Copper is a trace element that plays an important role in neuronal development, maturation, and function. It also acts as a cofactor for various copper-binding proteins or serves as an active component of their structure. Acquired copper deficiency has been associated with numerous neurological diseases. Recent research has demonstrated that serum copper concentrations are elevated following spinal cord injury, similar to the elevated copper levels observed after ischemic insult in a rat model of myocardial infarction. This suggests that spinal cord damage may impair the effective utilization of copper due to local ischemia following spinal cord injury. Studies have shown that copper supplementation may form part of a therapeutic strategy for patients with spinal cord injury. It has been reported to promote T-cell differentiation and proliferation, reduce malondialdehyde levels, decrease myeloperoxidase activity and apoptotic cell numbers, and enhance superoxide dismutase activity and glutathione levels. Additionally, copper supplementation may stimulate the transcriptional activity of hypoxia-inducible factor and restore angiogenic capacity, thereby increasing capillary density. Furthermore, researchers have found that dihydrolipoamide dehydrogenase, an enzyme involved in inducing cuproptosis, can influence the immune microenvironment of spinal cord injury by promoting copper toxicity. This leads to increased peripheral M2 macrophage polarization and systemic immunosuppression. This led us to hypothesize that copper may influence three major pathological pathways after spinal cord injury, inflammation, oxidative stress, and cell death, which are critical targets for therapeutic intervention. On the one hand, copper deficiency can cause spinal cord tissue damage; on the other hand, elevated serum copper may induce copper toxicity, contributing to cell death. Therefore, in this review, we investigate the possible link between spinal cord injury and copper in the perspective of inflammation, oxidative stress, and cell death. Additionally, we review published studies on copper metabolism and explore potential therapeutic strategies by considering various sources and mechanisms of copper delivery.

Copper is an essential micronutrient required for mitochondrial respiration, antioxidant defense, and metabolic homeostasis. Accumulating evidence demonstrates that dysregulated copper handling, including deficiency, redistribution, or overload, is a reproducible feature of multiple cardiometabolic disorders, including heart failure, diabetes mellitus, obesity, and NAFLD/MASLD. Human, animal, and cellular studies consistently implicate altered copper trafficking and compartmentalization in mitochondrial dysfunction, oxidative stress, and tissue remodeling across these conditions. The recent identification of cuproptosis, a copper-dependent form of regulated cell death characterized by mitochondrial copper binding to lipoylated tricarboxylic acid cycle enzymes, has expanded mechanistic understanding of copper toxicity in cancer. However, the defining molecular hallmarks of canonical cuproptosis, including lipoylated protein aggregation, iron-sulfur cluster loss, and respiration-dependent cell death, have not yet been demonstrated in vivo in cardiometabolic tissues. Accordingly, cuproptosis is discussed here as a testable mechanistic hypothesis rather than an established driver of cardiometabolic pathology. In this review, we synthesize current evidence for copper dysregulation in cardiometabolic disease and carefully distinguish established copper-dependent pathology from speculative cuproptotic mechanisms. We explicitly address the apparent paradox that the cardiac tissue context in cardiometabolic disease is dominated by a copper-deficient phenotype, which is the opposite of the mitochondrial copper-loading state required for canonical cuproptosis, and reconcile this through the concept of intracellular copper redistribution and tissue-selective susceptibility. We evaluate clinical and preclinical studies of copper-modulating therapies with attention to tissue specificity and safety, and we outline a framework for rigorously testing cuproptosis in vivo using convergent molecular, functional, and clinical criteria. Together, this review clarifies what is known about copper biology in metabolic disease and defines the experimental standards required to determine whether cuproptosis contributes to these conditions.

