High‑altitude polycythemia: Unveiling the molecular landscape beyond erythropoietin (Review)

Villafuerte FC and Corante N: Chronic mountain sickness: Clinical aspects, etiology, management, and treatment. High Alt Med Biol. 17:61–99. 2016. View Article : Google Scholar : PubMed/NCBI

Gatterer H, Villafuerte FC, Ulrich S, Bhandari SS, Keyes LE and Burtscher M: Altitude illnesses. Nat Rev Dis Primers. 10:432024. View Article : Google Scholar : PubMed/NCBI

Yang SH, Li B, Gao L and Li NH: Prevalence and risk factors of chronic mountain sickness in Pamirs plateau. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 34:336–339. 2018.In Chinese.

Hancco I, Bailly S, Baillieul S, Doutreleau S, Germain M, Pépin JL and Verges S: Excessive erythrocytosis and chronic mountain sickness in dwellers of the highest city in the world. Front Physiol. 11:7732020. View Article : Google Scholar : PubMed/NCBI

Song Z, Zhang A, Luo J, Xiong G, Peng H, Zhou R, Li Y, Xu H, Li Z, Zhao W and Zhang H: Prevalence of high-altitude polycythemia and hyperuricemia and risk factors for hyperuricemia in high-altitude immigrants. High Alt Med Biol. 24:132–138. 2023. View Article : Google Scholar : PubMed/NCBI

Zila-Velasque JP, Grados-Espinoza P, Goicochea-Romero PA, Tapia-Sequeiros G, Pascual-Aguilar JE, Ruiz-Yaringaño AJ, Barros-Sevillano S, Ayca-Mendoza J and Nieto-Gutierrez W: Mountain sickness in altitude inhabitants of Latin America: A systematic review and meta-analysis. PLoS One. 19:e03056512024. View Article : Google Scholar : PubMed/NCBI

Basang Z, Zhang S, Ke X, Duoji Z, Yang L, Qiangba D, De Y, Gesang D, Hu Z, Ma Y, et al: Differences in pathogenetic mechanism between tibetan and han high-altitude polycythemia based on a whole genome-wide association study. Phenomics. 5:169–182. 2025. View Article : Google Scholar : PubMed/NCBI

Bao H, Wang D, Zhao X, Wu Y, Yin G, Meng L, Wang F, Ma L, Hackett P and Ge RL: Cerebral edema in chronic mountain sickness: A new finding. Sci Rep. 7:432242017. View Article : Google Scholar : PubMed/NCBI

Yin R, Wu Y, Li M, Liu C, Pu X and Yi W: Association between high-altitude polycythemia and hypertension: A cross-sectional study in adults at Tibetan ultrahigh altitudes. J Hum Hypertens. 38:555–560. 2024. View Article : Google Scholar : PubMed/NCBI

Bailey DM, Brugniaux JV, Filipponi T, Marley CJ, Stacey B, Soria R, Rimoldi SF, Cerny D, Rexhaj E, Pratali L, et al: Exaggerated systemic oxidative-inflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression. J Physiol. 597:611–629. 2019. View Article : Google Scholar

Mima D, Wang LP, Zhai Y, De Q, Ba S, Da G, Wang BY, Zhao JB and Tang Y: Prevalence and risk factors for dementia in the Tibetan region: A population-based cross-sectional study. J Affect Disord. 334:159–165. 2023. View Article : Google Scholar : PubMed/NCBI

Wang Z, Tenzing N, Xu Q, Liu H, Ye Y, Wen Y, Wuren T and Cui S: Apoptosis is one cause of thrombocytopenia in patients with high-altitude polycythemia. Platelets. 34:21573812023. View Article : Google Scholar : PubMed/NCBI

Gazal S, Espinoza JR, Austerlitz F, Marchant D, Macarlupu JL, Rodriguez J, Ju-Preciado H, Rivera-Chira M, Hermine O, Leon-Velarde F, et al: The genetic architecture of chronic mountain sickness in Peru. Front Genet. 10:6902019. View Article : Google Scholar : PubMed/NCBI

Simpson LL, Meah VL, Steele AR, Gasho C, Howe CA, Dawkins TG, Busch SA, Oliver SJ, Moralez G, Lawley JS, et al: Global REACH 2018: Andean highlanders, chronic mountain sickness and the integrative regulation of resting blood pressure. Exp Physiol. 106:104–116. 2021. View Article : Google Scholar

