the NF-κB subunit p65, enhancing their phosphorylation and activation. This modification promoted autophagy impairment, inflammatory cytokine expression, tubular injury, and macrophage accumulation. CUT and Tag analysis further revealed AARS1-dependent transcriptional control of <i>HK2</i>, <i>PFKP</i>, <i>ZEB1</i>, and <i>PPP6C</i>, linking AARS1 to glycolytic reprogramming and fibrotic signaling. Mechanistically, AARS1 operated within a glycolysis–lactate–NF-κB feedback circuit, in which glycolysis-driven lactate increased the lactylation and activation of NF-κB, promoting <i>AARS1</i> transcription and reinforcing glycolytic reprogramming and chronic tubular stress. Genetic deletion of <i>Aars1</i> or pharmacological inhibition with β-alanine reduced protein lactylation, restored autophagy, attenuated inflammation, and significantly slowed DKD progression in both diabetic mouse models.</p> Conclusions <p>These findings identify AARS1 as a metabolic–epigenetic amplifier that rewires Akt- and NF-κB-dependent signaling to sustain chronic tubular stress and fibrotic remodeling in DKD, highlighting the AARS1–lactylation axis as a potential therapeutic target.</p>

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AARS1 promotes diabetic kidney disease through rewiring Akt and NF-κB signaling to suppress autophagy and sustain inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Lei Tian,
  • Yumeng Wang,
  • Chen Guan,
  • Ewud Agborbesong,
  • Julie Xia Zhou,
  • Shan Mou,
  • Xiaogang Li

摘要

Background

Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactylation has emerged as an important metabolic–epigenetic regulatory mechanism in diabetic tissues. Alanyl-tRNA synthetase 1 (AARS1) has recently been identified as a lactyltransferase, but whether and how AARS1-mediated lactylation contributes to tubular stress responses and DKD progression remains unclear.

Methods

Kidney-specific Aars1 knockout mice and β-alanine treatment were used in streptozotocin-induced and db/db diabetic mouse models. Human proximal tubular epithelial cells cultured under high-glucose conditions, including CRISPR/Cas9-mediated AARS1 knockout cells, were used for mechanistic studies. AARS1-dependent transcriptional programs were analyzed by CUT and Tag, ChIP assays, and luciferase reporter assays.

Results

AARS1 was upregulated in diabetic kidneys and directly lactylated Akt and the NF-κB subunit p65, enhancing their phosphorylation and activation. This modification promoted autophagy impairment, inflammatory cytokine expression, tubular injury, and macrophage accumulation. CUT and Tag analysis further revealed AARS1-dependent transcriptional control of HK2, PFKP, ZEB1, and PPP6C, linking AARS1 to glycolytic reprogramming and fibrotic signaling. Mechanistically, AARS1 operated within a glycolysis–lactate–NF-κB feedback circuit, in which glycolysis-driven lactate increased the lactylation and activation of NF-κB, promoting AARS1 transcription and reinforcing glycolytic reprogramming and chronic tubular stress. Genetic deletion of Aars1 or pharmacological inhibition with β-alanine reduced protein lactylation, restored autophagy, attenuated inflammation, and significantly slowed DKD progression in both diabetic mouse models.

Conclusions

These findings identify AARS1 as a metabolic–epigenetic amplifier that rewires Akt- and NF-κB-dependent signaling to sustain chronic tubular stress and fibrotic remodeling in DKD, highlighting the AARS1–lactylation axis as a potential therapeutic target.