Search Results (558)

Background/Objectives: Manganese (Mn) is a neurotoxic trace element whose excessive accumulation in the brain can induce hippocampal damage via oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. This study investigated whether honokiol (HNK) and its liposomal nanoformulation (HNK-LNPs) can ameliorate Mn-induced hippocampal neurotoxicity by modulating key antioxidant and mitochondrial regulatory pathways. Methods: Male Wistar rats were subjected to Mn exposure to induce hippocampal neurotoxicity and were treated with HNK or HNK-LNPs. We assessed oxidative status via NRF2/HO-1 signaling, antioxidant defenses (glutathione, GPx, SOD, CAT), and oxidative indices (ROS, MDA). Neuroinflammatory markers (NF-κB, TNF-α, IL-1β, IL-6, Iba-1), mitochondrial respiratory chain function and ATP levels, SIRT1/PGC-1α signaling, and neurotransmitter homeostasis were evaluated. We analyzed apoptosis using Bax, Bcl-2, caspase-3, and cytochrome c, along with histopathological and ultrastructural examination of the hippocampus. Results: Mn exposure was associated with NRF2/HO-1 downregulation, depleted endogenous antioxidants, increased ROS and MDA levels, and increased NF-κB–driven neuroinflammation and microglial Iba-1 expression. Mn was further associated with reduced ATP synthesis, dysregulation of SIRT1/PGC-1α signaling, and disrupted neurotransmitter balance, with a pro-apoptotic shift (elevated Bax, caspase-3, cytochrome c; reduced Bcl-2) and neuronal degeneration. Co-treatment with HNK, and more prominently with HNK-LNPs, was associated with reversing these alterations, restoring antioxidant and mitochondrial pathways, dampening inflammatory cascades, normalizing neurotransmitters, and favoring neuronal survival, with many indices approaching control values and consistently surpassing free HNK. Conclusions: Liposomal encapsulation significantly enhances honokiol’s neuroprotection against Mn-induced hippocampal neurotoxicity, likely via improved CNS bioavailability and coordinated modulation of NRF2/HO-1 and SIRT1/PGC-1α pathways. These findings support HNK-LNPs as a promising multi-mechanistic therapeutic strategy for metal-induced and related neurotoxic brain disorders. Full article

Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as “nature’s Ozempic”. Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far from inert. Objective: To synthesize the evidence on berberine as a perpetrator of supplement–drug interactions, propose a four-axis mechanistic taxonomy, with product quality treated separately as a modifier of exposure rather than as a mechanism, and derive a clinically actionable risk-stratification framework. Methods: Structured narrative review, prepared per the SANRA quality criteria; PubMed/MEDLINE, Scopus, Web of Science and Embase were searched up to May 2026. Results: Despite very low systemic exposure (oral bioavailability 0.68% in rats; low ng/mL plasma concentrations in humans), high luminal, enterocytic and hepatic concentrations generate interaction liability, documented in humans for a few pairs and mechanistic for most, along four mechanistic axes: inhibition, and transcriptional induction, of CYP3A4, with CYP2D6/CYP2C9 inhibition that is quasi-irreversible through a metabolite-intermediate complex; transporter modulation (P-glycoprotein, OCT1/OCT2, and MATE1); pharmacodynamic additivity (hypoglycemia, hypotension, and QT prolongation); and microbiome- and gut-barrier-mediated effects, the last of these being a candidate axis rather than a demonstrated one. Product-quality variability is treated separately, as a modifier of exposure. The clinical anchor is increased cyclosporine exposure in renal-transplant recipients (AUC +34.5%; trough 29.3% above control). These elements are integrated into a three-tier risk-stratification framework that combines perpetrator potency, victim-drug vulnerability, and patient vulnerability, with each tier being linked to a defined pharmacy action. Conclusions: In patients on multiple medications, and particularly when berberine is co-administered with drugs of narrow therapeutic index, it should be managed as an active pharmacological perpetrator rather than as an inert supplement. Unstandardized product quality and an unsettled European regulatory framework, under which national limits differ by more than an order of magnitude, further widen the uncertainty around the dose actually delivered. Berberine use should therefore be elicited routinely at medication reconciliation and stratified by mechanism, by victim-drug vulnerability, and by patient risk, with particular attention to metabolic self-medication in the GLP-1 era. Full article

