Redox-driven PCK1 sulfenylation: An early warning signal for progression from metabolically healthy obesity to diabetes.
7 affiliations
- 1Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; School of Chinese Medicine & State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 999077, China.
- 2Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
- 3Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- 4Dongfang Hospital Affiliated to Tongji University, Shanghai, 200120, China.
- 5Department of Chemistry, Fudan University, Shanghai, 200433, China.
- 6Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Free Radical Regulation and Application Research Center, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
- 7Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Free Radical Regulation and Application Research Center, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
Abstract
Sustained upregulation of hepatic gluconeogenesis is a major source of hyperglycemia in type 2 diabetes, and obesity is the primary driver. However, a substantial subset of obese individuals does not progress to diabetes, a condition termed metabolically healthy obesity, and the underlying mechanism has long remained unclear. ROS act both as physiological signals and as pathological drivers, but no molecular marker characterizes the transition between these two states, making it difficult to time antioxidant intervention against oxidative modification-mediated damage. Here we show that the activity of phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme of gluconeogenesis, is redox-sensitive. Excess accumulated ROS induce reversible sulfenylation at cysteine 288, near the catalytic center, directly driving gluconeogenesis in the absence of insulin. We therefore propose a dual regulatory model of glucose metabolism signaled by hepatic oxidative load. At low oxidative load, ROS activate AMP-activated protein kinase (AMPK) via glutathionylation to promote glycolysis, whereas once the load accumulates, PCK1 is activated via sulfenylation to drive gluconeogenesis, accompanied by a decline in AMPK glutathionylation. Hepatic oxidative load therefore acts as a switch governing the direction of hepatic glucose flux. In diabetic mice, the two modifications show a complementary, stage-dependent distribution paralleling this accumulation, with AMPK glutathionylation predominating in the compensatory stage and PCK1 sulfenylation becoming dominant as the load accumulates further. Their reciprocal dynamic therefore serves as an early warning signal for the transition of ROS from physiological to pathological states. On this basis, we intervened as oxidative load began to accumulate, and found that lowering hepatic ROS prevented the oxidative activation of PCK1, suppressed gluconeogenesis and ameliorated hyperglycemia. These findings reveal that the key gluconeogenic enzyme is directly regulated by redox signals independently of insulin, providing a molecular basis for the heterogeneity of diabetes progression in obesity and for the precise timing of antioxidant intervention.
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BibTeX
@article{wu2026redoxdriven,
title = {{Redox-driven PCK1 sulfenylation: An early warning signal for progression from metabolically healthy obesity to diabetes.}},
author = {Meiling Wu and Qiwen Luo and Sheng Ge and Lihan Jiang and Kelei Dong and Fulin Zhang and Wanrui Fu and Bo Feng and Liang Qiao and Shanlin Liu and Dongyun Shi},
journal = {Redox biology},
year = {2026},
month = sep,
doi = {10.1016/j.redox.2026.104419},
url = {https://europepmc.org/article/MED/42860109},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Redox-driven PCK1 sulfenylation: An early warning signal for progression from metabolically healthy obesity to diabetes.
AU - Meiling Wu
AU - Qiwen Luo
AU - Sheng Ge
AU - Lihan Jiang
AU - Kelei Dong
AU - Fulin Zhang
AU - Wanrui Fu
AU - Bo Feng
AU - Liang Qiao
AU - Shanlin Liu
AU - Dongyun Shi
PY - 2026
DA - 2026/09/29
JO - Redox biology
DO - 10.1016/j.redox.2026.104419
UR - https://europepmc.org/article/MED/42860109
AB - Sustained upregulation of hepatic gluconeogenesis is a major source of hyperglycemia in type 2 diabetes, and obesity is the primary driver. However, a substantial subset of obese individuals does not progress to diabetes, a condition termed metabolically healthy obesity, and the underlying mechanism has long remained unclear. ROS act both as physiological signals and as pathological drivers, but no molecular marker characterizes the transition between these two states, making it difficult to time antioxidant intervention against oxidative modification-mediated damage. Here we show that the activity of phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme of gluconeogenesis, is redox-sensitive. Excess accumulated ROS induce reversible sulfenylation at cysteine 288, near the catalytic center, directly driving gluconeogenesis in the absence of insulin. We therefore propose a dual regulatory model of glucose metabolism signaled by hepatic oxidative load. At low oxidative load, ROS activate AMP-activated protein kinase (AMPK) via glutathionylation to promote glycolysis, whereas once the load accumulates, PCK1 is activated via sulfenylation to drive gluconeogenesis, accompanied by a decline in AMPK glutathionylation. Hepatic oxidative load therefore acts as a switch governing the direction of hepatic glucose flux. In diabetic mice, the two modifications show a complementary, stage-dependent distribution paralleling this accumulation, with AMPK glutathionylation predominating in the compensatory stage and PCK1 sulfenylation becoming dominant as the load accumulates further. Their reciprocal dynamic therefore serves as an early warning signal for the transition of ROS from physiological to pathological states. On this basis, we intervened as oxidative load began to accumulate, and found that lowering hepatic ROS prevented the oxidative activation of PCK1, suppressed gluconeogenesis and ameliorated hyperglycemia. These findings reveal that the key gluconeogenic enzyme is directly regulated by redox signals independently of insulin, providing a molecular basis for the heterogeneity of diabetes progression in obesity and for the precise timing of antioxidant intervention.
SN - 2213-2317
ER -