The protective effect of CUR is ascribed to its neutralization of free radicals and chelating properties [81]. CUR can act at the same time as a metal chelator and antioxidant. The CUR chemical structure allows to form chelate complexes with high stability, thereby removing toxic metal ions and inhibiting Aβ polymerization and following the generation of toxic conformations [82]. This is achieved primarily due to the optimal properties of CUR’s natural complexing agent and the presence of a 1,3-diketone moiety that provides the tautomeric form. The more stable enol form acts as a complexing agent [83] with high binding activity and coordinates metal ions around itself [84,85,86], creating complexes [87,88]. The presence of this form makes it an appropriate chelating agent for ingested toxic metals. The keto-enol part is the reaction center [84,85,86,87,88] and provides protection against active free radicals [88]. The enol form of the diketone is better stabilized due to charge delocalization and generates 1:2 and 1:3 type chelates with metal ions [89,90,91,92]. CUR, owing to its clear lipophilicity, easily passes through the blood–brain barrier and cell membranes, which makes it possible to scavenge toxic metals intracellularly [93].

Aluminum is ubiquitous in the environment in the form of salts and oxides. Al can enter the organism with drinking water, air, and plant food. One of the Al-specific sources is its ever-increasing use in the food industry (e.g., dishes, packaging material, food additives) and pharmacology [95]. At the molecular level, it can cause protein precipitation and the formation of insoluble protein compounds, which affects reducing the enzyme activity and their systems [96]. Moreover, Al intoxication leads to changes in blood composition, blood disorders (lymphocytosis, eosinopenia, anemia), disorders of calcium-phosphorus metabolism, decreased stability of DNA synthesis, DNA damage, and development of soft tissue fibrosis [97,98]. Furthermore, Al is known as a neurotoxic metal, which may show its negative effects on the nervous system, particularly at higher concentrations; causing movement disorders, seizures, memory loss, psychopathic traits, learning disabilities, depressive tendencies, and encephalopathy [99]. Al is assumed to play a significant role in the occurrence of severe neurodegeneration such as Alzheimer’s disease [95,100]. One of the treatment approaches for Al-induced neurotoxicity is the search for antagonists that halt the absorption of metal [101], replenish nutritional deficiency, and prevent the launching of oxidative processes caused by ROS exposure and disruption or depletion of the antioxidant system during Al intoxication.

It was found that CUR interacts strongly with Al (III), implying that CUR has the potential of removing Al (III) ions and averting interaction between Al (III) and amyloid β-protein (Aβ); thereby, stopping the toxicity of Aβ and detrimental effects of oxidative stress [102]. CUR reduced the bonding affinity of Al³⁺ to DNA [103]. Memory improvement, reversing oxidative damage, and weakening of acetylcholinesterase activity have been observed with CUR long-term administration. Moreover, CUR prevented damage to neurons under oxidative stress conditions, induction of Al³⁺-caused cognitive impairment, and markedly lowered the Al concentration in Al-treated rats [104]. CUR administration led to a decrease in the expression of NF-κB and TNF-α which are known as the markers of inflammatory reactions [100]. Furthermore, curcumin treatment led to the reduction in ROS and lipid peroxidation in the cerebellum as well as improvement of reduced glutathione and glutathione-S-transferase in the cerebrum which showed the neuroprotective behavior of curcumin on Al-induced neurodegenerative and behavioral disorders in rats [105]. Recently, it is reported that nano-curcumin has better biological and antioxidant activity than native curcumin on Al-induced toxicity in rats [106] which might be due to the favorable interaction of nanoparticles of curcumin with Al³⁺ in reducing Al toxicity.

Arsenic is a commonly occurring metal in the biosphere, observed in rocks, soils, and water resources. A potential threat to human health occurs when As enters the organism through the contaminated water supply or food. Since As engages in most biological catalytic reactions, its indirect or direct effect spreads to all organs [108]. The liver is the primary target for As poisoning [109]. The results of As toxicity is skin damage, cardiovascular and respiratory diseases, cancer, gangrene, brain dysfunction, etc. Meanwhile, there is currently no remedy endorsed for widespread use in As poisoning [110].