Background/Objectives: Aluminium is a widespread environmental element and food contaminant to which the general population is continuously exposed, primarily through diet and drinking water. Although gastrointestinal absorption is generally low, bioavailability varies according to chemical form, food matrix, and interactions with dietary components. Prolonged exposure can nevertheless result in gradual tissue accumulation. This review summarises current evidence on dietary aluminium exposure, factors influencing its bioavailability, toxicokinetics, biological effects, gut microbiota interactions, and population-level health risk. Methods: A comprehensive narrative literature review was conducted using publications retrieved from PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Original research articles, review papers, and reports issued by international organisations were critically evaluated with particular emphasis on dietary sources, drinking water, food additives, food contact materials, gastrointestinal absorption, toxicokinetics, biological mechanisms, gut microbiota, and health risk assessment. Results: Food represents the principal source of aluminium exposure in the general population, while drinking water usually contributes a smaller but continuous fraction of total oral intake. Dietary exposure varies substantially between populations and is influenced by food composition, processing practices, the use of aluminium-containing additives, and migration from food contact materials. Aluminium bioavailability is modified by chemical speciation and dietary constituents, including citrate, phosphates, silicates, phytates, polyphenols, and essential minerals. Despite limited absorption, prolonged exposure can lead to gradual aluminium accumulation, particularly in bone tissue and the central nervous system. Proposed biological mechanisms include oxidative stress, mitochondrial dysfunction, disruption of mineral homeostasis, and inflammatory signalling. Emerging evidence also indicates that aluminium may alter the gut microbiota, impair intestinal barrier integrity, and influence the gut–brain axis. Population exposure assessments show considerable regional variation, with some groups approaching or exceeding established tolerable weekly intake values. Conclusions: Dietary aluminium exposure represents a relevant issue in nutritional toxicology and food safety. Although current evidence does not establish that typical dietary exposure directly causes chronic disease, long-term exposure, differences in bioavailability, and the possibility of elevated intake in selected population groups justify continued monitoring and further prospective human studies. Future research should integrate dietary intake, aluminium speciation, nutritional status, biomarkers of internal exposure, and long-term health outcomes to improve risk assessment and support effective exposure-reduction strategies. Full article

Microplastics (MPs) and potentially toxic elements (PTEs) increasingly co-occur in agricultural and peri-urban soils, yet their combined effects on adsorption, mobility, bioavailability, and phytotoxicity are highly context-dependent. This review synthesizes plant–soil evidence by focusing on the interacting roles of MP polymer type, particle size and shape, aging/weathering state, soil geochemistry, dissolved organic matter, and rhizosphere processes. Across the reported studies, MP-PTE interactions show several major directions of changes: MPs may reduce PTE lability by promoting adsorption, aggregation, or sequestration within coated surfaces and soil aggregates; conversely, they may increase PTE mobility and plant exposure when reversible binding, dissolved organic ligands, pH shifts, or particle transport deliver labile PTEs to root-active zones. Dose-dependent and biphasic responses are also common, with low MP additions sometimes attenuating stress while higher doses intensify toxicity. Quantitatively, available crop studies show that intensified co-exposure can reduce plant biomass by approximately 10.2–29.3%, depending on crop species, plant organ, MP type, dose, and PTE identity, whereas antagonistic or neutral responses are also reported under other exposure conditions. The strongest evidence currently exists for Cd and As, but this review also considers Pb, Cu, Zn, Ni, Cr, and Hg to represent chemically distinct cationic, metalloid, and redox-sensitive PTEs. Overall, MPs should not be treated only as passive contaminant carriers; they act as dynamic reactivity modifiers that can function as sinks, vectors, or indirect regulators of PTE bioavailability depending on soil and rhizosphere boundary conditions. Full article

