2. Academic Validation
  3. Deletion of Pyruvate Carboxylase in Tubular Epithelial Cell Promotes Renal Fibrosis by Regulating SQOR/cGAS/STING-Mediated Glycolysis

Deletion of Pyruvate Carboxylase in Tubular Epithelial Cell Promotes Renal Fibrosis by Regulating SQOR/cGAS/STING-Mediated Glycolysis

  • Adv Sci (Weinh). 2025 Jan 21:e2408753. doi: 10.1002/advs.202408753.
Hao Huang 1 2 3 4 5,  Yuanyuan Han 1 3 4 5 6,  Yan Zhang 1 3 4 5 6,  Jianhua Zeng 1 3 4 5 6,  Xin He 1 3 4 5 6,  Jiawei Cheng 1 3 4 5 6,  Songkai Wang 1 3 4 5 6,  Yiwei Xiong 1 3 4 5 6,  Hongling Yin 5 7,  Qiongjing Yuan 1 3 4 5 6,  Ling Huang 1 3 4 5 6,  Yanyun Xie 1 3 4 5 6,  Jie Meng 3 8,  Lijian Tao 1 3 4 5 6,  Zhangzhe Peng 1 3 4 5 6
Affiliations

Affiliations

  • 1 Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 2 Department of Cell biology, School of Life Sciences, Central South University, Changsha, 410013, China.
  • 3 Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410013, China.
  • 4 FuRong Laboratory, Changsha, 410008, China.
  • 5 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, 410008, China.
  • 6 National Medical Metabolomics International Collaborative Research Center, Central South University, Changsha, 410008, China.
  • 7 Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 8 Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
PMID: 39836535 DOI: 10.1002/advs.202408753
Abstract

Renal fibrosis is a common pathway involved in the progression of various chronic kidney diseases to end-stage renal disease. Recent studies show that mitochondrial injury of renal tubular epithelial cells (RTECs) is a crucial pathological foundation for renal fibrosis. However, the underlying regulatory mechanisms remain unclear. Pyruvate carboxylase (PC) is a catalytic Enzyme located within the mitochondria that is intricately linked with mitochondrial damage and metabolism. In the present study, the downregulation of PC in various fibrotic animal and human kidney samples is demonstrated. Renal proximal tubule-specific Pcx gene knockout mice (PcxcKO) has significant interstitial fibrosis compared to control mice, with heightened expression of extracellular matrix molecules. This is further demonstrated in a stable PC knock-out RTEC line. Mechanistically, PC deficiency reduces its interaction with sulfide:quinone oxidoreductase (SQOR), increasing the ubiquitination and degradation of SQOR. This leads to mitochondrial morphological and functional disruption, increased mtDNA release, activation of the cGAS-STING pathway, and elevated glycolysis levels, and ultimately, promotes renal fibrosis. This study investigates the molecular mechanisms through which PC deficiency induces mitochondrial injury and metabolic reprogramming in RTECs. This study provides a novel theoretical foundation and potential therapeutic targets for the pathogenesis and treatment of renal fibrosis.

Keywords

SQOR; cGAS‐STING; glycolysis; pyruvate carboxylase; renal fibrosis.

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