2. Academic Validation
  3. Protein lactylation of citrate synthase promotes the AKI-CKD transition by activating the NLRP3 inflammasome

Protein lactylation of citrate synthase promotes the AKI-CKD transition by activating the NLRP3 inflammasome

  • Cell Rep. 2025 Aug 26;44(8):116084. doi: 10.1016/j.celrep.2025.116084.
Fang Yu 1,  Yan Meng 2,  Xiaoyue Wang 1,  Jia Chen 1,  Junling He 1,  Xiangling Yi 1,  Yani He 3,  Kehong Chen 4
Affiliations

Affiliations

  • 1 Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China; Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China.
  • 2 Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China.
  • 3 Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China; Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China; State Key Laboratory of Trauma and Chemical Poisoning, Burns and Combined Injury, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China. Electronic address: heyn@tmmu.edu.cn.
  • 4 Department of Nephrology, Daping Hospital, Army Medical Center, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China; Chongqing Key Laboratory of Precision Diagnosis and Treatment for Kidney Diseases, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China; State Key Laboratory of Trauma and Chemical Poisoning, Burns and Combined Injury, Army Medical University, No. 10 Changjiang Road, Yuzhong District, Chongqing 400042, China. Electronic address: chenkh@tmmu.edu.cn.
PMID: 40748753 DOI: 10.1016/j.celrep.2025.116084
Abstract

Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, lactylation modification has emerged as a mechanism for mediating chronic organ damage. We investigate lactylated protein profiles and the role of protein lactylation during the progression of AKI. In vitro and in vivo experiments demonstrate that protein lactylation activates NOD-like Receptor protein 3 (NLRP3) inflammasomes, promoting the AKI-CKD transition. Comprehensive lactylome profiling shows that lactylated proteins are involved in metabolic pathways, particularly the tricarboxylic acid cycle. Notably, the rate-limiting enzyme citrate synthase (CS) exhibits significantly elevated lactylation levels post-AKI induction, and K370 was the most significant lysine residue. In vitro, the modified/lactylated K370T group significantly decreases CS activity and mitochondrial function and activates the NLRP3 inflammasomes. Thus, CS lactylation promotes the AKI-CKD transition via NLRP3 inflammasome activation, suggesting that inhibiting CS lactylation may offer therapeutic potential for preventing this transition.

Keywords

CP: Immunology; CP: Molecular biology; NLRP3 inflammasome; acute kidney injury; chronic kidney disease; citrate synthase; ischemic/hypoxic injury; lactate; lactylation; mitochondrial dysfunction; renal inflammation; renal tubular cells.

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