Bermudez D, Azad P, Figueroa-Mujíca R, Vizcardo-Galindo G, Corante N, Guerra-Giraldez C, Haddad GG and Villafuerte FC: Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with chronic mountain sickness. Am J Physiol Regul Integr Comp Physiol. 318:R49–R56. 2020. View Article : Google Scholar :

Azad P, Zhou D, Tu HC, Villafuerte FC, Traver D, Rana TM and Haddad GG: Long noncoding RNA HIKER regulates erythropoiesis in Monge's disease via CSNK2B. J Clin Invest. 133:e1658312023. View Article : Google Scholar : PubMed/NCBI

Crawford JE, Amaru R, Song J, Julian CG, Racimo F, Cheng JY, Guo X, Yao J, Ambale-Venkatesh B, Lima JA, et al: Natural selection on genes related to cardiovascular health in highaltitude adapted andeans. Am J Hum Genet. 101:752–767. 2017. View Article : Google Scholar : PubMed/NCBI

He Y, Cui C, Guo Y, Zheng W, Yue T, Zhang H, Ouzhuluobu, Wu T, Qi X and Su B: High arterial oxygen saturation in the acclimatized lowlanders living at high altitude. Phenomics. 3:329–332. 2023. View Article : Google Scholar : PubMed/NCBI

Zhao C, Li Z, Ji L, Ma J, Ge RL and Cui S: PI3K-Akt signal transduction molecules maybe involved in downregulation of erythroblasts apoptosis and perifosine increased its apoptosis in chronic mountain sickness. Med Sci Monit. 23:5637–5649. 2017. View Article : Google Scholar : PubMed/NCBI

Ma J, Ji L, Li Z, Liu H, Zhao C, Xiong H, Wang S, Ge RL and Cui S: Downregulation of intrinsic apoptosis pathway in erythroblasts contributes to excessive erythrocytosis of chronic mountain sickness. Blood Cells Mol Dis. 76:25–31. 2019. View Article : Google Scholar : PubMed/NCBI

Chen Z, Dong Z, Zeng R, Xu M, Zhang Y, Dan Q and Wang G: Association between single nucleotide polymorphisms in EPAS1 and PPARA genes and high altitude polycythemia in Chinese Tibetan population. Front Genet. 16:15191082025. View Article : Google Scholar : PubMed/NCBI

Chen ZY, Wang L, Asavaritkrai P and Noguchi CT: Up-regulation of erythropoietin receptor by nitric oxide mediates hypoxia preconditioning. J Neurosci Res. 88:3180–3188. 2010. View Article : Google Scholar : PubMed/NCBI

Myllymäki MNM, Määttä J, Dimova EY, Izzi V, Väisänen T, Myllyharju J, Koivunen P and Serpi R: Notch downregulation and extramedullary erythrocytosis in hypoxia-inducible factor prolyl 4-hydroxylase 2-deficient mice. Mol Cell Biol. 37:e00529–16. 2017. View Article : Google Scholar :

Kwak J, Kim JH, Jang HN, Jung MH, Cho HS, Chang SH and Kim HJ: Erythropoietin ameliorates ischemia/reperfusion-induced acute kidney injury via inflammasome suppression in mice. Int J Mol Sci. 21:34532020. View Article : Google Scholar : PubMed/NCBI

Greenwald AC, Licht T, Kumar S, Oladipupo SS, Iyer S, Grunewald M and Keshet E: VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells. J Exp Med. 216:215–230. 2019. View Article : Google Scholar :

Flygare J, Rayon Estrada V, Shin C, Gupta S and Lodish HF: HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal. Blood. 117:3435–3444. 2011. View Article : Google Scholar

Lee J, Dey S, Rajvanshi PK, Merling RK, Teng R, Rogers HM and Noguchi CT: Neuronal nitric oxide synthase is required for erythropoietin stimulated erythropoiesis in mice. Front Cell Dev Biol. 11:11441102023. View Article : Google Scholar : PubMed/NCBI

Schmidt WFJ, Wachsmuth NB, Romero Pozo MC, Aguilar Valerio MT, Contreras Tapia IC, Vater M, Kaufmann J, Jimenez-Claros JC and Soria R: Possible strategies to reduce altitude-related excessive polycythemia. J Appl Physiol (1985). 134:1321–1331. 2023. View Article : Google Scholar : PubMed/NCBI

