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Peer-reviewedCC BY 4.0Metabolites

Coniferaldehyde Reverses PGK1–3-Phosphoglycerate–L-Serine Metabolic Reprogramming in Hindlimb Ischemia

  • Yun Dong1,2,3
  • Chunbo Ma3
  • Xueli Wang2,3
  • Jiaping Han2,3
  • Zina Zhu2,3
  • Suwen Hu2,3
  • Zixuan Hu3,4
  • Liangrong Wang2,3
4 affiliations
  1. 1Department of Anesthesiology, Ninghai First Hospital, Ningbo 315600, China
  2. 2Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
  3. 3The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, China
  4. 4Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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Abstract

Background/Objectives: Ischemic skeletal muscle undergoes metabolic remodeling that may influence vascular repair. We investigated whether coniferaldehyde (CA) regulates a phosphoglycerate kinase 1 (PGK1)–3-phosphoglycerate (3PG)–L-serine axis in mouse hindlimb ischemia (HLI). Methods: Gastrocnemius tissue from Sham, HLI, and HLI+CA mice (n = 6/group) underwent bulk RNA sequencing and untargeted metabolomics. Public single-cell data and hypoxic human skeletal muscle cells (HSkMCs) were used to examine PGK1. AlphaFold3 modeling, molecular dynamics simulation, and a cellular thermal shift assay (CETSA) were used to evaluate a potential CA–PGK1 interaction. HSkMC-conditioned media were applied to human umbilical vein endothelial cells (HUVECs), with 3PG supplementation where indicated. Results: Amino-acid biosynthesis and glycine/serine/threonine metabolism were enriched in HLI muscle. 3PG increased in HLI versus Sham (p = 0.0170) and decreased in HLI+CA versus HLI (p = 0.0358); L-serine followed the same pattern (p = 0.0274 and p = 0.0428, respectively). Pgk1 expression also increased in HLI versus Sham (p = 0.00348) and decreased in HLI+CA versus HLI (p = 0.00249). Hypoxia increased HSkMC PGK1 together with extracellular 3PG and serine, whereas CA attenuated all three. Modeling predicted a stable CA–PGK1 complex, and CETSA supported a potential CA–PGK1 interaction in cell lysates. Conditioned medium from CA-treated hypoxic HSkMCs improved HUVEC viability, redox, tube-formation, and wound-closure readouts, reduced reactive oxygen species, and increased glutathione peroxidase 4 (GPX4) and solute carrier, family 7 member 11 (SLC7A11); 3PG supplementation reversed these effects. Conclusions: CA modulates a PGK1-linked 3PG/L-serine metabolic axis, while 3PG exposure altered endothelial phenotypes in the conditioned-medium model.

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Cite

BibTeXRIS
BibTeX
@article{dong2026coniferaldehyde,
  title = {{Coniferaldehyde Reverses PGK1–3-Phosphoglycerate–L-Serine Metabolic Reprogramming in Hindlimb Ischemia}},
  author = {Yun Dong and Chunbo Ma and Xueli Wang and Jiaping Han and Zina Zhu and Suwen Hu and Zixuan Hu and Liangrong Wang},
  journal = {Metabolites},
  year = {2026},
  month = oct,
  doi = {10.3390/metabo16100756},
  url = {https://www.mdpi.com/2218-1989/16/10/756},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Coniferaldehyde Reverses PGK1–3-Phosphoglycerate–L-Serine Metabolic Reprogramming in Hindlimb Ischemia
AU  - Yun Dong
AU  - Chunbo Ma
AU  - Xueli Wang
AU  - Jiaping Han
AU  - Zina Zhu
AU  - Suwen Hu
AU  - Zixuan Hu
AU  - Liangrong Wang
PY  - 2026
DA  - 2026/10/09
JO  - Metabolites
DO  - 10.3390/metabo16100756
UR  - https://www.mdpi.com/2218-1989/16/10/756
AB  - Background/Objectives: Ischemic skeletal muscle undergoes metabolic remodeling that may influence vascular repair. We investigated whether coniferaldehyde (CA) regulates a phosphoglycerate kinase 1 (PGK1)–3-phosphoglycerate (3PG)–L-serine axis in mouse hindlimb ischemia (HLI). Methods: Gastrocnemius tissue from Sham, HLI, and HLI+CA mice (n = 6/group) underwent bulk RNA sequencing and untargeted metabolomics. Public single-cell data and hypoxic human skeletal muscle cells (HSkMCs) were used to examine PGK1. AlphaFold3 modeling, molecular dynamics simulation, and a cellular thermal shift assay (CETSA) were used to evaluate a potential CA–PGK1 interaction. HSkMC-conditioned media were applied to human umbilical vein endothelial cells (HUVECs), with 3PG supplementation where indicated. Results: Amino-acid biosynthesis and glycine/serine/threonine metabolism were enriched in HLI muscle. 3PG increased in HLI versus Sham (p = 0.0170) and decreased in HLI+CA versus HLI (p = 0.0358); L-serine followed the same pattern (p = 0.0274 and p = 0.0428, respectively). Pgk1 expression also increased in HLI versus Sham (p = 0.00348) and decreased in HLI+CA versus HLI (p = 0.00249). Hypoxia increased HSkMC PGK1 together with extracellular 3PG and serine, whereas CA attenuated all three. Modeling predicted a stable CA–PGK1 complex, and CETSA supported a potential CA–PGK1 interaction in cell lysates. Conditioned medium from CA-treated hypoxic HSkMCs improved HUVEC viability, redox, tube-formation, and wound-closure readouts, reduced reactive oxygen species, and increased glutathione peroxidase 4 (GPX4) and solute carrier, family 7 member 11 (SLC7A11); 3PG supplementation reversed these effects. Conclusions: CA modulates a PGK1-linked 3PG/L-serine metabolic axis, while 3PG exposure altered endothelial phenotypes in the conditioned-medium model.
SN  - 2218-1989
ER  -