{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:55:58Z","timestamp":1790744158347,"version":"4.1.0"},"reference-count":94,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qassim University","award":["QU-APC-2026"],"award-info":[{"award-number":["QU-APC-2026"]}],"id":[{"id":"https:\/\/ror.org\/01wsfe280","id-type":"ROR","asserted-by":"crossref"}]},{"award":["QU-APC-2026"],"award-info":[{"award-number":["QU-APC-2026"]}],"id":[{"id":"https:\/\/ror.org\/01wsfe280","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Iron overload associated with transfusion-dependent disorders promotes oxidative stress, mitochondrial bioenergetic dysfunction, and ferroptotic cell death. Although iron chelation therapy remains the cornerstone of management, the mechanistic links between iron burden, subcellular injury, and emerging biomarkers have not been comprehensively integrated within a clinically relevant framework. This systematic review aimed to synthesize clinical and preclinical evidence on the effects of iron chelation therapy on systemic iron burden, mitochondrial bioenergetics, oxidative stress, ferroptosis, and biomarker-guided management. A systematic literature search was conducted in PubMed\/MEDLINE, Embase, Scopus, and Web of Science for studies published from January 2000 to June 2026, following PRISMA 2020 guidelines. The database search yielded 465 records. After removing 120 duplicates, 345 unique records were screened by title and abstract, of which 210 did not satisfy the predefined eligibility criteria. The remaining 135 articles underwent full-text assessment; 45 were excluded because of inappropriate study design (n = 20), lack of relevant outcomes (n = 15), or unavailable full texts (n = 10). Of the 90 remaining articles, 29 studies (7 randomized controlled trials, 6 observational studies, 3 systematic reviews or guidelines, 6 experimental animal studies and 7 in vitro or cellular mechanistic studies) were included for qualitative narrative synthesis. An additional 61 review articles, guidelines, and epidemiological reports were retained for background context. Methodological quality was assessed using the Cochrane Risk of Bias 2, Newcastle\u2013Ottawa Scale, and SYRCLE tools. Clinical evidence indicated that deferoxamine, deferiprone, and deferasirox consistently reduce systemic iron burden, reflected by improvements in serum ferritin, liver iron concentration, and cardiac T2* magnetic resonance imaging. Circulating iron-related biomarkers, including non-transferrin-bound iron and labile plasma iron, provided additional information on redox-active iron exposure. Preclinical evidence further suggested that iron chelation may attenuate mitochondrial dysfunction, oxidative stress, lipid peroxidation, and ferroptotic signaling. However, mechanistic biomarkers of mitochondrial bioenergetics, oxidative injury, and ferroptosis remain insufficiently validated in prospective clinical populations. Considerable heterogeneity in study populations, interventions, biomarker methodologies, and clinical and mechanistic outcomes limited direct quantitative comparison and supported a narrative synthesis approach. Current evidence supports iron chelation as an effective strategy for reducing systemic iron burden, while emerging bioenergetic, redox, and ferroptosis-related biomarkers provide promising mechanistic insights into iron-mediated cellular injury. Nevertheless, their clinical utility remains uncertain because of limited prospective validation, methodological heterogeneity, and insufficient standardization. Future translational studies should integrate conventional iron indices with validated mitochondrial and redox biomarkers and determine whether biomarker-guided chelation strategies can improve clinically meaningful outcomes beyond conventional iron-burden monitoring.<\/jats:p>","DOI":"10.3390\/ijms27198657","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iron Chelation Therapy in Iron Overload Disorders: A Systematic Review with Narrative Synthesis of Bioenergetic Dysfunction, Oxidative Stress, and Biomarker-Guided Management"],"prefix":"10.3390","volume":"27","author":[{"given":"Khawlah Abdulrahman Salem","family":"Alburayh","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Al Qassim, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraf Mahmoud","family":"Emara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Al Qassim, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab Mohamed","family":"Elgharabawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nri3863","article-title":"Iron homeostasis in host defence and inflammation","volume":"15","author":"Ganz","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vogt, A.S., Arsiwala, T., Mohsen, M., Vogel, M., Manolova, V., and Bachmann, M.F. (2021). On Iron Metabolism and Its Regulation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094591"},{"key":"ref_3","first-page":"164","article-title":"Review on iron and its importance for human health","volume":"19","author":"Abbaspour","year":"2014","journal-title":"J. Res. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1152\/physrev.00008.2013","article-title":"Systemic iron homeostasis","volume":"93","author":"Ganz","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3324\/haematol.2019.232124","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume":"105","author":"Camaschella","year":"2020","journal-title":"Haematologica"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gozzelino, R., and Arosio, P. (2016). Iron homeostasis in health and disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010130"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10408360701713104","article-title":"Oxidative stress and iron homeostasis: Mechanistic and health aspects","volume":"45","author":"Galaris","year":"2008","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cappellini, M.D., Farmakis, D., Porter, J.B., Taher, A.T., and Viprakasit, V. (2023). Guidelines for the Management of Transfusion-Dependent Thalassaemia, Thalassaemia International Federation. [4th ed.].","DOI":"10.1097\/HS9.0000000000000732"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dietz, J.V., Fox, J.L., and Khalimonchuk, O. (2021). Down the iron path: Mitochondrial iron homeostasis and beyond. Cells, 10.","DOI":"10.3390\/cells10092198"},{"key":"ref_10","unstructured":"Taher, A.T., Farmakis, D., and Porter, J.B. (2025). Iron overload and chelation. Guidelines for the Management of Transfusion-Dependent \u03b2-Thalassaemia (TDT), Thalassaemia International Federation. [5th ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12754","DOI":"10.1074\/jbc.R117.787101","article-title":"Iron-sulfur cluster biogenesis and trafficking in mitochondria","volume":"292","author":"Braymer","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"757","DOI":"10.2147\/CIA.S158513","article-title":"Oxidative stress, aging, and diseases","volume":"13","author":"Liguori","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/eji.200939889","article-title":"Differential regulation of iron homeostasis during human macrophage polarized activation","volume":"40","author":"Recalcati","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"S\u0142omka, A., Pokrzywa, A., Strza\u0142a, D., Kubiaczyk, M., Wesolowska, O., Denkiewicz, K., and Styczy\u0144ski, J. (2024). The Role of Hepcidin in Myelodysplastic Syndromes (MDS): A Systematic Review of Observational Studies. Cancers, 16.","DOI":"10.3390\/cancers16020332"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature13148","article-title":"Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy","volume":"509","author":"Mancias","year":"2014","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Guo, C., Peng, J., Cheng, P., Yang, C., Gong, S., Zhang, L., Zhang, T., and Peng, J. (2024). Mechanistic elucidation of ferroptosis and ferritinophagy: Implications for advancing our understanding of arthritis. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1290234"},{"key":"ref_17","first-page":"815","article-title":"Ferritinophagy, a form of autophagic ferroptosis","volume":"18","author":"Sun","year":"2022","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1182\/asheducation-2017.1.265","article-title":"Iron overload in thalassemia: Different organs at different rates","volume":"2017","author":"Taher","year":"2017","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1073\/pnas.1821022116","article-title":"Ferroptosis as a target for protection against cardiomyopathy","volume":"116","author":"Fang","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cabantchik, Z.I. (2014). Labile iron in cells and body fluids: Physiology, pathology, and pharmacology. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00045"},{"key":"ref_21","first-page":"69","article-title":"Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes","volume":"103","author":"Reiniers","year":"2017","journal-title":"Haematologica"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1006\/abio.1997.2126","article-title":"Fluorescence analysis of the labile iron pool of mammalian cells","volume":"248","author":"Epsztejn","year":"1997","journal-title":"Anal. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e24722","DOI":"10.1097\/MD.0000000000024722","article-title":"Analytical evaluation of serum non-transferrin-bound iron and its relationships with oxidative stress and cardiac load in the general population","volume":"100","author":"Sugiura","year":"2021","journal-title":"Medicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"513","DOI":"10.7326\/M19-0916","article-title":"Iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: A randomized trial","volume":"172","author":"Angelucci","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1182\/blood-2013-04-497842","article-title":"Efficacy of deferasirox in reducing and preventing cardiac iron overload in \u03b2-thalassemia","volume":"123","author":"Pennell","year":"2010","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12968-015-0203-4","article-title":"Review of Journal of Cardiovascular Magnetic Resonance 2014","volume":"17","author":"Pennell","year":"2015","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbagen.2011.07.014","article-title":"Non-transferrin bound iron: A key role in iron overload and iron toxicity","volume":"1820","author":"Brissot","year":"2012","journal-title":"Biochim. Biophys. Acta BBA\u2014Gen. Subj."