Omega-3 fatty acids and chemotherapy-induced toxicities: mechanisms and emerging evidence with a pediatric focus

Background

Omega-3 fatty acids are polyunsaturated fats that are essential for proper cell structure and function. The primary types of omega-3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is an essential fatty acid, meaning that humans and other mammals cannot produce it on their own and must obtain it from dietary sources. Research has firmly established the positive effects of omega-3 fatty acids in adults, showing benefits for cardiovascular health, brain function, mental health, inflammation, autoimmune diseases, and skin health. However, there is limited information regarding these effects in children. This narrative review evaluates the pre-clinical and clinical evidence for omega-3 polyunsaturated fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as complementary agents in pediatric oncology. It highlights their potential antioxidant and anti-inflammatory properties in optimizing clinical outcomes, enhancing chemotherapy safety, and improving the quality of life for pediatric patients. These benefits include the suppression of reactive oxygen species (ROS) production, which helps prevent cell damage related to oxidative stress and protects healthy cells from the harmful effects of chemotherapy. Enhancing the body’s ability to neutralize ROS by promoting internal antioxidant systems may improve treatment tolerance and reduce side effects. Reducing toxicity by lowering inflammation and oxidative stress will enhance the safety and effectiveness of chemotherapy. Further large-scale clinical trials in the pediatric population are necessary to confirm the potential effects of n-3 fatty acids on chemotherapy toxicity.

Introduction

Childhood cancer is a serious global health issue that causes significant illness and death, even with improvements in treatments [1]. While the incidence of pediatric cancers is lower than that observed in adult populations, it imposes a substantial burden due to the distinct vulnerabilities of children and the lasting consequences associated with both the disease and its treatment regimen. Treatments such as surgery, radiation therapy, and chemotherapy are typically used to address these tumors, depending on the type and stage of the cancer. Chemotherapy targets rapidly di-viding cancer cells but can also harm healthy cells, leading to undesirable side effects [2]. These side effects can seriously affect a child’s overall health, make it harder to stick to treatment plans, and reduce the effectiveness of the therapy. The severity and timing of these side effects can vary based on individual genetic factors, specific chemotherapy plans, and the total amount of drugs used [3].

Given the serious impact of chemotherapy side effects, there is an urgent need for treatments that can protect healthy tissues without reducing the effectiveness of cancer treatments. Antioxidants have been widely studied for this purpose. Among them, omega-3 polyunsaturated fatty acids (n-3 PUFAs) stand out due to their many health benefits. Unlike some antioxidants that primarily fight harmful molecules in the body, n-3 PUFAs have anti-inflammatory and immune-boosting properties, which help protect healthy cells. These fatty acids include alpha-linolenic acid (ALA), considered essential because the human body cannot synthesize it and therefore must obtain it from food. While our bodies can convert ALA into other important n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), this conversion is limited but still important for human health [4]. Omega-3 fatty acids may be especially beneficial for children with cancer. Kids undergoing treatment have specific health needs and are more prone to oxidative stress and inflammation, which can worsen chemotherapy side effects. Research shows that n-3 PUFAs can help reduce chemotherapy-induced damage to the gut, support immune function, and improve nutrition, all of which are important for tolerating treatment and facilitating recovery [5–8].

Their safety and potential to enhance the effectiveness of chemotherapy make them promising options for additional therapy in children. Evidence from clinical trials in adult patients suggests that supplementation with n-3 PUFAs during chemotherapy may improve treatment tolerability, regardless of the type of cytostatic drug used [9–16]. Although direct evidence in children is still limited, these findings show potential for translation to pediatric care.

This narrative review evaluates the pre-clinical and clinical evidence for omega-3 polyunsaturated fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as complementary agents in pediatric oncology. It highlights their potential antioxidant and anti-inflammatory properties in optimizing clinical outcomes, enhancing chemotherapy safety, and improving the quality of life for pediatric patients.

Methods

This narrative review was conducted to provide a comprehensive and up-to-date synthesis of the most recent literature on the effects of omega-3 use in chemotherapy in: in vivo, in vitro, and pediatric models. The objective was not to perform a systematic review or meta-analysis, but to provide a structured view of the antioxidant effects of omega-3s in the pediatric population. A literature search was conducted using the Medline, and UpToDate databases. The search terms included “omega-3 fatty acids,” “chemotherapy toxicity,” “antioxidant effects,” “pediatric oncology,” and “oxidative stress,” “Cardiotoxicity”, “Hepatotoxicity”, “Nephrotoxicity”, “Neurotoxicity”, “Pediatric cancer and omega 3”, “Management of chemotherapy toxicity”, genetic Polymorphisms”. To ensure the relevance of the evidence, the results were limited to articles published between 2000 and 2025.

