{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:17Z","timestamp":1785428117490,"version":"3.56.0"},"reference-count":88,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11874209"],"award-info":[{"award-number":["11874209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["11874209"],"award-info":[{"award-number":["11874209"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A common hypoxic scenario in tumors involves unresolved acute hypoxia that eventually leads to sustained (chronic) hypoxia. This shift drives a characteristic \u201cHIF switch\u201d, where the key hypoxia-responsive factors change from HIF-1\u03b1 to HIF-2\u03b1 over time, and importantly, this switch is closely linked to stemness regulation. However, the mechanisms underlying this switch and its impact on stemness regulation are not yet fully understood. Here, we developed a mechanistic network model integrating the HIF-1\/HIF-2 signaling axis with the stemness regulators OCT4 and SOX2. We found that the duration and intensity of hypoxia jointly shape the dynamics of HIF-1\u03b1 and HIF-2\u03b1, ultimately regulating OCT4-mediated stemness. Under physioxia, HIF-2\u03b1\u2013mTORC2 positive feedback supports the gradual accumulation of HIF-2\u03b1 toward a modest steady level and low OCT4 expression, corresponding to a primed state. Under prolonged mild hypoxia, the concurrent induction of HIF-1\u03b1, albeit at low levels, and accelerated accumulation of HIF-2\u03b1 elevate OCT4 to intermediate levels, promoting stem-like traits. Under moderate hypoxia, PHD-2-mediated negative feedback triggers pulsatile HIF-1\u03b1 dynamics, driving a shift toward HIF-2\u03b1 dominance. Ultimately, cooperative HIF-1\u03b1\/HIF-2\u03b1 signaling induces REDD1 and suppresses mTORC1-dependent protein synthesis, pushing OCT4 into a high-expression state associated with differentiation. This work presents a unified framework for understanding how the HIF signaling hierarchy coordinates metabolic and transcriptional programs to direct cell fate across varying hypoxic landscapes.<\/jats:p>","DOI":"10.3390\/ijms27114697","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"4697","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mechanistic Model of the HIF-1\/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness"],"prefix":"10.3390","volume":"27","author":[{"given":"Haiyue","family":"Zhan","sequence":"first","affiliation":[{"name":"National Laboratory of Solid State Microstructures, Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Institute for Brain Sciences, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of High Performance Scientific Computation, School of Science, Xihua University, Chengdu 610039, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-8518","authenticated-orcid":false,"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"National Laboratory of Solid State Microstructures, Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Institute for Brain Sciences, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.semcancer.2023.11.008","article-title":"Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy","volume":"97","author":"Janji","year":"2023","journal-title":"Semin. Cancer Biol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Saxena, K., and Jolly, M.K. (2019). Acute vs. Chronic vs. Cyclic Hypoxia: Their Differential Dynamics, Molecular Mechanisms, and Effects on Tumor Progression. Biomolecules, 9.","DOI":"10.3390\/biom9080339"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ccr.2006.08.026","article-title":"Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype","volume":"10","author":"Fredlund","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2147\/HP.S93413","article-title":"The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy","volume":"3","author":"Muz","year":"2015","journal-title":"Hypoxia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","article-title":"Hypoxic microenvironment in cancer: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tibs.2012.06.004","article-title":"Passing the baton: The HIF switch","volume":"37","author":"Koh","year":"2012","journal-title":"Trends Biochem. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2009.03.018","article-title":"Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells","volume":"15","author":"Li","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nit, K., Tyszka-Czochara, M., and Bobis-Wozowicz, S. (2021). Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism. J. Pers. Med., 11.","DOI":"10.3390\/jpm11090905"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s12935-020-01719-5","article-title":"The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment","volume":"21","author":"Najafgholian","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nature00767","article-title":"Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL","volume":"417","author":"Hon","year":"2002","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.molcel.2008.04.009","article-title":"Oxygen sensing by metazoans: The central role of the HIF hydroxylase pathway","volume":"30","author":"Kaelin","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1007\/s00018-009-0147-7","article-title":"Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing","volume":"66","author":"Webb","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/onc.2009.441","article-title":"Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics","volume":"29","author":"Semenza","year":"2010","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.stem.2014.02.012","article-title":"Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency","volume":"14","author":"Mathieu","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Di Mattia, M., Mauro, A., Citeroni, M.R., Dufrusine, B., Peserico, A., Russo, V., Berardinelli, P., Dainese, E., Cimini, A., and Barboni, B. (2021). Insight into Hypoxia Stemness Control. Cells, 10.","DOI":"10.3390\/cells10082161"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.canlet.2020.12.020","article-title":"Metabolic adaptation in hypoxia and cancer","volume":"502","author":"Paredes","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1530\/REP-09-0300","article-title":"Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions","volume":"139","author":"Forristal","year":"2010","journal-title":"Reproduction"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mas-Bargues, C., Sanz-Ros, J., Rom\u00e1n-Dom\u00ednguez, A., Ingl\u00e9s, M., Gimeno-Mallench, L., El Alami, M., Vi\u00f1a-Almunia, J., Gambini, J., Vi\u00f1a, J., and Borr\u00e1s, C. (2019). Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051195"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s11658-022-00408-7","article-title":"The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability","volume":"27","author":"Cabaj","year":"2022","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1158\/1541-7786.MCR-11-0053","article-title":"Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha","volume":"9","author":"Lin","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/s41419-020-03150-0","article-title":"The HIF1\u03b1\/HIF2\u03b1-miR210-3p network regulates glioblastoma cell proliferation, dedifferentiation and chemoresistance through EGF under hypoxic conditions","volume":"11","author":"Wang","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2208947119","DOI":"10.1073\/pnas.2208947119","article-title":"Regulation of EGF-stimulated activation of the PI-3K\/AKT pathway by exocyst-mediated exocytosis","volume":"119","author":"An","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/1423-0127-20-63","article-title":"Priming adult stem cells by hypoxic pretreatments for applications in regenerative medicine","volume":"20","author":"Muscari","year":"2013","journal-title":"J. Biomed. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"589","DOI":"10.3904\/kjim.2016.302","article-title":"The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: A possible link to epigenetic regulation","volume":"32","author":"Yeo","year":"2017","journal-title":"Korean J. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1002\/stem.1446","article-title":"Hypoxia induces re-entry of committed cells into pluripotency","volume":"31","author":"Mathieu","year":"2013","journal-title":"Stem Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1101\/gad.1399906","article-title":"HIF-2alpha regulates Oct-4: Effects of hypoxia on stem cell function, embryonic development, and tumor growth","volume":"20","author":"Covello","year":"2006","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1038\/sj.emboj.7601153","article-title":"C-terminal-binding protein directly activates and represses Wnt transcriptional targets in Drosophila","volume":"25","author":"Fang","year":"2006","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.stemcr.2019.02.005","article-title":"Glycolysis Regulates Human Embryonic Stem Cell Self-Renewal under Hypoxia through HIF-2\u03b1 and the Glycolytic Sensors CTBPs","volume":"12","author":"Arthur","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1007\/s13238-019-0637-9","article-title":"Core pluripotency factors promote glycolysis of human embryonic stem cells by activating GLUT1 enhancer","volume":"10","author":"Yu","year":"2019","journal-title":"Protein Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1242\/jcs.03087","article-title":"A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha","volume":"119","author":"Qutub","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_31","first-page":"1454","article-title":"A dynamic model of the hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) network","volume":"126","author":"Nguyen","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5549","DOI":"10.1074\/jbc.M113.500405","article-title":"Tight Control of Hypoxia-inducible Factor-\u03b1 Transient Dynamics Is Essential for Cell Survival in Hypoxia","volume":"289","author":"Bagnall","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"0651","DOI":"10.34133\/research.0651","article-title":"Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1\u03b1-Coordinated Cellular Adaptation to Graded Hypoxia","volume":"8","author":"Wang","year":"2025","journal-title":"Research"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1873-3468.13525","article-title":"Modeling the regulation of p53 activation by HIF-1 upon hypoxia","volume":"593","author":"Wang","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/1873-3468.14258","article-title":"Regulation of epithelial-to-mesenchymal transition in hypoxia by the HIF-1\u03b1 network","volume":"596","author":"Wang","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13834","DOI":"10.1038\/srep13834","article-title":"Modeling the interplay between the HIF-1 and p53 pathways in hypoxia","volume":"5","author":"Zhou","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zaarour, R.F., Ribeiro, M., Azzarone, B., Kapoor, S., and Chouaib, S. (2023). Tumor microenvironment-induced tumor cell plasticity: Relationship with hypoxic stress and impact on tumor resistance. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1222575"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eabo5000","DOI":"10.1126\/sciadv.abo5000","article-title":"NARF is a hypoxia-induced coactivator for OCT4-mediated breast cancer stem cell specification","volume":"8","author":"Yang","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.1158\/0008-5472.CAN-10-3320","article-title":"HIF induces human embryonic stem cell markers in cancer cells","volume":"71","author":"Mathieu","year":"2011","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/74199","article-title":"Quantitative expression of Oct-3\/4 defines differentiation, dedifferentiation or self-renewal of ES cells","volume":"24","author":"Niwa","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s12272-015-0558-y","article-title":"Metabolism in embryonic and cancer stemness","volume":"38","author":"Jang","year":"2015","journal-title":"Arch. Pharmacal Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.gde.2017.06.008","article-title":"Metabolic switching and cell fate decisions: Implications for pluripotency, reprogramming and development","volume":"46","author":"Cliff","year":"2017","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.canlet.2020.05.015","article-title":"Hypoxia: Turning vessels into vassals of cancer immunotolerance","volume":"487","author":"Schito","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"L548","DOI":"10.1152\/ajplung.00314.2009","article-title":"Upregulation of Oct-4 isoforms in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension","volume":"298","author":"Firth","year":"2010","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1158\/0008-5472.CAN-10-4142","article-title":"The hypoxia-associated factor switches cells from HIF-1\u03b1- to HIF-2\u03b1-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion","volume":"71","author":"Koh","year":"2011","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1074\/jbc.M109.068577","article-title":"Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha","volume":"285","author":"Luo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"147288","DOI":"10.1016\/j.gene.2023.147288","article-title":"HIF1\u03b1 and HIF2\u03b1 regulate non-small-cell lung cancer dedifferentiation via expression of Sox2 and Oct4 under hypoxic conditions","volume":"863","author":"Xiong","year":"2023","journal-title":"Gene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/emmm.201101107","article-title":"Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF","volume":"4","author":"Lee","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Endo, H., Okuyama, H., Ohue, M., and Inoue, M. (2014). Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098858"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.cmet.2011.06.011","article-title":"Somatic Oxidative Bioenergetics Transitions into Pluripotency-Dependent Glycolysis to Facilitate Nuclear Reprogramming","volume":"14","author":"Folmes","year":"2011","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1038\/s42255-020-0267-9","article-title":"Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade","volume":"2","author":"Li","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41586-020-2428-0","article-title":"Intracellular pH controls WNT downstream of glycolysis in amniote embryos","volume":"584","author":"Oginuma","year":"2020","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s40778-024-00236-9","article-title":"RNA-Mediated Regulation of Glycolysis in Embryonic Stem Cell Pluripotency and Differentiation","volume":"10","author":"Fan","year":"2024","journal-title":"Curr. Stem Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41419-021-03598-8","article-title":"HIF1\u03b1\/HIF2\u03b1\u2013Sox2\/Klf4 promotes the malignant progression of glioblastoma via the EGFR\u2013PI3K\/AKT signalling pathway with positive feedback under hypoxia","volume":"12","author":"Wang","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.ccr.2007.02.006","article-title":"HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity","volume":"11","author":"Gordan","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Petruzzelli, R., Christensen, D.R., Parry, K.L., Sanchez-Elsner, T., and Houghton, F.D. (2014). HIF-2\u03b1 regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108309"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1152\/physrev.00058.2009","article-title":"Mammalian Kr\u00fcppel-like factors in health and diseases","volume":"90","author":"McConnell","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"368","DOI":"10.4103\/jomfp.JOMFP_22_20","article-title":"SOX2, OCT4 and NANOG: The core embryonic stem cell pluripotency regulators in oral carcinogenesis","volume":"24","author":"Swain","year":"2020","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1634\/stemcells.2007-0126","article-title":"A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells","volume":"25","author":"Singh","year":"2007","journal-title":"Stem Cells"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kalmar, T., Lim, C., Hayward, P., Mu\u00f1oz-Descalzo, S., Nichols, J., Garcia-Ojalvo, J., and Martinez Arias, A. (2009). Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000149"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"113614","DOI":"10.1016\/j.yexcr.2023.113614","article-title":"AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis","volume":"428","author":"Sharma","year":"2023","journal-title":"Exp. Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2020.01.015","article-title":"AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control","volume":"31","author":"Hall","year":"2020","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1101\/gad.221176.113","article-title":"A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo","volume":"27","author":"Do","year":"2013","journal-title":"Genes Dev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/s41419-019-2173-1","article-title":"Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1\u03b1\/TGF-\u03b2 feed-forward loop in hepatocellular carcinoma","volume":"10","author":"Su","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.theriogenology.2018.04.016","article-title":"Hypoxia-dependent accumulation of hypoxia-inducible factor-1 alpha induces transient cell cycle arrest in porcine trophectoderm cells","volume":"115","author":"Jeong","year":"2018","journal-title":"Theriogenology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1091\/mbc.e04-12-1056","article-title":"Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation","volume":"16","author":"White","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00432-014-1593-7","article-title":"Hypoxia-inducible factor (HIF)-independent expression mechanism and novel function of HIF prolyl hydroxylase-3 in renal cell carcinoma","volume":"140","author":"Tanaka","year":"2014","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"386","DOI":"10.7150\/ijms.15057","article-title":"OCT4 Remodels the Phenotype and Promotes Angiogenesis of HUVECs by Changing the Gene Expression Profile","volume":"13","author":"Mou","year":"2016","journal-title":"Int. J. Med. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"151386","DOI":"10.1016\/j.ejcb.2024.151386","article-title":"Regulation of the HIF switch in human endothelial and cancer cells","volume":"103","author":"Slawski","year":"2024","journal-title":"Eur. J. Cell Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2003133","DOI":"10.1002\/advs.202003133","article-title":"A Dimension Reduction Approach for Energy Landscape: Identifying Intermediate States in Metabolism-EMT Network","volume":"8","author":"Kang","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"16975","DOI":"10.1074\/jbc.M111.334466","article-title":"Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: Distinct roles of PHD2 and PHD3 proteins in controlling HIF-1\u03b1 activity in hypoxia","volume":"287","author":"Fujita","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Gaete, D., Rodriguez, D., Watts, D., Sormendi, S., Chavakis, T., and Wielockx, B. (2021). HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer-Potential Targets for Anti-Tumor Therapy?. Cancers, 13.","DOI":"10.3390\/cancers13050988"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"34495","DOI":"10.1074\/jbc.C800170200","article-title":"Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2","volume":"283","author":"Toschi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1080\/17460441.2019.1613370","article-title":"The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy","volume":"14","author":"Albadari","year":"2019","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1101\/gad.887201","article-title":"Regulation of translation initiation by FRAP\/mTOR","volume":"15","author":"Gingras","year":"2001","journal-title":"Genes Dev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.cellsig.2013.02.012","article-title":"Post-translational regulation of mTOR complex 1 in hypoxia and reoxygenation","volume":"25","author":"Tan","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e40273","DOI":"10.1097\/MD.0000000000040273","article-title":"Central role of hypoxia-inducible factor-1\u03b1 in metabolic reprogramming of cancer cells: A review","volume":"103","author":"Zhu","year":"2024","journal-title":"Medicine"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.1128\/MCB.21.10.3436-3444.2001","article-title":"Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells","volume":"21","author":"Seagroves","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1113\/JP280572","article-title":"Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology","volume":"599","author":"Kierans","year":"2021","journal-title":"J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S1097-2765(02)00650-0","article-title":"Transcription corepressor CtBP is an NAD+-regulated dehydrogenase","volume":"10","author":"Kumar","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.bbagrm.2016.03.006","article-title":"Sox2\/Oct4: A delicately balanced partnership in pluripotent stem cells and embryogenesis","volume":"1859","author":"Rizzino","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.stem.2013.10.005","article-title":"Transient activation of autophagy via Sox2-mediated suppression of mTOR is an important early step in reprogramming to pluripotency","volume":"13","author":"Wang","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/stmcls\/sxad079","article-title":"Selective Inhibition of mTORC1 Signaling Supports the Development and Maintenance of Pluripotency","volume":"42","author":"Kim","year":"2024","journal-title":"Stem Cells"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"9899","DOI":"10.1074\/jbc.M312254200","article-title":"Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases","volume":"279","author":"Koivunen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"441","DOI":"10.3945\/jn.111.150706","article-title":"Suppression of hypoxia-inducible factor-1\u03b1 contributes to the antiangiogenic activity of red propolis polyphenols in human endothelial cells","volume":"142","author":"Daleprane","year":"2012","journal-title":"J. Nutr."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"30772","DOI":"10.1074\/jbc.M304982200","article-title":"Characterization of the Human Prolyl 4-Hydroxylases That Modify the Hypoxia-inducible Factor","volume":"278","author":"Koivunen","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Wee, K.B., Surana, U., and Aguda, B.D. (2009). Oscillations of the p53-Akt network: Implications on cell survival and death. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004407"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4697\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:32:29Z","timestamp":1779885149000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,23]]},"references-count":88,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114697"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114697","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,23]]}}}