Goetze O, Schmitt J, Spliethoff K, Theurl I, Weiss G, Swinkels DW, Tjalsma H, Maggiorini M, Krayenbühl P, Rau M, et al: Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers. Hepatology. 58:2153–2162. 2013. View Article : Google Scholar : PubMed/NCBI

Xiang J, Wu DC, Chen Y and Paulson RF: In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood. 125:1803–1812. 2015. View Article : Google Scholar : PubMed/NCBI

Xu Y, Wang B, Zhang M, Zhang J, Li Y, Jia P, Zhang H, Duan L, Li Y, Li Y, et al: Carbon dots as a potential therapeutic agent for the treatment of cancer-related anemia. Adv Mater. 34:e22009052022. View Article : Google Scholar : PubMed/NCBI

Singh RP, Grinenko T, Ramasz B, Franke K, Lesche M, Dahl A, Gassmann M, Chavakis T, Henry I and Wielockx B: Hematopoietic stem cells but not multipotent progenitors drive erythropoiesis during chronic erythroid stress in EPO transgenic mice. Stem Cell Reports. 10:1908–1919. 2018. View Article : Google Scholar : PubMed/NCBI

Villafuerte FC, Corante N, Anza-Ramírez C, Figueroa-Mujíca R, Vizcardo-Galindo G, Mercado A, Macarlupú JL and León-Velarde F: Plasma soluble erythropoietin receptor is decreased during sleep in Andean highlanders with chronic mountain sickness. J Appl Physiol (1985). 121:53–58. 2016. View Article : Google Scholar : PubMed/NCBI

Liu YS, Huang H, Zhou SM, Tian HJ and Li P: Excessive iron availability caused by disorders of interleukin-10 and interleukin-22 contributes to high altitude polycythemia. Front Physiol. 9:5482018. View Article : Google Scholar : PubMed/NCBI

Anderson ER, Taylor M, Xue X, Martin A, Moons DS, Omary MB and Shah YM: The hypoxia-inducible factor-C/EBPα axis controls ethanol-mediated hepcidin repression. Mol Cell Biol. 32:4068–4077. 2012. View Article : Google Scholar : PubMed/NCBI

Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S and Peyssonnaux C: HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest. 119:1159–1166. 2009. View Article : Google Scholar : PubMed/NCBI

Schwartz AJ, Das NK, Ramakrishnan SK, Jain C, Jurkovic MT, Wu J, Nemeth E, Lakhal-Littleton S, Colacino JA and Shah YM: Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J Clin Invest. 129:336–348. 2019. View Article : Google Scholar :

Płoszczyca K, Czuba M, Chalimoniuk M, Witek K and Baranowski M: Hepcidin and erythroferrone response to 3 weeks of exposure to normobaric hypoxia at rest in trained cyclists. Front Physiol. 14:12798272023. View Article : Google Scholar

Lakhal S, Schödel J, Townsend AR, Pugh CW, Ratcliffe PJ and Mole DR: Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: New link between hypoxia signaling and iron homeostasis. J Biol Chem. 286:4090–4097. 2011. View Article : Google Scholar

Maurer E, Gütschow M and Stirnberg M: Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: Identification of a hypoxia-responsive element in the TMPRSS6 promoter region. Biol Chem. 393:535–540. 2012. View Article : Google Scholar : PubMed/NCBI

Heritage ML, Murphy TL, Bridle KR, Anderson GJ, Crawford DH and Fletcher LM: Hepcidin regulation in wild-type and Hfe knockout mice in response to alcohol consumption: Evidence for an alcohol-induced hypoxic response. Alcohol Clin Exp Res. 33:1391–1400. 2009. View Article : Google Scholar : PubMed/NCBI

Chiabrando D, Fiorito V, Marro S, Silengo L, Altruda F and Tolosano E: Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice. Blood Cells Mol Dis. 50:25–30. 2013. View Article : Google Scholar

Kremyanskaya M, Kuykendall AT, Pemmaraju N, Ritchie EK, Gotlib J, Gerds A, Palmer J, Pettit K, Nath UK, Yacoub A, et al: Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 390:723–735. 2024. View Article : Google Scholar : PubMed/NCBI