Inclusion/exclusion criteria and data extraction

We included interventional studies, including clinical trials and in vivo and in vitro preclinical studies as well as meta-analyses.

We thoroughly reviewed the full texts and critically assessed their methodological quality based on criteria such as the evaluation of the research problem, study design, sample, data collection methods, results, and limitations.

Methodological quality assessment and evaluation of the strength of evidence

To evaluate and summarize the evidence for each outcome discussed in the narrative review, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method, as well as the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) for the animal studies.

ω−3 fatty acids

Humans do not have the necessary enzymes to produce alpha-linolenic acid (ALA), which makes it an essential fatty acid that must be obtained through our diet. However, our bodies can convert ALA into other omega-3 fatty acids, such as EPA and DHA. While this conversion process is often inefficient, these fatty acids are crucial for various physiological functions [17].

Chemical properties and classification

The omega nomenclature identifies the carbon atom of the methyl-terminal fatty acid group as the primary carbon and locates the first double bond closest to this group. The primary ω−3 fatty acid is alpha-linolenic acid (C18:3 ω−3, ALA). This fatty acid can be elongated and desaturated to form long-chain polyunsaturated fatty acids such as eicosapentaenoic acid (C20:5 ω−3, EPA) and docosahexaenoic acid (C22:6 ω−3, DHA). It is important to note that while this conversion may be low, it is nonetheless a relevant metabolic pathway in humans. EPA and DHA are important structural components of membrane phospholipids. They serve as substrates for synthesizing lipid derivatives known as eicosanoids and docosahexaenoic which play significant roles in cellular metabolism and are recognized for their anti-inflammatory and cytoprotective effects [17, 18].

Although humans can synthesize n-3 polyunsaturated fatty acids (EPA/DHA) from essential precursors such as α-linolenic acid (ALA), this process can be sensitive to other factors, ranging from nutritional status, the presence of cofactors such as zinc, magnesium, vitamin B6, and nicotinic acid, and even oxidative stress [20]. In the context of patients with cancer these factors can be altered either by the tumor itself or the treatment, for example the hepatic lesion produced by some drugs, even changing the lipid metabolism, affecting the endogenous production of PUFAs n-3 [21], this is important because as Valenzuela et al., the liver is the organ with the greatest capacity to synthesize PUFAs in mammals [22], hence supplementation could be a way to obtain them.

Beneficial properties and dietary sources of omega-3

Numerous studies have demonstrated the general benefits of omega-3 fatty acids. Notably, extensive research has focused on their cardiovascular benefits, showing that omega-3 can help lower triglyceride levels in the blood, regulate blood pressure, and reduce the risk of cardiovascular events [23]. In terms of cerebrovascular benefits, omega-3 plays a significant structural role in neuronal membranes and is associated with improved cognitive development in children, as well as a slower cognitive decline in the elderly [24]. While more evidence is needed, some studies suggest that omega-3 supplementation, combined with psychological therapy, may help reduce depression [25]. Regarding liver health, omega-3 has shown promise in reducing non-alcoholic fatty liver disease and may also improve metabolic conditions by enhancing insulin sensitivity [26]. Additionally, docosahexaenoic acid (DHA) is essential for retinal function, and its consumption has been linked to benefits in dry eye disease [27]. During pregnancy, omega-3 supplementation has been associated with a reduction in preterm births and improvements in fetal neurodevelopment [28].

Omega-3 fatty acids (EPA and DHA) are primarily found in marine sources like fatty fish, including salmon, sardines, mackerel, and tuna. Linoleic acid, a plant-based precursor to Omega-3, is present in foods such as chia seeds, walnuts, canola oil, and flaxseed; however, studies indicate that the conversion of linoleic acid to Omega-3 is low [29]. The main recommendation is to increase the intake of marine sources by adopting strategies such as consuming omega-3 fortified foods, eating enriched eggs, including oily fish in your diet, and considering direct supplementation [30].

Anti-inflammatory properties of ω−3 fatty acids

They achieve this by reducing the production of pro-inflammatory cytokines and eicosanoids, such as prostaglandins and leukotrienes. This effect occurs because omega-3 fatty acids compete with omega-6 fatty acids for the enzymes involved in eicosanoid synthesis, leading to a decreased production of pro-inflammatory eicosanoids. Additionally, omega-3 fatty acids can modulate the activation of immune cells, such as macrophages and T cells, which further contributes to a reduction in the inflammatory response [19].