Roux-en-Y gastric bypass (RYGB) surgery is a highly effective technique for treating obesity. However, it may result in nutritional deficiencies. Here we report the case of a 55-year-old woman presenting with chronic diarrhea lasting 2 years, accompanied by lower limb paresthesia, macrocytic anemia, leukopenia, and thrombocytopenia. Her medical history included hypothyroidism treated with levothyroxine, and RYGB surgery performed in 2014, with intermittent micronutrient supplementation. The patient developed copper and zinc deficiencies. To our knowledge, this is the first report of a patient presenting with both deficiencies simultaneously with pancytopenia 10 years after RYGB. This case underscores the need to verify adherence to existing preoperative screening recommendations involving preoperative micronutrient measurements to assess micronutrient deficiency risks and multidisciplinary postoperative follow-up,the importance of monitoring micronutrient levels, close follow-up of both symptomatic and asymptomatic patients and evaluating adherence to supplementation regimens.

Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis. Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3-SCO1-MT-CO1-CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis. Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.

Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia-inducible factor 1 subunit alpha (HIF-1α)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1G93A transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.

Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.

The prevalence of malnutrition in patients with Systemic Sclerosis (SSc) is significant and adversely affects disease progression. This study aimed to investigate the nutritional status of patients with SSc and the relationship between micronutrients and nutritional status. This cross-sectional observational study included 50 patients with SSc. We measured levels of vitamins (A, B1, B6, B12, D, folic acid), trace elements (copper, zinc, selenium, chromium), and proteins (prealbumin, ceruloplasmin). ICP-MS was used for trace element analysis. The relationships between outcomes, patients' demographic characteristics, and nutritional status were assessed. Malnutrition was found in 48% of patients (46% moderate, 2% severe). Patients with diffuse SSc (dcSSc) had a significantly higher risk of moderate malnutrition than those with limited SSc (lcSSc) (70% vs. 30%, p = 0.004). Copper and zinc deficiencies were nearly universal, affecting 96% and 98% of patients, respectively. Median copper (12.9 vs 22.5μg/dL, p = 0.022) and zinc (11.1 vs 18.4μg/dL, p = 0.013) levels were significantly lower in the dcSSc group compared to lcSSc. Vitamin D deficiency was prevalent in 72% of the cohort. In our cohort, malnutrition was notably prevalent, particularly among patients with dcSSc. The observed high rates of zinc, copper, and vitamin D deficiencies point toward a need for heightened clinical vigilance. While further large-scale studies are required to confirm these trends, periodic screening of these micronutrients may play a supportive role in optimizing the nutritional status of SSc patients.

Cell death is critical for the onset and progression of liver diseases, as well as organismal growth and development. It can be broadly classified into regulated cell death and accidental cell death. Ferroptosis and cuproptosis are metal-dependent cell death processes that play important roles in disease management. Disrupted copper homeostasis, whether due to copper excess or deficiency, is strongly associated with the development of various diseases. Cuproptosis is a newly identified form of cell death characterized by excessive accumulation of copper inside cells. The liver is the primary organ for copper storage. Triggering cuproptosis in liver cells represents an innovative therapeutic strategy to treat liver diseases. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with liver-related diseases. We also review the current knowledge on the complex effects of cuproptosis on liver therapeutic strategies. As well as discussing future research directions that may lead to major advances in the prevention, intervention and treatment of liver-related diseases.

Characterizing clinical patterns and associated factors of zinc-induced copper deficiency: Insights from large-scale pharmacovigilance databases.