In turn, CUR has been shown to be a satisfactory antioxidant and protector for DNA, regressing As-induced damage in the nucleus. Supplementation with CUR has been shown to reduce the total toxic load of As in the liver and assist to increase the As excretion through the urinary tract [111,112]. Moreover, CUR decreased transaminase and phosphatase activity along with the plasma and brain acetylcholinesterase, as well as total protein and albumin levels under As-induced liver injury [113].

Therefore, CUR may have some protective role against biochemical alterations and associated DNA damage caused by As. According to in vitro studies results, CUR modulates autophagy/apoptosis in cells and has a cytoprotective effect against As-induced toxicity, preventing decreased antioxidant levels that cause cell membrane disruption [114].

Cadmium is a carcinogenic metal whose natural content gradually accumulates in the environment, due to anthropogenic emissions. The main route of Cd entry is skin absorption, ingestion, or inhalation. Cd with its wide range of toxic effects has become one of the most critical contaminants in the aquatic toxicology field owing to harmful human activity [116]. The problem that follows Cd accumulation is its competitive behavior with essential metals (Ca, Zn, Fe, Mg). Cd uses the same transport systems as essential metals, which blocks their entry into the cell, inducing toxicity [117,118].

Most studies have shown CUR’s positive healing properties against Cd toxicity. Electrochemical studies in mice have predicted a compatible metal-ligand form of Cd and CUR, which could remove metal ions from the body [119] and mitigate the adverse effects of Cd [120]. It is reported that the oral administration of CUR decreased the accumulation of toxic elements in the brain and liver in mice [121]. Co-treatment with CUR significantly reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6, as well as biomarkers’ affection of oxidative damage [122]. CUR can inhibit the expression of nuclear factor kappa B, which is responsible for regulating the transcription of genes that control inflammation, immune cell development, and cell death. CUR prevented the release of interleukin-6 and interleukin-8 in response to toxic Cd ions [123]. The studies confirmed the CUR protective effects against Cd-induced nephrotoxicity. It also can be used to prevent respiratory tract injury due to Cd inhalation. Overall, CUR can be added to the diet and can be fairly proposed to be used as a protective factor for Cd-induced nephrotoxic, hepatotoxic, and hematological changes.

Copper’s redox nature makes it essential for many biological processes, but at the same time renders it toxic effects due to the generation of the most dangerous ROS, hydroxyl radical (^•OH) [118]. An imbalance of Cu ions in the central nervous system engages in many neurodegenerative disease pathogenesis, the most common is amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases [132,133,134,135]. For Cu toxicity, the same chelating treatment is used as for other metal poisonings [136].

Through quantum chemical computations, it was discovered that due to the proton loss of the CUR enol form, the β-diketone part is the main site of chelation in the CUR-Cu(II) complex [137]. In studies conducted with CUR administration, CUR had ameliorating effects on the CuO nanoparticles toxicity in terms of the antioxidant, immunomodulatory, anti-apoptotic, and anti-inflammatory effects on the rats’ kidneys [138]. Moreover, considering the role of oxidative damage in mediating Cu toxicity, CUR suppressed neurotoxicity through its anti-radical and antioxidant properties [82]. CUR’s neuroprotective properties provide the basis for studying its effectiveness in several neurodegenerative diseases involving Cu, such as Alzheimer’s disease. Through the ability of CUR to penetrate the blood–brain barrier, CUR can block amyloid beta-peptide, a key disease factor that accumulates in the brain, and reduce its levels as well as remove the metal ions in the brain [139]. Thus, CUR as a restorative remedy for oxidative stress caused by Cu ions might be useful for therapeutic treatment, including neurodegenerative diseases.

Iron is an indispensable element in basic life processes such as DNA synthesis, respiration, and a regular participant in biochemical reactions [143]. However, Fe overload in parenchymal organs is associated with degenerative changes in the cellular parenchyma that causes irreversible dysfunction of the most vulnerable vital organs, such as the liver, pancreas, and heart. Chelation therapy is the recommended approach as an antidote for Fe intoxication [144].

Some chelators are responsible both for Fe excretion and may suppress the participation of free labile Fe in oxidation-reduction reactions [94]. Age-related hypokinesia causes muscle atrophy which is related to the Fe accumulation and potentiates the oxidative stress through the Fenton reaction. Thus, the key role of the chelating agent is to prevent the Fe participation in the Fenton reaction or the reaction of peroxides decomposition with the formation of hydroxyl radicals in the ROS generation [145].