Arachidonic acid (AA) is a component of cell membrane structure and is released from phospholipids when the enzyme phospholipase A2 is activated during the early stages of inflammation. After its release, arachidonic acid is metabolized by enzymes such as lipoxygenases and cyclooxygenases, producing bioactive eicosanoids, which include prostaglandins, leukotrienes, and thromboxanes. Arachidonic acid has two main pathways of action. The first pathway involves cyclooxygenases, which convert AA into thromboxane A2 (TXA2) and prostaglandins. Cyclooxygenase has two distinct isoenzymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed in most cells, while COX-2 is inducible in different cell types, and various stimuli increase its expression. Among the AA-derived prostaglandins, prostaglandin E2 is a potent mediator of inflammation, pain, fever, and increased vascular permeability. The second pathway involves the enzyme 5-lipoxygenase, forming various leukotrienes, including leukotriene B4 (LTB4), leukotriene C4, and leukotriene D4. These leukotrienes are powerful pro-inflammatory agents that enhance vascular permeability, stimulate immune cell activity, and promote the release of inflammatory cytokines such as interleukin-1, interleukin 6 and 8, as well as tumor necrosis factors, which are produced by macrophages and monocytes [19, 31, 32].

Risk factors for developing chemotherapy toxicity

Nutritional status in the cancer patient

Poor nutritional status, or malnutrition, is defined by the World Health Organization (WHO) as having a body mass index (BMI) below the 5th percentile. This condition is characterized by insufficient intake of both macronutrients and micronutrients. The incidence of malnutrition among children and adolescents with cancer can vary significantly at the time of diagnosis. For instance, it ranges from 5% to 10% in children with acute lymphoblastic leukemia (ALL) and can be as high as 50% in those diagnosed with solid tumors, such as neuroblastomas and sarcomas [33–35].During treatment or in advanced disease, there may be a significant deterioration of nutritional status in up to 80% of cases associated with increased weight loss and slower growth [33–35].

The causes and physiological mechanisms of malnutrition in pediatric cancer patients are complex and dynamic. They include iatrogenic effects from treatment, metabolic disorders such as muscle and fat tissue wasting, anemia, and an imbalance between nutritional intake and requirements. Additionally, hydro electrolytic disorders and complex endocrinological issues play a significant role; an estimated 57% of survivors experience at least one endocrinological disorder, and 23% have more than one. Chronic inflammatory states can lead to genotoxic stress and hormonal changes, resulting in a severe catabolic state [34–37].

This set of signs and symptoms develops a complex metabolic syndrome in advanced cancer called neoplastic cachexia, a multi-organ reaction derived from the patient-tumor interaction and conventional nutritional therapy is not sufficient [38]– [39]. Neoplastic cachexia defined when the weight loss is ≥ 5% of the daily body weight or weight/height less than the tenth percentile or more than 2% in patients with a baseline body mass index minor than 20 kg/m2 over six months [39]– [40].

Weight loss exceeding 15% in cancer patients leads to impaired physiological function. This is associated with a reduced therapeutic response, increased complications and infections, neuronal development issues, poor growth, muscle wasting, decreased quality of life, and lower survival rates [35–37, 41, 42].

In this regard, malnutrition is a critical predictor of survival in patients with brain tumors, younger patients with rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, Wilms tumor [37, 43, 44] neuroblastoma, non-Hodgkin lymphoma, acute non-lymphocytic leukemia, acute lymphoblastic leukemia and medulloblastoma [45–47].These types of cancer, which are susceptible to malnutrition, are more commonly found in the pediatric age group.

Malnutrition in children and adolescents with cancer can result in several micronutrient deficiencies which are reported in up to 96% [48, 49].These deficiencies may include calcium, zinc, selenium, vitamin D, and various vitamins from the B complex group (B1—thiamine, B2—riboflavin, B3—niacin, B5—pantothenic acid, B6—pyridoxine, B7—biotin, B9—folate and B12—cobalamin) [36, 39, 48, 50–52]. Additionally, deficiencies may occur in vitamin C [36, 50] iron [36, 39, 50, 51], copper [39, 50], vitamin A [36, 40, 51], vitamin E [50, 51] magnesium [36, 39, 50, 53], and omega-3 fatty acids [36, 48, 54].

Children with cancer often struggle to adhere to food intake. Supplementation can enhance tolerance and reduce the likelihood of secondary complications. Oral nutritional supplements (ONS) and food supplements (FS) are primary options for improving nutritional status in cancer patients at moderate nutritional risk or those who cannot meet their nutritional needs through a healthy diet al.one even those that promote increased oral intake [37, 46–48, 52, 55–57].

Research shows that starting omega-3 supplementation before chemotherapy can reduce dose-limiting toxicities, enabling patients to complete their prescribed chemotherapy regimens and achieve better cancer control [35, 55, 57].