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/ajh.26819","article-title":"The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron-carbohydrate administration","volume":"98","author":"Garbowski","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.yjmcc.2014.09.023","article-title":"The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection","volume":"78","author":"Bernardi","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41571-020-00462-0","article-title":"Broadening horizons: The role of ferroptosis in cancer","volume":"18","author":"Chen","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8837893","DOI":"10.1155\/2020\/8837893","article-title":"Mitochondria-targeted antioxidants: A step towards disease treatment","volume":"2020","author":"Jiang","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_35","first-page":"411","article-title":"An update on iron chelation therapy","volume":"10","author":"Poggiali","year":"2012","journal-title":"Blood Transfus."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100495","DOI":"10.1016\/j.lansea.2024.100495","article-title":"Deferoxamine, deferasirox, and deferiprone triple iron chelator combination therapy for transfusion-dependent \u03b2-thalassaemia with very high iron overload: A randomised clinical trial","volume":"30","author":"Premawardhena","year":"2024","journal-title":"Lancet Reg. Health\u2014Southeast Asia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1182\/blood-2013-04-497842","article-title":"A 1-year randomized controlled trial of deferiprone versus deferoxamine for myocardial iron removal in \u03b2-thalassemia major (CORDELIA)","volume":"123","author":"Pennell","year":"2014","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/ajh.24668","article-title":"New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study","volume":"92","author":"Taher","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"557","DOI":"10.3324\/haematol.2009.014696","article-title":"Tailoring iron chelation by iron intake and serum ferritin: The prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias","volume":"95","author":"Cappellini","year":"2010","journal-title":"Haematologica"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pongamnuaykrit, M., Tantiworawit, A., Niprapan, P., Punnachet, T., Hantrakun, N., Piriyakhuntorn, P., Rattanathammethee, T., Hantrakool, S., Chai-Adisaksopha, C., and Rattarittamrong, E. (2025). The efficacy and safety of deferasirox monotherapy as a second-line treatment in transfusion-dependent thalassemia with iron overload. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176212"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e43238","DOI":"10.1097\/MD.0000000000043238","article-title":"The direct costs of transfusion-dependent beta-thalassemia in Saudi Arabia: A cost of illness analysis study","volume":"104","author":"Radhwi","year":"2025","journal-title":"Medicine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1053\/euhj.2001.2822","article-title":"Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload","volume":"22","author":"Anderson","year":"2001","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1182\/blood-2005-07-2948","article-title":"Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis","volume":"107","author":"Pennell","year":"2006","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1182\/blood-2009-09-243154","article-title":"Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study","volume":"115","author":"Taher","year":"2010","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1182\/blood-2005-08-3430","article-title":"A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with \u03b2-thalassemia","volume":"107","author":"Cappellini","year":"2006","journal-title":"Blood"},{"key":"ref_46","first-page":"e48276","article-title":"Efficacy and Safety of Combined Deferiprone and Deferasirox in Iron-Overloaded Patients: A Systematic Review","volume":"15","author":"Salem","year":"2023","journal-title":"Cureus"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.4103\/0256-4947.81527","article-title":"Six-year outcome of the national premarital screening and genetic counseling program for sickle cell disease and \u03b2-thalassemia in Saudi Arabia","volume":"31","author":"Memish","year":"2011","journal-title":"Ann. Saudi Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1081\/CLT-200068842","article-title":"Iron ingestion: An evidence-based consensus guideline for out-of-hospital management","volume":"43","author":"Manoguerra","year":"2005","journal-title":"Clin. Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00395-023-00990-7","article-title":"Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis","volume":"118","author":"Fefelova","year":"2023","journal-title":"Basic Res. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/apha.12162","article-title":"Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload","volume":"210","author":"Sripetchwandee","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1124\/jpet.108.149807","article-title":"Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke","volume":"330","author":"Hanson","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1089\/ars.2013.5593","article-title":"Targeting chelatable iron as a therapeutic modality in Parkinson\u2019s disease","volume":"21","author":"Devos","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.2217\/nnm-2020-0038","article-title":"Combating iron overload: A case for deferoxamine-based nanochelators","volume":"15","author":"Jones","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1172\/JCI129382","article-title":"Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of \u03b2-thalassemia","volume":"130","author":"Manolova","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41569-022-00735-4","article-title":"The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease","volume":"20","author":"Fang","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Battaglia, A.M., Chirillo, R., Aversa, I., Sacco, A., Costanzo, F., and Biamonte, F. (2020). Ferroptosis and cancer: Mitochondria meet the \u201cIron Maiden\u201d cell death. Cells, 9.","DOI":"10.3390\/cells9061505"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nchembio.2239","article-title":"ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition","volume":"13","author":"Doll","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1021\/acscentsci.9b01063","article-title":"GTP cyclohydrolase 1\/tetrahydrobiopterin counteract ferroptosis through lipid remodeling","volume":"6","author":"Kraft","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41586-021-03539-7","article-title":"DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer","volume":"593","author":"Mao","year":"2021","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41586-019-1705-2","article-title":"The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis","volume":"575","author":"Bersuker","year":"2019","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.apsb.2024.12.027","article-title":"Parkin inhibits iron overload-induced cardiomyocyte ferroptosis by ubiquitinating ACSL4 and modulating PUFA-phospholipids metabolism","volume":"15","author":"Xiao","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Pinto, V., and Forni, G. (2020). Management of iron overload in beta-thalassemia patients: Clinical practice update based on case series. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228771"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1007\/s00277-024-06092-1","article-title":"Real-world experience with iron chelation therapy in transfusion-dependent thalassemia: Impact of the oral chelators\u2019 era","volume":"103","author":"Pines","year":"2024","journal-title":"Ann. Hematol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/j.1600-0609.2009.01228.x","article-title":"Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia: The ESCALATOR study","volume":"82","author":"Taher","year":"2009","journal-title":"Eur. J. Haematol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Gamaleldin, M.M.A., Abdelhalim, S.M.N.S., and Abraham, I. (2026). Recent Advances in Thalassemia Management: From Curative Therapies to Artificial Intelligence. Thalass. Rep., 16.","DOI":"10.3390\/thalassrep16020007"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/S0268-960X(08)70004-3","article-title":"Cardiac iron across different transfusion-dependent diseases","volume":"2","author":"Wood","year":"2008","journal-title":"Blood Rev."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Fu, C., and Yang, X. (2025). Cardiac injury caused by iron overload in thalassemia. Front. Pediatr., 13.","DOI":"10.3389\/fped.2025.1514722"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1182\/blood-2003-08-2841","article-title":"Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major","volume":"104","author":"Davis","year":"2004","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1532-429X-13-45","article-title":"On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure","volume":"13","author":"Pennell","year":"2011","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_70","first-page":"1","article-title":"Labile plasma iron as an indicator of patient adherence to iron chelation treatment","volume":"71","author":"Yacobovich","year":"2018","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1182\/blood-2004-09-3468","article-title":"Redox active plasma iron in C282Y\/C282Y hemochromatosis","volume":"105","author":"Cohen","year":"2005","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1182\/blood-2004-02-0630","article-title":"Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded beta-thalassemia\/HbE patients treated with an oral chelator","volume":"104","author":"Pootrakul","year":"2004","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"741","DOI":"10.3324\/haematol.12413","article-title":"Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders","volume":"93","author":"Angelucci","year":"2008","journal-title":"Haematologica"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e2009034","DOI":"10.4084\/mjhid.2009.0034","article-title":"Iron