AMPK activation stabilizes HIF-2α by disrupting VHL binding and promotes erythroid differentiation under anemic stress via the mTOR pathway
- 1The College of Food and Health of Guangzhou City Polytechnic , ,
Abstract
Objective: Anemia affects over two billion people globally, and ESA resistance poses major clinical hurdles. HIF-2α governs erythropoiesis, yet how AMPK/mTOR energy sensors regulate HIF-2α in erythroid cells remains unclear. This study explored whether AMPK activation stabilizes HIF-2α via impaired VHL binding to boost erythroid differentiation under anemic stress through mTOR signaling.
Methods: UT-7/EPO cells were cultured under 1% O2 with low EPO to mimic anemic stress, treated with AMPK/mTOR pharmacological modulators. CHX chase and Co-IP detected HIF-2α stability and VHL interaction; Ser672 phosphorylation, erythroid and iron-related genes, hepcidin and intracellular iron were measured.
Results: Anemic stress suppressed cell viability, stabilized HIF-2α, activated AMPK and inhibited mTOR, upregulated erythroid markers and triggered apoptosis. AICAR extended HIF-2α half-life, disrupted HIF-2α-VHL binding and elevated Ser672 phosphorylation, while mTOR activator MHY1485 reversed these effects. AMPK activation elevated EPOR, DMT1, FPN1, lowered hepcidin and ferritin, and restored intracellular iron; these effects vanished upon HIF-2α knockdown or mTOR overactivation.
Conclusions: AMPK stabilizes HIF-2α by blocking VHL binding to facilitate erythroid maturation and iron homeostasis under anemic stress via mTOR. The AMPK/mTOR/HIF-2α cascade controls stress erythropoiesis, and targeting this axis may treat ESA-insensitive anemia.
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BibTeX
@article{cen2026ampk,
title = {{AMPK activation stabilizes HIF-2α by disrupting VHL binding and promotes erythroid differentiation under anemic stress via the mTOR pathway}},
author = {Yun Cen and Pingjing Cai and Jinjin Jiang and Lihua Huang and Yiwei Hua},
journal = {Frontiers in physiology},
year = {2026},
month = oct,
doi = {10.3389/fphys.2026.1932780},
url = {https://europepmc.org/article/PMC/PMC13719455},
note = {CC BY},
}
RIS
TY - JOUR
TI - AMPK activation stabilizes HIF-2α by disrupting VHL binding and promotes erythroid differentiation under anemic stress via the mTOR pathway
AU - Yun Cen
AU - Pingjing Cai
AU - Jinjin Jiang
AU - Lihua Huang
AU - Yiwei Hua
PY - 2026
DA - 2026/10/16
JO - Frontiers in physiology
DO - 10.3389/fphys.2026.1932780
UR - https://europepmc.org/article/PMC/PMC13719455
AB - Objective: Anemia affects over two billion people globally, and ESA resistance poses major clinical hurdles. HIF-2α governs erythropoiesis, yet how AMPK/mTOR energy sensors regulate HIF-2α in erythroid cells remains unclear. This study explored whether AMPK activation stabilizes HIF-2α via impaired VHL binding to boost erythroid differentiation under anemic stress through mTOR signaling. Methods: UT-7/EPO cells were cultured under 1% O2 with low EPO to mimic anemic stress, treated with AMPK/mTOR pharmacological modulators. CHX chase and Co-IP detected HIF-2α stability and VHL interaction; Ser672 phosphorylation, erythroid and iron-related genes, hepcidin and intracellular iron were measured. Results: Anemic stress suppressed cell viability, stabilized HIF-2α, activated AMPK and inhibited mTOR, upregulated erythroid markers and triggered apoptosis. AICAR extended HIF-2α half-life, disrupted HIF-2α-VHL binding and elevated Ser672 phosphorylation, while mTOR activator MHY1485 reversed these effects. AMPK activation elevated EPOR, DMT1, FPN1, lowered hepcidin and ferritin, and restored intracellular iron; these effects vanished upon HIF-2α knockdown or mTOR overactivation. Conclusions: AMPK stabilizes HIF-2α by blocking VHL binding to facilitate erythroid maturation and iron homeostasis under anemic stress via mTOR. The AMPK/mTOR/HIF-2α cascade controls stress erythropoiesis, and targeting this axis may treat ESA-insensitive anemia.
SN - 1664-042X
ER -