At the other extreme, overnutrition or obesity, defined by a BMI equal to or greater than the 85th percentile, according to the World Health Organization, varies between 40% and 50% after the conclusion of therapy and among the patients most frequently reported to be overweight are survivors of leukemia, lymphomas, sarcomas and brain tumors. At the clinical level, obesity poses challenges for optimal chemotherapy dosing by affecting the pharmacokinetics/dynamics of the chemotherapeutic agents indicated based on their lipophilic properties; constituting a predictor of lower tolerance to treatment, greater secondary problems as cardiometabolic complications and an increase in morbidity and mortality [35, 46, 54, 58].

In this group, supplementation is linked to promoting metabolic balance, particularly glycemia, insulin control and sensitivity, and effects on blood lipid concentrations [35, 44].

Genetic factors

Extensive evidence in mice and humans supports the role of genetics in cancer drug response and toxicity. It has been postulated that variation in susceptibility to chemotherapy-induced toxicity is due to common polymorphisms in genes related to drug metabolism and transport [59–61]. Toxicity can vary based on tumor type, age, renal function, drug type, drug combination, dosage, number of treatment cycles, and performance status [62]. Single nucleotide variants (SNVs) in the CYP, ABC, GST, ERC, and XPCC gene families may contribute to interindividual variations in drug toxicity [63–68].

In the pediatric population, certain genetic variants have been linked to a higher risk of developing various types of toxicity, including gastrointestinal, hematological, neurological, endocrine, and cardiotoxic effects [69]. Variants in the ABCC5 gene, which encodes ATP-binding cassette transporters, have also been associated with anthracycline-induced cardiotoxicity in patients with acute lymphoblastic leukemia (ALL) [67].

Evidence indicates that the oxidative metabolism of anthracyclines, which is mediated by the enzyme CYP3A5, plays a significant role in the metabolism and clearance of daunorubicin. This enzyme’s activity is influenced by gene polymorphisms. One such polymorphism is the rs4880 variant in the SOD2 gene, which encodes the enzyme superoxide dismutase found in mitochondria. This enzyme is responsible for metabolizing superoxide radicals that are produced when anthracycline compounds are oxidized to hydrogen peroxide. In turn, this process significantly increases the cardiotoxicity associated with anthracycline treatment [70].

Genetic variants have been linked to a higher risk of chemotherapy-induced toxicity in cancer patients. It is important to identify and understand these variants in order to predict how individuals will respond to these treatments. By recognizing patients who carry variants that put them at greater risk of experiencing adverse side effects, healthcare providers can tailor treatments to enhance effectiveness while minimizing potential toxicities. This personalized approach aims to optimize patient care and outcomes.

Oxidative stress

Free radicals generated by chemotherapeutic drugs also harm normal cells, resulting in toxic side effects such as neurotoxicity, hematological toxicity, mucositis [71–74]. Oxidative stress can stimulate cell proliferation, promote angiogenesis, and enhance resistance to cell death, creating favorable conditions for tumor growth and metastasis. Therefore, it is crucial to maintain a delicate balance between the production of reactive oxygen species and the antioxidant defense systems within cells [75, 76]. Omega-3 fatty acids, especially DHA, accumulate in the phospholipid membrane and mitochondrial cardiolipin, which helps protect mitochondria from oxidative stress. Additionally, DHA can stimulate the body’s antioxidant systems by activating signaling pathways that prevent DNA damage [77].

The clinical consequences of oxidative stress are manifested in various toxicities associated with chemotherapy. For example, one of the most common toxicities associated with chemotherapy is mucositis. This significant dose-limiting side effect can impact various parts of the gastrointestinal tract, primarily affecting the small intestine and the oral and oropharyngeal mucosal linings [74, 78, 79]. In addition, antineoplastic treatments can affect the integrity of the blood-brain barrier, leading to severe and long-lasting cognitive impairment. This clinical situation can lead to interruption and/or modification of the drug schedule or even discontinuation, potentially affecting patient survival and clinical outcomes [80, 81]. For instance, cisplatin can cause damage that triggers an inflammatory response. This response includes the activation of glial cells, microglia, and astrocytes. Such inflammation may result in neuronal damage and neuroinflammation, worsening the toxicity in the nervous system [82, 83]. Neurotoxicity is a dose-limiting event. The symptomatology’s incidence and severity vary according to the drug used and the type of neoplasm. Calls et al. [84] reported that treatment with platinum derivatives causes acute toxicity in 90% of patients within the first hours after drug administration.