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance, pancreatic β-cell dysfunction, and dysregulated glucose and lipid metabolism. Sustained hyperglycemia and hyperlipidemia promote excessive reactive oxygen species (ROS) production, antioxidant defense depletion, and chronic low-grade inflammation, thereby aggravating insulin signaling impairment, β-cell injury, and diabetes-related complications. Although current glucose-lowering therapies have improved glycemic control, weight management, and cardiorenal outcomes, oxidative stress and inflammation remain incompletely addressed in many individuals with T2DM. Curcumin, a natural polyphenol derived from Curcuma longa L., exhibits antioxidant, anti-inflammatory, lipid-regulating, insulin-sensitizing, and tissue-protective activities. Evidence suggests that curcumin may alleviate T2DM-associated oxidative stress by suppressing ROS generation, reducing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, modulating the advanced glycation end-product/receptor for advanced glycation end-product (AGE/RAGE) axis, activating nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling, preserving mitochondrial homeostasis, and protecting β-cells. It may also inhibit nuclear factor-κB (NF-κB) and mitogen-activated protein kinase/c-Jun N-terminal kinase (MAPK/JNK) signaling, decrease pro-inflammatory cytokines and C-reactive protein (CRP), improve metabolic tissue inflammation, and attenuate gut-derived inflammation by regulating gut microbiota and intestinal barrier function. However, current clinical evidence mainly supports modest improvements in metabolic, inflammatory, oxidative stress-related, and selected complication-related biomarkers rather than definitive disease-modifying outcomes. Moreover, formulation heterogeneity, low bioavailability, limited pharmacokinetic reporting, and insufficient long-term endpoint data remain major translational barriers. This review summarizes the molecular mechanisms, clinical evidence, formulation-dependent interpretation, safety considerations, and translational limitations of curcumin as a candidate adjunctive intervention for T2DM, rather than as a replacement for evidence-based antidiabetic therapy. Full article

Selenium (Se) is an essential trace element for humans and animals, with nutritional functions and abiotic stress regulation capacity, and has been confirmed to alleviate heavy metal toxicity and inhibit its accumulation in crops. Soil lead contamination has become a prominent environmental safety problem in agricultural production, particularly in South China, and lead over-standard in edible crops poses irreversible threats to the human nervous system and blood circulation through food chain transmission. As an efficient exogenous antagonist, Se can comprehensively regulate the absorption, translocation, and compartmentalization of lead in soil–plant systems. This review systematically summarizes the interactive effects of soil physicochemical properties, crop genotypes, and Se speciation on plant lead uptake, and focuses on phytochelatin synthase (PCS), the core rate-limiting enzyme for intracellular heavy metal chelation, to elucidate the molecular cascade of Se-mediated PCS-dependent lead detoxification. We further outline multi-pathway agronomic Se applications for lead reduction; analyze key limiting factors, including Se concentration, application method, and rhizosphere microbial community; and discuss contradictory results and unresolved questions in existing studies. Current evidence confirms that appropriate Se treatment increases glutathione (GSH) content via antioxidant system regulation, upregulates PCS gene transcription and activity, promotes phytochelatins (PCs) polymerization, and forms stable PC-Pb complexes sequestered in vacuoles to reduce cytoplasmic lead mobility. Additionally, Se reshapes rhizosphere microbial community composition to lower soil Pb²⁺ bioavailability and enhances lignin and pectin biosynthesis in root cell walls to physically block root Pb²⁺ influx. Nevertheless, critical knowledge gaps remain unaddressed: (1) upstream signal transduction cascades triggering Se-induced differential PCS expression; (2) precise Pb²⁺ binding sites and affinity of PC oligomers; (3) valence-dependent disparities in selenate, selenite, and nano-Se (SeNPs) modulating PCS activity; and (4) standardized field Se fertilization protocols tailored to staple and tropical tuber crops such as cassava. This review provides systematic theoretical reference and technical foundations for dissecting Se-Pb antagonistic molecular networks, developing Se-enriched low Pb²⁺ functional fertilizers, and mitigating Pb²⁺ contamination risk in agricultural commodities. Full article