CUR, an iron-binding antioxidant, prevents the destruction of cell membranes and stimulates the regeneration of hepatocytes, thereby having a protective effect on liver function in Fe overdose. According to a study conducted on T51B cells treated with ferric ammonium citrate, CUR bounded but not blocked Fe absorption and did not interfere with its bioavailability [94]. CUR has shown a detoxifying effect by preventing the formation of ROS and abolishing the signaling cascades of Fe-induced stress response. Furthermore, in a study on MIN6 cells, CUR functioned as a moderator of Fe-dependent necrotic cell death, known as ferroptosis, and prevented Fe-induced cell damage during ROS production [146].

Lead is a toxic metal whose compounds are insoluble in water but highly soluble in stomach acid. The main mechanism of its adverse action is associated with gastrointestinal tract disorders [149]. The Pb study’s importance is explained by its threatening toxicity through extreme spreading in the environment and its multilateral use in industry and everyday life. The toxic mechanism of Pb is associated with the blocking of thiol enzymes, interaction with biopolymers’ carboxyl and phosphate groups, nucleotides, and esterase enzyme inactivation [150,151].

Morphological and functional changes have been revealed that negatively affect the hematopoiesis and the nervous system in the fish body with oversaturated of Pb ions [152]. Fish are more sensitive to toxicity, the key role in the immune response in their body belongs to immunocompetent cells, primarily lymphocytes [153]. It has been reported that Pb led to a shift in white blood cell count and apoptosis has also been recorded [152]. A study conducted over 8 weeks with Pb added to aquarium water has shown an increase in fish mortality and stunting along with a decrease in indicators such as final wet weight and specific growth rate. However, after co-treatment with CUR, DNA damage was markedly reduced, the effects of Pb toxicity in the kidneys were weakened, and the inflammatory process was attenuated [154].

Pb increases lipid peroxidation and reduces the functional abilities of the brain cell, but CUR significantly reduced the Pb toxic effect on nerve cells in rat studies [155]. Furthermore, in rat experiments with Pb accumulation in the liver and kidneys, it was shown that CUR is an effective inducer of the post-accumulation effects of oxidative toxicity. The results have shown a decrease in the Pb amount in the affected organs and the relief of degenerative changes caused by Pb [156].

Zinc is an essential trace element for all life forms. Zn is part of more than 40 enzymes and engages in carbohydrate metabolism and the metabolism of vitamin A. This element is necessary for bone formation. In addition, it exhibits antiviral and antitoxic effects, and Zn toxicity has rarely been reported [159].

Zinc oxide nanoparticles (ZnONP) are of major interest, as they are widely distributed in various fields. ZnONP are used in pharmaceuticals and cosmetology as agents exhibiting antibacterial activity. However, along with beneficial properties, the harmful effect of ZnONP on various body systems has been recorded [160]. Therefore, the toxic effects of Zn and ZnONP require a protective agent. CUR has shown promising results in preventing Zn toxicity in vivo studies (Table 8). Analyzing the content of ZnONP in the brain after administration on rats, it has been found that nanoparticles or its metabolic products cross the blood–brain barrier and cause histological damage to the cerebellum, which in turn was successfully prevented after the addition of CUR [52].

CUR is also proven to be a successful Zn ions chelator and can function as a radical scavenger that accumulates Zn ions [161]. Therefore, apoptosis and necrosis of hepatocytes can be prevented by suppressing the oxidative damage of cells through the CUR treatment [162]. In addition, CUR is a vindicated protector of nephrotoxicity which can reduce kidney damage and suppresses necrosis factors, and inflammation processes [163].

Mercury in its natural state at room temperature is a liquid metal. Humans typically contact with Hg from three main sources: dental amalgam fillings, some vaccines, and fish caught in rivers and seas contaminated with Hg waste [10,164]. In addition, Hg-containing devices—such as electric lamps, thermometers, barometers, etc.—are potential sources of Hg in the home [165,166].

Chronic Hg poisoning can lead to ataxia, a lack of coordination that causes a cerebellar gait. It can also cause hand tremors, excessive salivation, and a metallic taste in the mouth. Another representative symptom could be a blue line that appears on the alveolar margin of the gums, as in Pb and bismuth poisoning. The classic symptoms of Hg vapor poisoning include intention tremors, erethism (memory loss, lack of self-control, irritability, excitability, loss of self-confidence, drowsiness, and depression), and gingivitis [167].