Another example of a drug with high toxicity and widely used in children is doxorubicin (DOX), an antineoplastic for the treatment of solid tumors. Numerous studies have demonstrated that several factors contribute to doxorubicin-induced acute cardiotoxicity, with oxidative stress and cell death being the most significant [85, 86]. Doxorubicin-induced oxidative stress is considered as the primary cause of cardiotoxicity, which is related to an imbalance in reactive oxygen species and reactive nitrogen species (RNS) levels and is associated with antioxidant dysregulation [87].

Omega-3 fatty acids as antioxidants during chemotherapy in adult and pediatric cancer patients

It has been recorded that Omega-3 in adult cancer patients may have an anti-inflammatory mediator and modulate oxidative stress. One of the most studied mechanisms is the anti-cachectic effects, mediated by protecting the muscle from catabolism. During chemotherapy, Omega-3 has been shown to improve appetite, reduce fatigue, and lower the risk of infections. Regarding inflammatory mechanisms, Omega-3 may decrease levels of IL-6 and TNFα [88, 89]. The main differences between adult and pediatric patients are as follows: In the pediatric population, there is a lack of information, as there are no randomized controlled trials (RCTs), and most studies conducted are observational in nature. Another key difference is in dosage recommendations; for adults, the dosage is given in grams per day (g/day), while for pediatric patients, it is measured in milligrams per kilogram per day (mg/kg/day) [35, 90].

Clinical studies indicate that omega-3 fatty acids provide several benefits for cancer patients. They have been shown to enhance the effectiveness of chemotherapy, minimize its side effects, increase survival rates, and improve quality of life. Additionally, omega-3 fatty acids may lead to shorter hospital stays, reduce the severity of post-operative infections, and enhance appetite, body weight, nutrition, and clinical performance markers, including liver and pancreatic function. The reports indicate that EPA and DHA enhance the therapeutic index of chemotherapeutic drugs by either increasing their efficacy or reducing their toxicity across various cancer types, including breast cancer [91, 92].

Research has indicated that cancer patients often experience reduced levels of enzyme antioxidants (AEs) and increased levels of reactive oxygen species following chemotherapy. This imbalance can lead to various side effects, including nephrotoxicity, cardiotoxicity, and peripheral neuropathy. These complications not only hinder effective tumor treatment but may also pose a risk to the patient’s life [8, 93]. Reducing the generation of reactive oxygen species and neutralizing them with antioxidants, such as n-3 polyunsaturated fatty acids, may help alleviate drug-induced toxicities. This approach could enhance treatment tolerance and improve overall clinical outcomes for children with cancer [7, 130].

3-polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), significantly influence the structure and function of mitochondria, which are essential organelles for energy production and maintaining cellular redox balance [94]. The incorporation of ω−3 fatty acids into mitochondrial membranes alters their lipid composition and increases membrane fluidity [95]. This enhancement can optimize the efficiency of electron transport within the respiratory chain and reduce the production of reactive oxygen species (ROS) [96], which are molecules responsible for oxidative stress and cellular damage during aggressive therapies. By reducing ROS levels, ω−3 fatty acids help mitigate the adverse effects of cancer treatments related to mitochondrial damage and oxidative stress.

Additionally, ω−3 fatty acids stimulate mitochondrial biogenesis [97] by activating transcription factors such as PPAR-α [98] and NRF2 [99], which improve mitochondrial proliferation and functionality. Increased biogenesis allows for the renewal and expansion of the mitochondrial population, which is crucial for sustaining energy production in cells experiencing therapeutic stress. This functional improvement includes an increase in bioenergetic capacity, as demonstrated by greater efficiency in ATP synthesis [98].

During the β-oxidation of these fatty acids [100], important reducing agents, primarily NADH, are produced. These agents are essential for regenerating reduced glutathione [101], the main cellular antioxidant found in mitochondria. Glutathione plays a critical role in neutralizing free radicals and protecting mitochondria, especially since they lack certain enzymes, such as catalase, which help combat oxidative stress in other cellular compartments [96].

Hepatotoxicity

Drug-induced hepatotoxicity can occur acutely or chronically and may present in a hepatocellular pattern (direct effect on liver cells), a cholestatic pattern (injury to the canalicular membrane and transporters), or a mixed pattern [102]. Intrinsic reactions are dose-dependent and predictable, typically occurring shortly after exposure. Examples include methotrexate, trabectedin, gemtuzumab ozogamicin, cyclophosphamide, and other alkylating agents. In contrast, idiosyncratic reactions are unpredictable and occur independently of dosage [103].

To date, no specific treatment for drug-induced liver injury has been found; some supportive measures used to prevent or reduce it are adjustment of drugs with possible interactions, hyperhydration, alkalinization to favor the elimination of methotrexate metabolites (7-OH-methotrexate and 4-deoxy-4-amino-N-10-methylpteroic acid), and leucovorin salvage and even new alternatives have been sought, such as the use of silymarin [104, 105].