Introduction: This study sought to explore the impact of dietary Cu deficiency on colonic health, including assessments of histopathology, barrier function, inflammatory response, and gut microbiota composition. Methods: Weaned mice were fed a copper-deficient diet for four weeks, followed by one week of intraperitoneal copper sulfate administration as a proof-of-concept rescue intervention. Colonic pathology was assessed by H&E staining, goblet cell changes by AB-PAS staining, and intestinal barrier integrity by immunofluorescence. Inflammatory cytokine levels were measured by ELISA, while protein and mRNA expression of inflammatory markers were detected by Western blot and qRT-PCR. Gut microbiota composition, diversity, and signature genus abundance were analyzed by 16S sequencing. Results: Compared to the control group, CuD mice exhibited histopathological damage in the colon, including mucosal thinning and inflammatory cell infiltration. The number of goblet cells and the expression of mucin MUC2 were significantly reduced, and the expression of tight junction proteins (ZO-1, Occludin) was downregulated, indicating impairment of both the physical and chemical intestinal barriers. Concurrently, Cu deficiency markedly elevated systemic and colonic levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and enhanced NF-κB phosphorylation. To explore potential microbial contributions to these colonic alterations, we subsequently analyzed the gut microbiota composition by 16S rRNA sequencing. This analysis revealed that Cu deficiency significantly reduced the α-diversity and species richness of the gut microbiota. This dysbiosis was characterized by a decreased abundance of beneficial bacteria (e.g., Bacteroidota, Muribaculaceae) and an increased abundance of Desulfobacterota, a pro-inflammatory taxon, as well as Akkermansia, a mucin-degrading bacterium with context-dependent effects on gut health. Intraperitoneal administration of copper sulfate (CuD + CuSO4) partially reversed the histopathological and inflammatory changes; its effect on the gut microbiota was not assessed. Conclusions: Dietary Cu deficiency is associated with colonic injury, and these alterations were accompanied by intestinal barrier disruption, an activated inflammatory response, and gut microbiota dysbiosis. These findings provide experimental evidence highlighting the importance of copper nutrition in maintaining colonic homeostasis, though further mechanistic studies are needed to establish causal relationships.

The electrochemical reduction of nitrate to ammonia presents a sustainable alternative to conventional nitrogen fixation methods, yet developing molecular model systems that can reveal fundamental mechanistic principles remains a key challenge. Here, we report a well-defined copper bipyridine chloride complex, [Cu(bpy)2Cl]+, that catalyzes nitrate reduction in aqueous phosphate buffer (pH = 7), achieving ∼100% Faradaic efficiency for ammonia at -0.89 V vs RHE and a partial current density exceeding 30 mA cm-2. Structure-activity relationships were investigated by introducing substituents at the 4-position of the pyridine units (R= H, tBu, OMe, CF3). This study revealed that a sterically accessible and electron deficient copper center exhibits enhanced activity toward nitrate reduction. Detailed mechanistic insights were obtained via a combination of in situ Fourier transform infrared (FTIR), electrochemical mass spectrometry, and ultraviolet-visible (UV-vis) spectroscopy, revealing stepwise N-O bond cleavage and proton-coupled electron transfer through NO2, NO, and hydroxylamine intermediates. To expand the catalytic scope beyond nitrate, [Cu(bpy)2Cl]+ was also shown to selectively reduce organonitro substrates, achieving up to 90% Faradaic efficiency for aniline formation from nitrobenzene. This electrochemical and spectroscopic study highlights the crucial role of molecular design, advancing the understanding of nitrate electroreduction pathways and guiding future catalyst development.