Modi NB, Khanna S, Rudraraju S and Valone F: Pharmacokinetics and pharmacodynamics of rusfertide, a hepcidin mimetic, following subcutaneous administration of a lyophilized powder formulation in healthy volunteers. Drugs R D. 24:539–552. 2024. View Article : Google Scholar : PubMed/NCBI

Jain C, Parimi S, Huang W, Hannifin S, Singhal R, Das NK, Lee KE and Shah YM: Myeloid Hif2α is not essential to maintain systemic iron homeostasis. Exp Hematol. 125-126:25–36.e1. 2023. View Article : Google Scholar

Del Balzo U, Signore PE, Walkinshaw G, Seeley TW, Brenner MC, Wang Q, Guo G, Arend MP, Flippin LA, Chow FA, et al: Nonclinical characterization of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat, a novel treatment of anemia of chronic kidney disease. J Pharmacol Exp Ther. 374:342–353. 2020. View Article : Google Scholar : PubMed/NCBI

Yan P, Li N, Ma M, Liu Z, Yang H, Li J, Wan C, Gao S, Li S, Zheng L, et al: Hypoxia-inducible factor upregulation by roxadustat attenuates drug reward by altering brain iron homoeostasis. Signal Transduct Target Ther. 8:3552023. View Article : Google Scholar : PubMed/NCBI

Zhang W, Jiao L, Liu R, Zhang Y, Ji Q, Zhang H, Gao X, Ma Y and Shi HN: The effect of exposure to high altitude and low oxygen on intestinal microbial communities in mice. PLoS One. 13:e02037012018. View Article : Google Scholar : PubMed/NCBI

Han Y, Xu J, Yan Y and Zhao X: Dynamics of the gut microbiota in rats after hypobaric hypoxia exposure. PeerJ. 10:e140902022. View Article : Google Scholar : PubMed/NCBI

Zhu LL, Ma ZJ, Ren M, Wei YM, Liao YH, Shen YL, Fan SM, Li L, Wu QX, Gao ZS, et al: Distinct features of gut microbiota in high-altitude tibetan and middle-altitude han hypertensive patients. Cardiol Res Pract. 2020:19578432020. View Article : Google Scholar : PubMed/NCBI

Liang T, Liu F, Ma L, Zhang Z, Liu L, Huang T, Li J, Dong W, Zhang H, Li Y, et al: Migration effects on the intestinal microbiota of Tibetans. PeerJ. 9:e120362021. View Article : Google Scholar : PubMed/NCBI

Šket R, Debevec T, Kublik S, Schloter M, Schoeller A, Murovec B, Vogel Mikuš K, Makuc D, Pečnik K, Plavec J, et al: Intestinal metagenomes and metabolomes in healthy young males: Inactivity and hypoxia generated negative physiological symptoms precede microbial dysbiosis. Front Physiol. 9:1982018. View Article : Google Scholar : PubMed/NCBI

Zhang Y, Luo H, Niu Y, Yang X, Li Z, Wang K, Bi H and Pang X: Chronic intermittent hypoxia induces gut microbial dysbiosis and infers metabolic dysfunction in mice. Sleep Med. 91:84–92. 2022. View Article : Google Scholar : PubMed/NCBI

Wang RX, Henen MA, Lee JS, Vögeli B and Colgan SP: Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor. Gut Microbes. 13:19383802021. View Article : Google Scholar : PubMed/NCBI

Ornelas A, Welch N, Countess JA, Zhou L, Wang RX, Dowdell AS and Colgan SP: Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers. Gut Microbes. 15:22677062023. View Article : Google Scholar : PubMed/NCBI

Zhou C, Li L, Li T, Sun L, Yin J, Guan H, Wang L, Zhu H, Xu P, Fan X, et al: SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1α. J Mol Med (Berl). 98:1189–1202. 2020. View Article : Google Scholar : PubMed/NCBI

Bereded NK, Abebe GB, Fanta SW, Curto M, Waidbacher H, Meimberg H and Domig KJ: The gut bacterial microbiome of Nile tilapia (Oreochromis niloticus) from lakes across an altitudinal gradient. BMC Microbiol. 22:872022. View Article : Google Scholar : PubMed/NCBI

Hu C, Wang P, Yang Y, Li J, Jiao X, Yu H, Wei Y, Li J and Qin Y: Chronic intermittent hypoxia participates in the pathogenesis of atherosclerosis and perturbs the formation of intestinal microbiota. Front Cell Infect Microbiol. 11:5602012021. View Article : Google Scholar