Background/Objectives: Osteonecrosis of the jaw, a non-healing wound, is a side effect in patients treated with nitrogen-containing bisphosphonates (e.g., zoledronate) after some oral procedures. Considering zoledronate toxicity in surgical wounds and the capacity of calcium phosphate synthetic compounds to adsorb it, the aim of this work was to demonstrate and elucidate the mechanism underlying this adsorption. Methods: Four different calcium phosphate synthetic bone substitutes were used in this study: AdBone^® BCP (0.5–1 mm), Guidor^® easy-graft (0.5–1 mm), Maxresorb^® (0.5–1 mm) and Maxresorb^® (0.8–1.5 mm). The materials were incubated in aqueous zoledronate solutions. Samples of the solutions obtained after 1, 2, 3, 6, 24, 48, 72 and 120 h of conditioning were then analyzed by spectrophotometry to measure their absorbance and subsequently characterized by micro-elemental analysis. Results: All four materials demonstrated time-dependent zoledronate adsorption. AdBone^® BCP achieved the most rapid and sustained sequestration, reaching 80% reduction at 24 h and stabilizing at 85% from 72 h onwards without re-release. Maxresorb^® formulations showed comparable kinetics through 72 h (70–75%) but exhibited partial re-release at 120 h. Guidor^® easy-graft showed negligible adsorption through the first 24 h, consistent with the physical barrier effect of its PLGA coating. Spectrophotometric findings were independently confirmed by elemental analysis. Conclusions: This work confirms zoledronate adsorption by calcium phosphate synthetic biomaterials. Among the tested materials, AdBone^® BCP demonstrated the most favorable adsorption profile, with kinetics well matched to the critical window of alveolar wound healing. These findings support the use of biphasic calcium phosphate bone substitutes as a local strategy to reduce free zoledronate bioavailability at the surgical site, potentially lowering the risk of MRONJ in patients undergoing dentoalveolar procedures under bisphosphonate therapy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and poses a significant public health challenge. Allicin, a major bioactive organosulfur compound derived from garlic, has emerged as a promising candidate for MASLD prevention and management due to its antioxidant, anti-inflammatory, and metabolic regulatory properties. Despite its potential, evidence regarding allicin’s efficacy on MASLD remains limited and heterogeneous because existing studies have evaluated different garlic-derived interventions across diverse experimental settings. This review therefore distinguishes studies of purified allicin from those of raw garlic, garlic powder, aged garlic extract, black garlic, garlic essential oil, and individual garlic compounds. Preclinical studies using allicin suggest beneficial effects on hepatic steatosis, inflammation, glucose homeostasis, and lipid metabolism. Human studies, however, have evaluated raw garlic consumption or garlic powder supplementation rather than allicin alone. Findings from other garlic preparations and individual compounds are attributed only to the intervention tested, because differences in composition, stability, bioavailability, metabolism, and pharmacological activity preclude their attribution to allicin. Moreover, the available clinical trial evidence comprises five publications derived from only two randomized controlled trials conducted in Iran, both lasting 12–15 weeks. In addition, preclinical evidence most consistently supports regulation of hepatic lipid metabolism, particularly the AMP-activated protein kinase/sterol regulatory element-binding protein-1c-related signaling, as a potential mechanism underlying the anti-steatotic effects of allicin. Additional pathways may involve inflammatory signaling, oxidative stress, gut microbiota, and bile acid-related regulation, although the evidence for several of these mechanisms remains suggestive. Nevertheless, the precise molecular targets and signaling networks underlying these effects remain incompletely understood, and the relevance of allicin to aging-related MASLD is largely unexplored because previous studies have used young animals. Future studies should incorporate aged models and long-term randomized controlled trials across diverse populations to clarify the mechanisms, therapeutic potential, and safety of allicin in MASLD. Full article

This study presents the first integrated multi-compartment assessment linking soil heavy- metal contamination and satellite-derived tropospheric air pollution in Lebanon’s Bekaa Valley. Six metals (Cd, Cr, Cu, Ni, Pb, Zn) were measured in 295 agricultural topsoils using DTPA extraction—which targets the labile, bioavailable pool most relevant to food-chain transfer in calcareous soils—and were compared with Sentinel-5P TROPOMI vertical columns of SO₂, NO₂ and HCHO extracted at point, 1000 m and 5000 m scales. Chromium was the dominant element, and composite pollution indices indicated overall good but transitional soil quality, with a majority of sites at warning level. Principal component analysis, spatial autocorrelation and land-use analysis converged on three plausible source groupings—predominantly geogenic (Cr, Ni), localized anthropogenic (Cd, Pb) and agricultural (Cu)—although, in the absence of isotopic or other direct source tracing, these assignments remain indicative rather than confirmed. Soil metals and atmospheric columns were largely uncorrelated (|r| < 0.3 for 17 of 18 pairs); this decoupling is consistent with the contrasting temporal integration and spatial support of the two compartments rather than with a single shared pathway. Multi-scale analysis supported a parsimonious dual-scale (point + 5000 m) sampling framework. The study offers a transferable assessment framework for other Mediterranean regions and underscores the need for locally calibrated, total-metal soil background values. Because these indices and threshold comparisons are computed from DTPA-extractable concentrations, they serve here as one-directional, bioavailability-based screening tools rather than regulatory determinations: an exceedance conservatively flags a site for confirmatory total-metal analysis, whereas a non-exceedance does not establish compliance. Full article