Anorexia nervosa (AN) is a serious illness in which more than half of all deaths are due to malnutrition. Critically low energy and protein intake are known causes of massive weight loss, whereas micronutrient deficiencies due to a low-calorie food pattern remain poorly characterized in children with AN. Micronutrient deficiencies in AN, such as selenium deficiency, are known to increase anxiety and the risk of suicide. Two large studies in adults highlighted frequent selenium and copper deficiencies; this information is lacking in children. The present study aimed to provide a comprehensive description of the micronutrient status in pediatric AN and evaluate whether deficiencies differ according to AN subtype (restricting, R, binge-eating/purging, BP). A retrospective, single-center, descriptive study was conducted in a cohort of children with AN who were evaluated at a specialist eating disorders center from 2016 to 2022. The sample comprised 349 patients (mean age 14.7 ± 1.8 years); 91.4% had AN-R, 8.6% BP. Mean weight loss was 18.2% ± 10.7%, and initial BMI was 16.7 ± 1.1 kg/m2 according to the International Obesity Task Force. At least one micronutrient deficiency was found in 90% of patients; 51.3% experienced multiple deficiencies. The most common were selenium (23.5%), copper (18.4%), and vitamin A (29.1%). The prevalence of deficiencies was similar between AN-R and AN-BP, except for potassium and calcium which were significantly lower in AN-BP. Micronutrients deficiencies are frequent in pediatric AN with no difference according to subtype. The functional impact and the benefit of supplementation remain to be studied.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease for which the mechanisms linking lipid dysregulation to fibrosis remain poorly defined. Hepatic phosphatidylcholine (PC) content is reduced in MASH, but how this alteration drives disease progression is unclear. Here, we identify a role for copper (Cu) homeostasis as a downstream effector of impaired PC biosynthesis. Using single-nucleus RNA sequencing in complementary genetic and dietary mouse models, we found that reduced hepatic PC is associated with marked depletion of hepatic Cu and a concomitant increase in circulating Cu, indicating disrupted Cu distribution. Mechanistically, PC depletion impaired plasma membrane localization of the high-affinity Cu transporter CTR1 (SLC31A1) in hepatocytes, limiting Cu uptake. In human hepatic stellate cells, Cu promoted fibrogenic activation, whereas suppression of Cu import or pharmacologic inhibition of MAPK signaling attenuated fibronectin deposition. In vivo, liver-directed Cu supplementation restored hepatic Cu levels and reduced steatosis but failed to improve fibrosis. In contrast, pharmacologic Cu chelation with bathocuproinedisulfonic acid (BCS) reduced fibrosis without affecting inflammation. Together, these findings identify Cu redistribution as a consequence of impaired PC biosynthesis and implicate Cu-dependent signaling in stellate cell activation, fibrogenesis and MASH pathogenesis.

Impairments to the complex machinery regulating copper homeostasis lead to neurodevelopmental diseases, demonstrating the importance of copper for neuronal health and maintenance. The exact mechanisms by which the brain responds to copper deficiency following disruptions to the copper transporters ATP7A and CTR1 in conditions such as Menkes disease remain unclear, though failure to supply complex IV of the respiratory chain with copper is suspected to account for substantial pathology. Here, we studied mechanisms of copper deficiency using systems biology approaches to contrast isogenic CTR1- and COX17-deficient cells, which model copper deficiency at the level of the whole cell or complex IV, respectively. Multiomics approaches revealed distinct signaling mechanisms elicited by compartment-specific genetic defects of copper homeostasis, spanning multiple organelles and biological functions. Specifically, COX17 KO cells exhibited elevated AMPK activity and blunted mTOR activity relative to CTR1-null cells. Manipulating mTOR activity elicited inverse effects on survival in CTR1-deficient cells and flies as compared with their COX17-deficient counterparts. Increased mTOR activity and downstream protein synthesis are adaptive in models of copper deficiency but deleterious in COX17-deficient cells and flies. We propose that mTOR activation represents a resilience mechanism that fails following sustained copper deficiency and impairments to mitochondrial respiration.

To investigate how copper deficiency during pregnancy affects placental structure, metabolism, and trophoblast function, contributing to fetal growth restriction (FGR). Pregnant C57BL/6N mice were treated with ammonium tetrathiomolybdate (ATTM) to induce copper deficiency, with two different dosages (30 and 60 mg·kg-1·d-1) administered daily from gestational day 1 to day 14. On day 15, assessments were made on fetal growth, placental development, and spatial metabolomics. In parallel, trophoblast cells (HTR8/SVneo) were subjected to copper chelation or SLC31A1 knockdown to model copper deficiency in vitro. Cell invasiveness and proliferation were evaluated using appropriate assays, along with the measurement of molecular markers to assess the impact of copper deficiency. Copper deficiency significantly reduced maternal serum copper levels, leading to FGR, as evidenced by shorter crown-rump lengths, lower fetal weights, and altered fetal-to-placental weight ratios. Structural abnormalities in the placental junctional zone, including reduced size and altered morphology, were observed. Metabolomic analysis revealed disrupted lipid metabolism, with alterations in glycerophospholipids and fatty acids, and lipid droplet accumulation. Copper deficiency impaired trophoblast migration and invasion, linked to decreased MMP2 and MMP9 expression in vivo and in vitro. In vitro studies also showed altered lipid metabolism in SLC31A1-knockdown trophoblast cells. Copper deficiency disrupts placental structure and lipid metabolism, impairs trophoblast function, and contributes to FGR, highlighting the critical role of copper in fetal development and maternal health.