Li C and Shi S: Gut microbiota and metabolic profiles in chronic intermittent hypoxia-induced rats: Disease-associated dysbiosis and metabolic disturbances. Front Endocrinol (Lausanne). 14:12243962023. View Article : Google Scholar

Chen A, Teng C, Wei J, Wu X, Zhang H, Chen P, Cai D, Qian H, Zhu H, Zheng X and Chen X: Gut microbial dysbiosis exacerbates long-term cognitive impairments by promoting intestinal dysfunction and neuroinflammation following neonatal hypoxia-ischemia. Gut Microbes. 17:24710152025. View Article : Google Scholar : PubMed/NCBI

Khanna K, Mishra KP, Chanda S, Ganju L, Singh SB and Kumar B: Effect of synbiotics on amelioration of intestinal inflammation under hypobaric hypoxia. High Alt Med Biol. 22:32–44. 2021. View Article : Google Scholar

Hu J, Lang H, Fan D, Wen T, Shi J, Xiao C, Li Y, Kang C, Shi P, Shen L and Lin N: Curcumin supplementation accelerates high-altitude acclimatization, prevents polycythemia and modulates gut microbiota in male Han population: A randomized controlled trial. Front Nutr. 12:15723762025. View Article : Google Scholar : PubMed/NCBI

Rao J, Li J, Liu Y, Lu P, Sun X, Sugumaran PK and Zhu D: The key role of PGC-1α in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure. Mol Cell Biochem. 367:9–18. 2012. View Article : Google Scholar : PubMed/NCBI

Song K, Zhang Y, Ga Q, Bai Z and Ge RL: Increased insulin sensitivity by high-altitude hypoxia in mice with high-fat diet-induced obesity is associated with activated AMPK signaling and subsequently enhanced mitochondrial biogenesis in skeletal muscles. Obes Facts. 13:455–472. 2020. View Article : Google Scholar : PubMed/NCBI

Qian X, Li X, Shi Z, Bai X, Xia Y, Zheng Y, Xu D, Chen F, You Y, Fang J, et al: KDM3A senses oxygen availability to regulate PGC-1α-mediated mitochondrial biogenesis. Mol Cell. 76:885–895.e7. 2019. View Article : Google Scholar

Sharma J, Johnston MV and Hossain MA: Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation. BMC Neurosci. 15:92014. View Article : Google Scholar : PubMed/NCBI

Yan W, Zhang H, Liu P, Wang H, Liu J, Gao C, Liu Y, Lian K, Yang L, Sun L, et al: Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol. 108:3292013. View Article : Google Scholar

Pak O, Scheibe S, Esfandiary A, Gierhardt M, Sydykov A, Logan A, Fysikopoulos A, Veit F, Hecker M, Kroschel F, et al: Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension. Eur Respir J. 51:17010242018. View Article : Google Scholar : PubMed/NCBI

Ahmed ASI, Blood AB and Zhang L: MicroRNA-210 mediates hypoxia-induced pulmonary hypertension by targeting mitochondrial bioenergetics and mtROS flux. Acta Physiol (Oxf). 240:e142122024. View Article : Google Scholar : PubMed/NCBI

Li S, Lyu Q, Shi Q, Bai Y, Ren X and Ma J: Intermittent short-duration reoxygenation relieves high-altitude pulmonary hypertension via NOX4/H2O2/PPAR-γ axis. Clin Sci (Lond). 138:103–115. 2024. View Article : Google Scholar : PubMed/NCBI

Chitra L and Boopathy R: Altered mitochondrial biogenesis and its fusion gene expression is involved in the high-altitude adaptation of rat lung. Respir Physiol Neurobiol. 192:74–84. 2014. View Article : Google Scholar

Yang L, Ye F, Zeng L, Li Y and Chai W: Knockdown of HMGB1 suppresses hypoxia-induced mitochondrial biogenesis in pancreatic cancer cells. Onco Targets Ther. 13:1187–1198. 2020. View Article : Google Scholar : PubMed/NCBI

Xu Y, Wang P, Hu T, Ning K and Bao Y: Notoginsenoside R1 attenuates H/R injury in H9c2 cells by maintaining mitochondrial homeostasis. Curr Issues Mol Biol. 47:442025. View Article : Google Scholar : PubMed/NCBI