Clinical studies investigating the benefits of omega-3 polyunsaturated fatty acids for reducing the toxic side effects of chemotherapy have mostly focused on adult patients. One clinical trial demonstrated the benefits of omega-3 supplementation in children with acute lymphoblastic leukemia (ALL) who are undergoing chemotherapy. The results indicate a reduction in hepatotoxicity caused by methotrexate. This improvement is achieved by decreasing oxidative stress, as evidenced by reduced levels of malondialdehyde (MDA) and increased levels of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). Consequently, a recovery of normal liver function was observed in the group that received omega-3 supplementation compared to the group that did not [7].

Nephrotoxicity

Nephrotoxicity occurs when renal function is impaired due to damage to the nephron’s architecture, which includes the glomerulus, tubules, or renal microvasculature, affecting filtration, reabsorption, or excretion [106]. Antineoplastic drugs that are known to cause nephrotoxicity include platinum agents (such as cisplatin and carboplatin), antimetabolites (like methotrexate), alkylating agents (including cyclophosphamide and ifosfamide), and anthracyclines (such as doxorubicin and epirubicin). Cisplatin is one of the most commonly used drugs in chemotherapy; however, it is associated with the risk of acute renal tubular injury, necrosis, and long-term renal dysfunction [107].

Efforts have been made to reduce the nephrotoxicity caused by cisplatin. One strategy involves hydration; however, after decades of research, clear recommendations on the type, volume, and duration of hydration are still lacking. Additionally, magnesium supplementation may be beneficial, particularly for patients with low magnesium levels (hypomagnesemia). Forced diuresis using mannitol is another potential option [108]. For methotrexate, a similar approach involving volume expansion (hyperhydration) is used, along with high urine flow and alkalinization of the urine. This is necessary because methotrexate is poorly soluble in acidic urine. The bacterial enzyme glucarpidase can also be utilized to hydrolyze methotrexate into its inactive metabolite [109]. Despite these prevention and treatment strategies for managing nephrotoxicity caused by various oncology drugs, this issue remains a significant challenge.

Cardiotoxicity

Cardiotoxicity refers to the dysfunction of cardiac muscle caused by exposure to antineoplastic treatments, potentially leading to heart failure [110]. This condition can be classified based on the timing of its onset:

1. Acute or Subacute Cardiotoxicity: This occurs from the start of chemotherapy and can extend up to two weeks after its completion.

2. Chronic Cardiotoxicity: This type emerges one year or more after treatment ends and can be further divided into:

• Early Chronic Cardiotoxicity: This occurs within the first year after therapy.

• Late Chronic Cardiotoxicity: This arises after the initial year [111].

Certain antineoplastic drugs, such as doxorubicin, trastuzumab, 5-fluorouracil, and cyclophosphamide, may have their clinical utility limited by the risk of cardiotoxicity. The likelihood of developing this adverse effect increases with higher doses, regardless of whether the cardiotoxicity manifests acutely or chronically, particularly in cancer survivors.

Doxorubicin is an oncology drug that carries a significant risk of cardiotoxicity. The heart is especially susceptible to its adverse effects, primarily because these effects vary among different tissues. Additionally, the myocardium has low levels of antioxidant enzymes, which further contributes to this vulnerability [112]. The current measures used to combat cardiotoxicity include the following:

Dexrazoxane is the only drug approved by the FDA for preventing cardiotoxicity caused by anthracyclines. It works as an iron chelator and inhibits the production of reactive oxygen species (ROS) resulting from the interaction between anthracyclines and non-heme iron. This mechanism ultimately helps alleviate the oxidative stress in mitochondria induced by doxorubicin. However, dexrazoxane also has adverse effects, including myelotoxicity and the potential increased risk of secondary malignancies, although the latter remains a controversial topic [113]. While the use of medications such as statins, angiotensin-converting enzyme inhibitors (e.g., enalapril), beta-blockers (e.g., metoprolol, carvedilol), and spironolactone has been suggested, these treatments are generally implemented once myocardial damage has already occurred to prevent further progression. Additionally, alternative formulations, such as pegylated and non-pegylated liposomal doxorubicin, have been explored. Despite these efforts, there is still no consensus on a prophylactic treatment strategy [114].