CUR has been examined in several Hg-induced toxicity studies. CUR treatment provided protective effects on Hg-induced oxidative stress parameters, and it was found to be effective in reversing Hg-induced serum biochemical changes [168]. However, it also reported that CUR supplementation in excess of metal ions from Hg, Al, or As can inhibit utilization of some essential trace minerals such as Se or Zn which may ultimately affect the antioxidant defense system. Similarly, it showed that CUR as a strong antioxidant can limit the levels of other antioxidants in the liver to maintain the optimum antioxidant levels in organisms [168].

Pi3K-Akt has been proposed as a key signaling pathway in Hg-induced splenic injury. In vivo experiment in mice has shown that CUR attenuated spleen apoptosis by reversing the same pathway as well as mitigated HgCl₂-induced toxicity in the immune system through the Nrf2-ARE activation pathway [169]. Here, the protective role of Nrf2, once released from Keap1, is mainly derived from the activation at the level of the antioxidant response elements (ARE), thereby giving rise to the production of antioxidant enzymes. In another study, it has examined the effects of Hg on neurobehavioral and neurochemical disorders in mouse offspring where CUR increased the levels of cerebral monoamines (dopamine, norepinephrine, and serotonin) in Hg-treated pups. Overall, behavioral disorders, such as anxiety behavior, were suppressed by CUR in treating pups. Conclusively, CUR has shown a desirable mechanism in preventing Hg toxicity and could be recommended for use to avoid toxicants such as Hg [170].

Selenium is an indispensable, vital trace element for organisms [151]. It is represented by the active center of many Se-containing proteins involved in the antioxidant defense mechanisms, thyroid hormone metabolism, and performing immune function [171].

Se supports the Se-containing enzymes function and selenoproteins contained in plasma [10]. Se affects the metabolism of leukotriene, thromboxane, and prostacyclin. Se deficiency disrupts the functioning of the brain [172] and suppresses immune defense reactions, especially nonspecific, cellular, and humoral immunity [173].

In excess concentration, Se can exhibit toxic properties [174]. Symptoms of toxic effects of excess Se include a metallic taste, headaches, nausea, hair loss, and damaged nails. Sensory loss, convulsions, pneumonia, pulmonary edema, and circulatory collapse are also symptoms. Cases of Se toxic effects have been registered not only during exposure to Se associated with industrial production but also during its self-administration [174].

Studies of the role of CUR in combating Se-induced toxicity in the liver and kidneys of Wistar rats have yielded promising results. Kidney tissue of Se alone administered rats was critically damaged: cystic degeneration, cytoplasmic vacuolization, cellular proliferation with fibrosis, and vesicle formation. Conversely, CUR pretreatment prevented all degenerative changes caused by Se [175]. There have been several studies of Se-induced cataractogenesis with CUR co-treatment. The findings showed that CUR suppressed Se-induced accumulation of reactive oxygen species and cataract formation in the isolated lens from experimental rat pups, possibly due to inhibition of the enzymatic and non-enzymatic antioxidant defense system and prevention of uncontrolled formation of superoxide radicals, as well as due to inhibition of iNOS activity [176,177].

The results implied that CUR might take place as an agent against hepatic and renal toxicities, probably due to its ability to inhibit iNOS levels and proved an antioxidant potential of CUR in preventing Se-exposed toxicity.

Chromium compounds are highly toxic to humans, primarily hexavalent chromium (Cr⁺⁶). The main manifestations of excess Cr are inflammatory diseases with a tendency to ulceration of the mucous membranes, an allergic effect, dermatitis and eczema, bronchial asthma, and risk of cancer [178,179].

The studies reported the effects of CUR against Cr toxicity in the male reproductive system have detected success in the prevention of the Cr destructive action in studied parameters (body weight, the weight of the testis, accessory sex organ weight). CUR through its antioxidant properties protected male germ cells, and testicular histology from oxidative damage by Cr-induced free radicals [180]. The study on Cr-induced renal dysfunction has reported that CUR treatment attenuated tissue damage, decreased free radicals, and reduced antioxidant factors in both kidney tissue and mitochondria. Moreover, the authors highlighted that the protection of mitochondrial function played a crucial role in the defense mechanism of CUR pretreatment against Cr toxicity in the kidneys [181]. Thus, the present studies suggest that CUR may have a protective role against Cr toxicity.