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

作者：Tian L, Wang Y, Guan C, Agborbesong E, Zhou JX, Mou S, Li X · 发表于：Cellular & molecular biology letters · 年份：2026 · DOI：10.1186/s11658-026-00953-5 · 研究领域：AARS1、Autophagy、Diabetic kidney disease、Inflammation、Lactylaltion

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...