Neurotoxicity

Neurotoxicity is a significant side effect of many chemotherapeutic agents. The severity of these effects is usually related to the dose and concentration of the drugs. In some cases, these effects may resolve on their own once treatment is stopped and the drug is eliminated from the body [115]. However, when these drugs are used at high therapeutic doses for extended periods, they can adversely affect the plasticity of the nervous system, leading to irreversible damage [116]. Central nervous system effects may include various degrees of encephalopathy, cognitive and memory deficits, impaired concentration, and diminished executive function. According to the Toxic Neuropathy Consortium of the Peripheral Nerve Society, one common neurological complication is chemotherapy-induced peripheral neuropathy. Its incidence can range from 2.8% to 100%, depending on specific risk factors and the method of measurement [117]. The chemotherapeutic agents most commonly linked to neurotoxicity include platinum compounds (such as Cisplatin), taxanes (like Paclitaxel), vinca alkaloids (such as Vincristine), and other agents like Bortezomib [118]. Ifosfamide can lead to central nervous system toxicity in 10–40% of patients receiving high doses, as both ifosfamide and its metabolites can cross the blood-brain barrier (BBB)92. Platinum-based drugs, particularly cisplatin, have been associated with neurotoxic effects due to alterations in the neurogenesis of the dorsal root ganglia (DRG), which is involved in somatic and visceral sensitivity. Additionally, it affects the area postrema (AP), which is related to nausea and vomiting [119]. This can result in symptoms such as headaches, encephalopathy, cortical blindness, focal neurological deficits, strokes, and seizures in both children and adults [120].

Understanding compounds that can fully protect against the neurotoxic effects of antineoplastic drugs would allow for increased dosages and/or prolonged treatment duration, enhancing their therapeutic efficacy.

Effect of omega-3 on toxicity in different in vivo, in vitro models, and pediatric population

Research has demonstrated the effectiveness of omega-3 supplementation both in vitro and in vivo, including a clinical trial involving children. These studies focus on using omega-3s to manage liver toxicity caused by certain medications. The outcomes of these studies are summarized in Table.

Omega-3 in the management of hepatotoxicity

Involvement of the PI3K/Akt/GSK-3β axis and activation of the Nrf2/HO-1 antioxidant pathway in the potential hepatoprotective effects of ω−3FA

Research has shown that omega-3 fatty acids can reduce oxidative stress by activating antioxidant defense pathways, specifically through the Nrf2/HO-1 pathway. This effect may be linked to the inhibition of GSK-3β, a kinase that, when activated, can trigger apoptosis. By promoting Nrf2 activation, omega-3 fatty acids enhance the body’s ability to regulate antioxidant response elements—specific DNA sequences that facilitate the expression of protective antioxidant genes and phase II defense enzymes [121]. In several studies, elevated GSH, GPx, SOD, and Heme-oxygenase 1 (HO-1) were observed, along with decreased MDA and increased hepatic levels of Nrf2 and HO-1 as the dosage of omega-3 increased [121–123].

Anti-inflammatory oxylipins derived from ω−3FA help counteract liver injury

A second mechanism proposed suggests that anti-inflammatory oxylipins derived from omega-3 fatty acids (ω−3FA) help mitigate liver injury. Oxylipins are bioactive lipid mediators that can be synthesized from n-3 and n-6 fatty acids. They may either be produced in the body after consumption or obtained directly from food sources, making their availability influenced by dietary intake [124] Monirujjaman et al. [125], proposed that the anti-inflammatory effects result from oxylipins synthesized from omega-3 fatty acids. This was correlated with a significant reduction in interleukin-6 (IL-6) and interleukin-18 (IL-18) levels in the liver tissue of rats that ingested fish oil. Furthermore, in liver tissue with chemotherapy-induced lesions, it was observed that the levels of anti-inflammatory oxylipins decreased while pro-inflammatory oxylipins increased (Table 1).

Table 1.

Evidence of ω−3FA against toxicity produced by chemotherapeutic agents in models: in vivo, in vitro and pediatric population