chelation therapy in thalassemia syndromes","volume":"29","author":"Cianciulli","year":"2009","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1749-6632.1998.tb10479.x","article-title":"Survival and disease complications in thalassemia major","volume":"850","author":"Rugolotto","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e732","DOI":"10.1097\/HS9.0000000000000732","article-title":"2021 Thalassaemia International Federation guidelines for the management of transfusion-dependent thalassemia","volume":"6","author":"Farmakis","year":"2020","journal-title":"HemaSphere"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1016\/S0140-6736(00)02357-6","article-title":"Survival in beta-thalassaemia major in the UK: Data from the UK Thalassaemia Register","volume":"355","author":"Modell","year":"2000","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/ajh.26798","article-title":"Overall and complication-free survival in a large cohort of patients with \u03b2-thalassemia major followed over 50\u2009years","volume":"98","author":"Forni","year":"2023","journal-title":"Am. J. Hematol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bj.2015.10.001","article-title":"Current and future alternative therapies for beta-thalassemia major","volume":"39","author":"Bhukhai","year":"2016","journal-title":"Biomed. J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1182\/blood-2012-05-370098","article-title":"How I treat transfusional iron overload","volume":"120","author":"Hoffbrand","year":"2012","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1182\/blood.2023022502","article-title":"Management of iron overload: Lessons from transfusion-dependent hemoglobinopathies","volume":"145","author":"Coates","year":"2025","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.freeradbiomed.2014.03.039","article-title":"Physiology and pathophysiology of iron in hemoglobin-associated diseases","volume":"72","author":"Coates","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1182\/blood-2003-03-0807","article-title":"Labile plasma iron in iron overload: Redox activity and susceptibility to chelation","volume":"102","author":"Esposito","year":"2003","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/S0891-5849(02)01006-7","article-title":"The labile iron pool: Characterization, measurement, and participation in cellular processes","volume":"33","author":"Kakhlon","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Fu, C., Cao, N., Zeng, S., Zhu, W., Fu, X., Liu, W., and Fan, S. (2023). Role of mitochondria in the regulation of ferroptosis and disease. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1301822"},{"key":"ref_86","first-page":"197","article-title":"Exploring the impact of iron overload on mitochondrial DNA in \u03b2-thalassemia: A comprehensive review","volume":"23","author":"Narahari","year":"2024","journal-title":"Gene Expr."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Frangoul, H., de la Fuente, J., Chopra, Y., Meisel, R., Amrolia, P.J., Algeri, M., Sharma, A., Cappellini, M.D., Corbacioglu, S., and Kattamis, A. (2026). Exa-cel in children with transfusion-dependent \u03b2-thalassemia or sickle cell disease. N. Engl. J. Med., Epub ahead of printing.","DOI":"10.1056\/NEJMoa2603387"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1186\/s12967-024-05740-4","article-title":"The role of mitochondria in iron overload-induced damage","volume":"22","author":"Zhao","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1056\/NEJMoa2501277","article-title":"CRISPR-Cas12a gene editing of HBG1 and HBG2 promoters to treat \u03b2-thalassemia","volume":"394","author":"Frangoul","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_91","unstructured":"Wells, G.A., Shea, B., O\u2019Connell, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2026, August 06). The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Ottawa Hospital Research Institute. Available online: https:\/\/www.ohri.ca\/programs\/clinical_epidemiology\/oxford.asp."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Hooijmans, C.R., Rovers, M.M., de Vries, R.B.M., Leenaars, M., Ritskes-Hoitinga, M., and Langendam, M.W. (2014). SYRCLE\u2019s risk of bias tool for animal studies. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-43"},{"key":"ref_93","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2022). Cochrane Handbook for Systematic Reviews of Interventions Version 6.3, Cochrane. Available online: https:\/\/www.cochrane.org\/authors\/handbooks-and-manuals\/handbook."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8657\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:11:03Z","timestamp":1790741463000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":94,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198657"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198657","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}