Yuan ZJ, Xiao Y, Liu Z, Zhang AQ, Li B and Gao SX: Effect of total secondary ginsenosides on apoptosis and energy metabolism of H9c2 cells under hypoxia based on mitochondrial biogenesis. Zhongguo Zhong Yao Za Zhi. 50:1255–1266. 2025.In Chinese. PubMed/NCBI

Chai N, Zheng H, Zhang H, Li L, Yu X, Wang L, Bi X, Yang L, Niu T, Liu X, et al: Spermidine alleviates intrauterine hypoxia-induced offspring newborn myocardial mitochondrial damage in rats by inhibiting oxidative stress and regulating mitochondrial quality control. Iran J Pharm Res. 21:e1337762023. View Article : Google Scholar : PubMed/NCBI

Strapazzon G, Malacrida S, Vezzoli A, Dal Cappello T, Falla M, Lochner P, Moretti S, Procter E, Brugger H and Mrakic-Sposta S: Oxidative stress response to acute hypobaric hypoxia and its association with indirect measurement of increased intracranial pressure: A field study. Sci Rep. 6:324262016. View Article : Google Scholar : PubMed/NCBI

Zhang P, Li Z, Yang F, Ji L, Yang Y, Liu C, Liu H, Ma J, Liu J, Dang Z, et al: Novel insights into plasma biomarker candidates in patients with chronic mountain sickness based on proteomics. Biosci Rep. 41:BSR202022192021. View Article : Google Scholar : PubMed/NCBI

Song J, Yoon D, Christensen RD, Horvathova M, Thiagarajan P and Prchal JT: HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis. J Mol Med (Berl). 93:857–866. 2015. View Article : Google Scholar : PubMed/NCBI

Kuhikar R, Khan N, Philip J, Melinkeri S, Kale V and Limaye L: Transforming growth factor β1 accelerates and enhances in vitro red blood cell formation from hematopoietic stem cells by stimulating mitophagy. Stem Cell Res Ther. 11:712020. View Article : Google Scholar

Yang M, Wen T, Chen H, Deng J, Yang C and Zhang Z: Knockdown of insulin-like growth factor 1 exerts a protective effect on hypoxic injury of aged BM-MSCs: Role of autophagy. Stem Cell Res Ther. 9:2842018. View Article : Google Scholar : PubMed/NCBI

Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M and Wang J: Essential role for Nix in autophagic maturation of erythroid cells. Nature. 454:232–235. 2008. View Article : Google Scholar : PubMed/NCBI

Zhang J and Ney PA: NIX induces mitochondrial autophagy in reticulocytes. Autophagy. 4:354–356. 2008. View Article : Google Scholar : PubMed/NCBI

Zhang J and Ney PA: Reticulocyte mitophagy: Monitoring mitochondrial clearance in a mammalian model. Autophagy. 6:405–408. 2010. View Article : Google Scholar : PubMed/NCBI

Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J, Shen Z, Jiang L, Wang L, Yang W, et al: BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2. Autophagy. 13:1754–1766. 2017. View Article : Google Scholar : PubMed/NCBI

Sagrillo-Fagundes L, Bienvenue-Pariseault J and Vaillancourt C: Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells. PLoS One. 14:e02024582019. View Article : Google Scholar : PubMed/NCBI

Lin Z, Lu Y, Yu G, Teng H, Wang B, Yang Y, Li Q, Sun Z, Xu S, Wang W and Tian P: Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation. Sci China Life Sci. 66:2354–2369. 2023. View Article : Google Scholar : PubMed/NCBI

Zhaxi Q, Gesang L, Huang J, Suona Y, Ci B, Danzeng Z, Zhang R and Liu B: Hypermethylation of BMPR2 and TGF-β promoter regions in tibetan patients with high-altitude polycythemia at extreme altitude. Biochem Genet. 63:2409–2421. 2025. View Article : Google Scholar

Zheng GP, Nian W, Shi XF and Xie YB: Progress in multiomics research on high altitude polycythemia. Zhonghua Xue Ye Xue Za Zhi. 45:795–800. 2024.In Chinese. PubMed/NCBI