Iron (Fe) and copper (Cu) are essential yet potentially toxic metals with interconnected metabolic pathways; however, the mechanisms underlying Fe-Cu crosstalk remain poorly defined. Here, we show that CITF1 (COPPER DEFICIENCY INDUCED TRANSCRIPTION FACTOR 1), a Cu homeostasis regulator in Arabidopsis thaliana, physically interacts with FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR), the central Fe homeostasis regulator, forming a nutrient-responsive transcriptional module. Under Cu deficiency, the CITF1-FIT complex accumulates and promotes expression of the Cu uptake genes COPT2 (COPPER TRANSPORTER 2), FRO4 (FERRIC REDUCTION OXIDASE 4), and FRO5 (FERRIC REDUCTION OXIDASE 5). Proteasome-dependent degradation regulates CITF1 and FIT stability, with Cu deficiency delaying their turnover in a CITF1-dependent manner. Under Fe deficiency, CITF1 expression is downregulated, allowing FIT to interact with bHLH38/39/100/101 partners and activate Fe uptake genes, as CITF1 disrupts these interactions. Thus, CITF1 negatively regulates Fe acquisition. Consistent with this, citf1-1 and citf1-2 mutants show reduced sensitivity to Fe deficiency. Under Cu deficiency, the citf1-2 and fit-2 mutants have additive effects and under Fe deficiency, the double mutant shows partial suppression of the fit-2 slow growth phenotype, supporting the positive and negative roles of CITF1 in Cu and Fe homeostasis, respectively. Complete loss of CITF1 function in the homozygous citf1-1 fit-2 double mutant causes embryo lethality, revealing roles for CITF1 and FIT in embryo development. These findings establish CITF1 as a nutrient-responsive regulator of Cu/Fe crosstalk, functioning through interactions with FIT to prioritize Cu or Fe acquisition and balance micronutrient homeostasis.

Copper deficiency is a rare and often overlooked cause of anemia, neutropenia, and neuropathy. We describe a case where a 47-year-old man sought medical attention because of weight loss, fatigue, and neurological symptoms. Initial evaluation suggested myelodysplastic syndrome, with anemia and neutropenia. Furthermore, the bone marrow was hypercellular with prominent cytoplasmic vacuoles in myeloid precursors. Subsequently, the clinical picture was determined to result from severe copper deficiency secondary to excessive zinc exposure. Further history revealed long-term use of a zinc-containing denture adhesive. After copper supplementation and discontinuation of the adhesive, blood status normalized and symptoms largely resolved. This case highlights the importance of considering copper deficiency in unexplained bone marrow failure.

Background Metformin is associated with vitamin B12 deficiency, and we recently reported latent iron and copper deficiency among metformin users, suggesting a potential contribution to anemia risk. However, real-world evidence on hemoglobin trajectories after metformin initiation remains limited. We evaluated short- and long-term hemoglobin changes after metformin initiation compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in Japanese patients with type 2 diabetes. Methods This single-center retrospective cohort study used electronic medical record data from Kobe University Hospital from January 2014 to June 2025. Short-term hemoglobin changes were defined as changes from Day 0 to Day 180, and long-term trajectories were evaluated from Day 0 to Day 1,826 (five years). Patients initiating metformin or a DPP-4 inhibitor were selected using predefined eligibility and exclusion criteria and matched by propensity scores. Hemoglobin changes over 180 days and up to five years were analyzed using multiple regression and mixed-effects models. Results The short-term cohort included 72 matched pairs, and the long-term cohort included 182 matched pairs. Hemoglobin decreased from 14.74 ± 0.22 to 14.39 ± 0.23 g/dL (mean ± SEM) from Day 0 to Day 180 in the metformin group, whereas no significant change was observed in the DPP-4 inhibitor group. Pre-initiation hemoglobin change, but not metformin dose, was independently associated with subsequent hemoglobin change. Over five years, annual hemoglobin slopes did not differ significantly between groups (-0.0572 vs. -0.0725 g/dL/year, p = 0.31). Older patients showed more negative annual hemoglobin slopes in both groups. Conclusions Metformin initiation was associated with a short-term hemoglobin decrease, whereas excess long-term decline was not observed in this cohort. Long-term changes were modest and age-related, supporting continued monitoring in older patients.