Background/Objectives: Endometriosis is a chronic estrogen-dependent disease with a complex and incompletely understood etiology. Environmental exposure to toxic elements, including cadmium, lead, mercury, and arsenic, may contribute to its development and progression. Proposed mechanisms include endocrine disruption, oxidative stress, chronic inflammation, and epigenetic alterations. Methods: This narrative review was based on a structured literature search of the PubMed, Scopus, and Web of Science databases for studies published up to 15 June 2026. The search included the following keywords: endometriosis, cadmium, lead, mercury, arsenic, toxic elements, heavy metals, environmental exposure, diet, nutrition, and biomonitoring. Results: This review summarizes current evidence on the relationship between toxic element exposure and endometriosis, including sources of exposure, biomonitoring findings, proposed biological mechanisms, and human studies. The influence of nutritional status on metal bioavailability is also considered. Among the toxic elements reviewed, cadmium has been studied most extensively and shows the most consistent association with endometriosis. Evidence for lead is less consistent, whereas data on mercury and arsenic remain limited. Although the available epidemiological evidence does not establish a causal relationship, biomonitoring and experimental studies support a possible role of toxic elements in the development and progression of endometriosis. Conclusions: Current evidence supports a possible role of toxic elements in endometriosis, although a causal relationship has not been established. Cadmium has been investigated most extensively, while evidence for other toxic elements remains limited. Nutritional status should be considered when evaluating biomonitoring findings, particularly in relation to cadmium exposure. Full article

Copper is an essential trace element that plays critical roles in enzymatic processes and cellular metabolism. However, excessive exposure to its ions can lead to toxicity through oxidative stress mechanisms. Therefore, the chemical ‘speciation’ of copper(II) ions (Cu(II)) in biological fluids such as saliva is of critical importance. However, currently this phenomenon remains poorly understood, despite its importance for our understanding of bioavailability, toxicity, and sensory perception. Therefore, this study employed ¹H nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy, and scanning electron microscopy (SEM) to investigate the molecular nature and complexation characteristics of low-molecular-mass Cu(II) complexes formed in human whole mouth salivary supernatant (WMSS) samples. Findings obtained revealed that Cu(II) ions form distinct complexes with salivary biomolecules, particularly amino acids such as histidine and glutamine, aromatic metabolites, proteins, and further small organic biomolecules, e.g., carboxylic acid anions. These results provide new insights into copper speciation in the oral cavity, with implications for dietary Cu(II) ion availability, metallic taste perception, and potential toxicological risks associated with elevated oral exposure levels. Full article

The growing demand for rare earth elements (REEs), heavy metals (HMs) and precious metals (PMs) has intensified interest in sustainable recovery strategies from secondary resources, including mining residues, industrial effluents and waste electrical and electronic equipment (WEEE). These streams represent exposure interfaces, because soluble and bioavailable metal species may persist, bioaccumulate and contribute to oxidative stress, genotoxicity, carcinogenic outcomes and chronic systemic effects. This systematic review, conducted following PRISMA guidelines, evaluates the thermoacidophilic red microalga Galdieria spp. as an extremophilic platform for metal bioremediation, recovery and upstream risk reduction. Galdieria spp. combines tolerance to low pH, elevated temperature and high metal loads with rapid surface biosorption and, in living biomass, slower intracellular sequestration and detoxification. Its interaction with REEs, PMs and toxic HMs is mediated by cell-wall functional groups, extracellular polymeric substances, redox-active processes and metabolic flexibility shaped partly by horizontal gene transfer (HGT). The review discusses matrix complexity and adsorption–desorption cycles, highlighting their implications for real industrial streams. Overall, Galdieria spp. emerges as a robust extremophilic bio-interface for selective metal recovery, hazardous waste mitigation, circular-economy biorefinery models and prevention of metal-associated risks to environmental and human health, while current scale-up limitations and process-oriented research priorities are identified. Full article