Chen YC, Hsu PY, Chin CH, Hsiao CC, Liou CW, Wang TY, Lin YY, Lee CP, Lin HC, Lin MC and Su MC: H3K23/H3K36 hypoacetylation and HDAC1 up-regulation are associated with adverse consequences in obstructive sleep apnea patients. Sci Rep. 11:206972021. View Article : Google Scholar : PubMed/NCBI

Matsui H, Iriyama T, Sayama S, Inaoka N, Suzuki K, Yoshikawa M, Ichinose M, Sone K, Kumasawa K, Nagamatsu T, et al: Elevated placental histone H3K4 methylation via upregulated histone methyltransferases SETD1A and SMYD3 in preeclampsia and its possible involvement in hypoxia-induced pathophysiological process. Placenta. 115:60–69. 2021. View Article : Google Scholar : PubMed/NCBI

Narayanan S, Eliasson Angelstig S, Xu C, Grünler J, Zhao A, Zhu W, Xu Landén N, Ståhle M, Zhang J, Ivan M, et al: HypoxamiR-210 accelerates wound healing in diabetic mice by improving cellular metabolism. Commun Biol. 3:7682020. View Article : Google Scholar : PubMed/NCBI

Wang S, Ma J, Qiu H, Liu S, Zhang S, Liu H, Zhang P, Ge RL, Li G and Cui S: Plasma exosomal microRNA expression profiles in patients with high-altitude polycythemia. Blood Cells Mol Dis. 98:1027072023. View Article : Google Scholar

Liu F, Hu C, Ding J, Fu C, Wang S and Li T: GATA-1 promotes erythroid differentiation through the upregulation of miR-451a and miR-210-3p expressions in CD34⁺ cells in high-altitude polycythemia. High Alt Med Biol. 24:59–67. 2023. View Article : Google Scholar : PubMed/NCBI

Chen YC, Hsu PY, Su MC, Chin CH, Liou CW, Wang TY, Lin YY, Lee CP, Lin MC and Hsiao CC: miR-21-5p under-expression in patients with obstructive sleep apnea modulates intermittent hypoxia with re-oxygenation-induced-cell apoptosis and cytotoxicity by targeting pro-inflammatory TNF-α-TLR4 signaling. Int J Mol Sci. 21:9992020. View Article : Google Scholar

Chen Y, Zeng H and Liu H: MiR-21 participates in the neuroprotection of diazoxide against hypoxic-ischemia encephalopathy by targeting PDCD4. Brain Inj. 36:876–885. 2022. View Article : Google Scholar : PubMed/NCBI

Tayae E, Amr E, Zaki A and Elkaffash D: LncRNA HIF1A-AS2: A potential biomarker for early diagnosis of acute myocardial infarction and predictor of left ventricular dysfunction. BMC Cardiovasc Disord. 23:1352023. View Article : Google Scholar : PubMed/NCBI

Tian P, Xu Z, Guo J, Zhao J, Chen W, Huang W, Wang M, Mi C, Zhang Y, Yang Y and Zhang H: Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis. Redox Biol. 70:1030732024. View Article : Google Scholar

Bhadury J, Einarsdottir BO, Podraza A, Bagge RO, Stierner U, Ny L, Dávila López M and Nilsson JA: Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts. Oncotarget. 7:23801–23811. 2016. View Article : Google Scholar : PubMed/NCBI

Teramo KA, Klemetti MM and Widness JA: Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs. Pediatr Res. 84:807–812. 2018. View Article : Google Scholar : PubMed/NCBI

Zhang X, Sai B, Wang F, Wang L, Wang Y, Zheng L, Li G, Tang J and Xiang J: Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer. 18:402019. View Article : Google Scholar : PubMed/NCBI

Ikeda S, Kitadate A, Abe F, Saitoh H, Michishita Y, Hatano Y, Kawabata Y, Kitabayashi A, Teshima K, Kume M, et al: Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer Sci. 108:641–652. 2017. View Article : Google Scholar : PubMed/NCBI

Wang Z, Liu Y, Shao M, Wang D and Zhang Y: Combined prediction of miR-210 and miR-374a for severity and prognosis of hypoxic-ischemic encephalopathy. Brain Behav. 8:e008352017. View Article : Google Scholar

Afsar S, Syed RU, Bin Break MK, Alsukaybi RH, Alanzi RA, Alshobrmi AM, Alshagdali NM, Alshammari AD, Alharbi FM, Alshammari AM, et al: The dual role of MiR-210 in the aetiology of cancer: A focus on hypoxia-inducible factor signalling. Pathol Res Pract. 253:1550182024. View Article : Google Scholar