Genetic disorders involving metal metabolism dysregulation pose significant challenges in diagnosis, treatment, and monitoring. Traditional diagnostic methods, such as genetic sequencing and biochemical assays, often fail to detect early metabolic imbalances, delaying interventions. Inductively Coupled Plasma (ICP) Spectroscopy, including ICPMass Spectrometry (ICP-MS) and ICP-Optical Emission Spectroscopy (ICP-OES), has emerged as a highly sensitive and precise tool for analyzing trace metal concentrations in biological samples, offering new insights into metalassociated genetic disorders. This article explores the role of ICP spectroscopy in early diagnosis, biomarker discovery, and treatment monitoring for disorders such as Wilson's disease (copper accumulation), hemochromatosis (iron overload), Menkes disease (copper deficiency), and lead poisoning-related neurodevelopmental disorders. ICP-MS enables the detection of ultratrace metal levels, ensuring early intervention before clinical symptoms appear. Additionally, ICP techniques facilitate personalized medicine approaches, allowing for individualized treatment plans based on a patient's metal homeostasis profile. Recent advancements in HR-ICP-MS, single-cell ICP-MS, and laser ablation ICP-MS have further expanded the applications of ICP spectroscopy in genomic and proteomic research, enabling detailed elemental mapping and improved disease modelling. The integration of ICP spectroscopy with omics technologies is paving the way for precision medicine, optimizing treatments for genetic disorders at an individualized level. As ICP technology continues to evolve, it holds immense potential for advancing genetic disorder research, improving diagnostic accuracy, and enhancing therapeutic strategies, ultimately transforming the landscape of metallomics-based medicine.

Abstract Background Isolated Methylmalonic acidaemia (MMA) is a rare inherited metabolic disorder. Nutritional intervention for MMA patients includes dietary restriction of proteins along with medical food and dietary supplements. Decreased bone mineral density (BMD) is a widely accepted complication of protein restricted diet and accumulation of acids and toxic metabolites. Aim of the study To assess bone health in patients with isolated MMA and investigate the contributing factors. Patients and methods The study included all patients biochemically confirmed with isolated MMA above the age of 5 years. Clinical, dietary, and biochemical data were systematically collected. Patient compliance was assessed using author-derived score. Bone mineral density (BMD) was evaluated using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed using serum osteocalcin level, while bone resorption was evaluated using carboxy-terminal telopeptide of collagen type 1 (S-CTX) in addition to selected other bone health laboratory parameters. Results The study included 24 patients. A history of fractures was present in 5 patients (20.83%). Decreased total body BMD was found in 14 patients (54.5 %) with a mean Z score of -1.31 ± 1.38 SD. Decreased spine BMD was present in 21 patients (79.16%) with a mean Z score of -1.9 ± 1.1 SD. This decrease was significantly related to non-compliance, chronic acidosis, disease severity, and low serum copper. There was no significant relation between BMD and creatinine, calcium, vitamin D, zinc, selenium, osteocalcin, or S-CTX levels. Conclusion Isolated MMA patients have defective bone formation and increased bone resorption manifested by decreased BMD and related to poor compliance, chronic acidosis, disease severity and copper deficiency.