Chelation Therapy

Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation, that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic disease.

Alzheimer's disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals' roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions' current status in several AD features, and some conflicting reports are present herein.

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox) expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.

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.