Vonkova B, Blahakova I, Hruban L, Janku P and Pospisilova S: MicroRNA-210 expression during childbirth and postpartum as a potential biomarker of acute fetal hypoxia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 163:259–264. 2019. View Article : Google Scholar

Ma Y, Zhou Y, Xiao Q, Zou SS, Zhu YC, Ping P and Chen XF: Seminal exosomal miR-210-3p as a potential marker of Sertoli cell damage in varicocele. Andrology. 9:451–459. 2021. View Article : Google Scholar

Vangrieken P, Remels AHV, Al-Nasiry S, Bast A, Janssen GMJ, von Rango U, Vroomans D, Pinckers YCW, van Schooten FJ and Schiffers PMH: Placental hypoxia-induced alterations in vascular function, morphology, and endothelial barrier integrity. Hypertens Res. 43:1361–1374. 2020. View Article : Google Scholar : PubMed/NCBI

Li Y, Wang C, Ma H and Wang M: Multi-omics analysis reveals the molecular mechanisms and therapeutic targets in high altitude polycythemia. Ann Biol Clin (Paris). 83:20–34. 2025.PubMed/NCBI

Agrawal A, Rathor R and Suryakumar G: Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: A comprehensive in vivo study. Cell Stress Chaperones. 22:429–443. 2017. View Article : Google Scholar : PubMed/NCBI

Zhuan B, Wang X, Wang MD, Li ZC, Yuan Q, Xie J and Yang Z: Hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated endoplasmic reticulum stress. Aging (Albany NY). 12:23684–23697. 2020. View Article : Google Scholar : PubMed/NCBI

Laban H, Siegmund S, Zappe M, Trogisch FA, Heineke J, Torre C, Fisslthaler B, Arnold C, Lauryn J, Büttner M, et al: NFAT5/TonEBP limits pulmonary vascular resistance in the hypoxic lung by controlling mitochondrial reactive oxygen species generation in arterial smooth muscle cells. Cells. 10:32932021. View Article : Google Scholar : PubMed/NCBI

Sang D, Wang K, Sun X, Wang Y, Lin H, Jia R and Qu F: NIR-driven intracellular photocatalytic O₂ evolution on Z-scheme Ni₃S₂/Cu_1.8S@HA for hypoxic tumor therapy. ACS Appl Mater Interfaces. 13:9604–9619. 2021. View Article : Google Scholar : PubMed/NCBI

Yang R, Huang J, Liao M, Huang J, Gao B, Zhang H, Zhou J, Xu J and Lu Q: An oxygen-sufficient nanoplatform for enhanced imaging-guided microwave dynamic therapy against hypoxic tumors. Int J Nanomedicine. 17:5525–5545. 2022. View Article : Google Scholar : PubMed/NCBI

Chen J, Tang Q, Wang Y, Xu M, Sun S, Zhang J, Wu R, Yue X, Li X, Chen Q and Liang X: Ultrasound-induced piezocatalysis triggered NO generation for enhanced hypoxic tumor therapy. ACS Appl Mater Interfaces. 15:15220–15234. 2023. View Article : Google Scholar : PubMed/NCBI

Zhao H, Sun L, Liu J, Shi B, Zhang Y, Qu-Zong CR, Dorji T, Wang T, Yuan H and Yang J: Meta-analysis identifying gut microbial biomarkers of Qinghai-Tibet Plateau populations and the functionality of microbiota-derived butyrate in high-altitude adaptation. Gut Microbes. 16:23501512024. View Article : Google Scholar : PubMed/NCBI

Bakshi J and Mishra KP: Identification of biomarkers for gastrointestinal barrier injury and protective role of sodium butyrate in hypobaric hypoxia exposed rats. Int Immunopharmacol. 165:1154242025. View Article : Google Scholar : PubMed/NCBI

Pan C, Chen Z, Li C, Han T, Liu H and Wang X: Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases. J Cell Mol Med. 25:5341–5350. 2021. View Article : Google Scholar : PubMed/NCBI

Ali Sheikh MS: The mir-21 inhibition enhanced HUVEC cellular viability during hypoxia-reoxygenation injury by regulating PDCD4. Mediators Inflamm. 2022:96619402022. View Article : Google Scholar : PubMed/NCBI