Lycium barbarum polysaccharides are major bioactive constituents of Lycium barbarum fruit and are widely recognized for antioxidant, immunomodulatory, and intestinal protective activities. Selenium nanoparticles are considered a safer selenium formulation than conventional inorganic selenium because they generally provide improved bioavailability and reduced toxicity. In this study, Lycium barbarum polysaccharide-stabilized selenium nanoparticles were prepared under mild conditions, characterized, and evaluated for antibacterial, antibiofilm, and antidiarrhoeal activities. The optimized nanoparticles exhibited a hydrodynamic diameter of 304.4 ± 32.9 nm, a polydispersity index of 0.369 ± 0.05, and a zeta potential of −20.8 ± 1.5 mV, indicating good colloidal stability. Scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy supported the structural assignment of spherical elemental selenium particles with a polysaccharide-rich surface layer. In vitro assays showed concentration-dependent inhibition of Escherichia coli, with minimum inhibitory and minimum bactericidal concentrations of 100 and 200 μg Se/mL, respectively. Biofilm formation was also markedly reduced, and scanning electron microscopy demonstrated severe bacterial surface damage after treatment. In a KM mouse model of Escherichia coli-induced diarrhea, oral administration of the nanoparticles significantly lowered diarrhea scores, improved body weight recovery, and alleviated intestinal mucosal injury compared with untreated infected mice. Major organs showed no obvious histopathological abnormalities under the experimental conditions. Overall, these findings identify Lycium barbarum polysaccharide-stabilized selenium nanoparticles as a promising selenium-based nanomaterial for controlling bacterial diarrhea and protecting intestinal health. These results provide a practical foundation for future mechanistic, pharmacokinetic, microbiological, and translational studies aimed at broader intestinal applications. Full article

Iron (Fe) and selenium (Se) deficiencies are global health concerns associated with adverse health outcomes. Plants constitute a dietary source of these elements, particularly for individuals following plant-based diets. However, plant Fe availability is limited by soil processes that reduce Fe mobility and uptake, whereas Se accumulation is constrained by the low abundance of Se in soils. Increasing Fe and Se concentrations in edible plant parts through biofortification represents a sustainable strategy to alleviate micronutrient deficiency. This review examines the mechanisms governing Fe and Se uptake, translocation, metabolism, and genetic regulation, and discusses current biofortification strategies, including agronomic practices, natural and microbial-based approaches, conventional breeding and marker-assisted selection, transgenic technologies, and nanoparticles. While cereals remain the principal targets of large-scale biofortification programs, recent advances in horticultural crops are also highlighted because of their growing nutritional and commercial importance. Current evidence indicates that integrated agronomic and genetic approaches are more effective than single interventions, although simultaneous Fe and Se biofortification remains largely underexplored. Successful biofortification is also strongly influenced by soil properties, nutrient interactions, and crop genotype. Emerging tools, including plant–microbe interactions and synthetic biology, offer promising opportunities to enhance micronutrient accumulation and bioavailability. Further research should optimize integrated Fe–Se biofortification strategies while addressing agronomic and socioeconomic constraints to support their large-scale adoption and contribute to sustainable food systems. Full article

Background: Copper is a trace element involved in key physiological and biochemical processes in humans, animals, and plants, and its homeostasis is tightly regulated. However, excessive exposure may cause adverse health and environmental effects. Copper-based plant protection products contribute to dietary exposure to copper and remain indispensable for the control of several crop diseases. Methods: This review summarizes the current state scientific and regulatory evidence on agricultural copper, identifies major knowledge gaps, and discusses strategies to support its sustainable use. A structured literature review was conducted using the PECO framework to define eligibility criteria, while key principles of the PRISMA 2020 statement were applied to improve the transparency of study identification and selection. Results: The available evidence confirms the dual role of copper as an essential micronutrient and a potentially toxic element, with adverse effects depending on exposure level, chemical form, bioavailability, and physiological status. Although copper remains an effective agricultural tool, long-term use may promote soil accumulation and environmental impacts. Current environmental risk assessment frameworks, originally developed for organic chemicals, do not fully account for the environmental behavior of inorganic metals. The review also examines copper occurrence, biological functions, agricultural uses, environmental fate, toxicity, and regulatory frameworks. Conclusions: Sustainable copper use requires balancing crop protection benefits with human health and environmental protection. Dietary exposure from authorized copper-based PPPs is generally considered negligible according to current EFSA PRIMo assessments, whereas occupational exposure and environmental accumulation remain important concerns. Future environmental risk assessment frameworks should better account for the environmental fate, natural background concentrations, bioavailability, and speciation of inorganic metals such as copper, thereby improving the scientific basis of regulatory decision-making. Full article