Hypoxia-inducible factor-1α–mediated metabolic reprogramming in sepsis-associated organ dysfunction: organ-specific metabolic mismatch and therapeutic perspectives
- 1Emergency Center, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China
- 2Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China
Abstract
Sepsis-associated organ dysfunction arises from immune dysregulation, heterogeneous microcirculatory perfusion, impaired oxygen utilization, and cellular metabolic disturbances. Hypoxia-inducible factor-1α (HIF-1α) links oxygen sensing and inflammatory signaling to substrate use and mitochondrial function, but its effects vary with cell type, organ energy demand, and disease stage. This review uses metabolic flexibility and organ-specific metabolic mismatch to integrate these differences. Metabolic flexibility denotes the capacity to adjust energy-producing pathways during stress and restore efficient oxidative metabolism after stress subsides; mismatch develops when cellular energy production no longer meets immediate organ function or repair requirements. HIF-1α-related glycolysis supports early antimicrobial responses in myeloid cells and short-term hypoxic tolerance in some parenchymal cells. Persistent glycolysis combined with restricted pyruvate and fatty acid oxidation and impaired mitochondrial renewal may instead prolong inflammation and limit barrier repair, tubular transport, myocardial contraction, hepatic clearance, and neurological recovery. Differences among the lungs, kidneys, heart, intestine, liver, and brain indicate that global HIF activation or inhibition is unlikely to produce uniform benefit. Cell type-resolved localization, dynamic metabolic flux, mitochondrial function, and organ-level endpoints are therefore required to distinguish adaptive reprogramming from persistent bioenergetic dysfunction and to guide phase-matched metabolic intervention.
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BibTeX
@article{wu2026hypoxiainducible,
title = {{Hypoxia-inducible factor-1α–mediated metabolic reprogramming in sepsis-associated organ dysfunction: organ-specific metabolic mismatch and therapeutic perspectives}},
author = {Yuge Wu and Jiantao Lu and Yue Mo and Yaoqi Xu and Xiaoxi Yan and Caifen Yan and Yingzhen Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1998563},
url = {https://doi.org/10.3389/fimmu.2026.1998563},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hypoxia-inducible factor-1α–mediated metabolic reprogramming in sepsis-associated organ dysfunction: organ-specific metabolic mismatch and therapeutic perspectives
AU - Yuge Wu
AU - Jiantao Lu
AU - Yue Mo
AU - Yaoqi Xu
AU - Xiaoxi Yan
AU - Caifen Yan
AU - Yingzhen Wang
PY - 2026
DA - 2026/10/12
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1998563
UR - https://doi.org/10.3389/fimmu.2026.1998563
AB - Sepsis-associated organ dysfunction arises from immune dysregulation, heterogeneous microcirculatory perfusion, impaired oxygen utilization, and cellular metabolic disturbances. Hypoxia-inducible factor-1α (HIF-1α) links oxygen sensing and inflammatory signaling to substrate use and mitochondrial function, but its effects vary with cell type, organ energy demand, and disease stage. This review uses metabolic flexibility and organ-specific metabolic mismatch to integrate these differences. Metabolic flexibility denotes the capacity to adjust energy-producing pathways during stress and restore efficient oxidative metabolism after stress subsides; mismatch develops when cellular energy production no longer meets immediate organ function or repair requirements. HIF-1α-related glycolysis supports early antimicrobial responses in myeloid cells and short-term hypoxic tolerance in some parenchymal cells. Persistent glycolysis combined with restricted pyruvate and fatty acid oxidation and impaired mitochondrial renewal may instead prolong inflammation and limit barrier repair, tubular transport, myocardial contraction, hepatic clearance, and neurological recovery. Differences among the lungs, kidneys, heart, intestine, liver, and brain indicate that global HIF activation or inhibition is unlikely to produce uniform benefit. Cell type-resolved localization, dynamic metabolic flux, mitochondrial function, and organ-level endpoints are therefore required to distinguish adaptive reprogramming from persistent bioenergetic dysfunction and to guide phase-matched metabolic intervention.
SN - 1664-3224
ER -