Iron Chelation Therapy in Iron Overload Disorders: A Systematic Review with Narrative Synthesis of Bioenergetic Dysfunction, Oxidative Stress, and Biomarker-Guided Management.

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-Ottawa 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.