Experimental model		Chemotherapeutic agent	Study characteristics	Effect and mechanism	GRADE/SYRCLE	Reference
Hepatotoxicity
Phase 2 clinical trial. 70 pediatric ALL patients in the maintenance phase		Methotrexate	-Group A: patients with standard-risk ALL who were in the maintenance phase (day 0) and received oral MTX (20 mg/m2) weekly (n = 32) + 1000 mg providing 180 mg of EPA and 120 mg of DHA The age of patients ranged from 4–16 years -Group B: ALL patients who received oral MTX (20 mg/m2) weekly + placebo (sunflower soft gelatin capsules.) (n = 33) The age of patients ranged from 3–15 years Limitations Small sample size. Short-term follow-up No systematic method is mentioned to ensure or quantify adherence to omega-3 supplementation	The ω−3 fatty acids helped to maintain normal liver function and oxidant-antioxidant balance. Group A receiving ω−3 fatty acids maintained normal liver function tests without significant changes (BT, BI, ALT, AST, FA, GGT), contrary to group B (p = < 0.001) CAT, SOD, and GPX maintained normal values compared to the group given ω−3, in contrast to the placebo, which decreased (p = < 0.001) MAD was significantly higher in the placebo group (p = < 0.001)	GRADE Moderate	[7]
In vivo. Albino rats were divided into 5 groups (7–8 rats per group)		Anthracycline: Doxorubicin	-Group 1: Negative control Group 2: Doxorubicin: Intraperitoneal injection of DOX (20 mg/Kg) to induce liver toxicity -Group 3: Doxorubicin + ω−3FA (25 mg/Kg) -Group 4: DOX + ω−3FA (50 mg/Kg) -Group 5: DOX + ω−3FA (100 mg/Kg) Duration: 28 days	ω−3FA exerted hepatoprotective effects against liver injury by modulating the PI3K/Akt/GSK-3β axis and activating the Nrf2/HO-1 antioxidant defense pathway Rats treated with ω−3FA showed: -Significant reductions in ALT, AST, total and direct bilirubin (P < 0.05) -Reductions in hepatic MDA levels (P < 0.05) -Increased hepatic GSH levels (P < 0.05) -Dose-dependent increases in hepatic Nrf2, HO-1, PI3K, pAkt, and reductions in GSK-3β levels were observed in DOX-treated rats (P < 0.05)	SYRCLE Low (Risk of bias)	[121]
In vivo. 18 female rats (Fischer 344)		Irinotecan (CPT-11) + 5-fluorouracil (5-FU)	-Group of rats with tumor: control diet (n = 6) -Group of healthy rats without tumor implantation and chemotherapy (n = 6) -Group of Rats with Chemotherapy + Fish Oil EPA + DHA diet (2.3 g/100 g) (n = 6)	Anti-inflammatory oxylipins derived from ω−3FA help counteract liver injury EPA + DHA: -Prevented chemotherapy-induced increases in liver oxidized glutathione (p < 0.011) and 4-HNE (lipid peroxidation marker) (p < 0.006) -It reduced the levels of IL-6 (p = 0.09), eotaxin (p = 0.007), and Il-18 (p < 0.05). -Diet with EPA and DHA reduced n-6 PUFA-derived oxylipins (proinflammatory), while increasing those derived from EPA and DHA (anti-inflammatory)	SYRCLE Low (Risk of bias)	[125]
In vivo. 24 Sprague Dawley rats		Anthracycline: Doxorubicin	-Group 1: The control group received the same volume of saline solution (n = 8) -Group 2: DOX alone (n = 8). -Group 3: DOX plus ω−3 FA (400 mg/Kg) (n = 8) To induce nephrotoxicity and hepatotoxicity, DOX 30 mg/kg body weight was injected intraperitoneally in a single dose	ω−3FA had a protective effect against oxidative stress damage at the hepatic and renal tissue level induced by doxorubicin Tissue levels: -Decreased MDA and increased GSH, GSH-Px, SOD significantly (p < 0.05) at both hepatic and renal tissue level in ω−3 FA supplemented rats -Activity of antioxidant enzymes GPX and SOD was significantly lower in the group receiving only doxorubicin concerning the group receiving doxorubicin + ω−3 FA in hepatic and renal tissue (p < 0.05)	SYRCLE Low (Risk of bias)	[126]
Nephrotoxicity
In vivo. Male Balb/c mice		Cisplatin	Randomly divided into 6 groups (n = 10) -Group 1 normal -Group 2 saline solution -Group 3 Soy-PL (soy phospholipids 300 mg per kg) -Group 4 DHA 300 mg/kg -Group 5 DHA-PL 300 mg/kg Group 6 EPA 300 mg/kg Group 7 EPA-PL 300 mg/kg For 10 days 7th day Intraperitoneal injection of cisplatin 20 mg/kg	Decreased acute kidney injury through reduced oxidative stress -Supplementation with DHA-PL and EPA-PL significantly reduced markers of acute kidney injury BUN, Cr, Cys-C, and KIM-1 (p < 0.01) -DHA-PL and EPA-PL significantly increased the expression of the anti-apoptotic protein (BCL-2, and reduced the expression of pro-apoptotic proteins (BAX, Caspase-3, Caspase-9, and Cyt-C) (p < 0.05) -DHA-PL significantly increased protein expression of SIRT1 and PGC1α (p < 0.05) (which cisplatin could inhibit their protein expression, SIRT1 and PGC1α l) -DHA-PL, EPA-PL, and EPA significantly decreased MDA levels and increased antioxidant enzymes (SOD, GSH, CAT) (P < 0.05) DHA-PL and EPA-PL suppressed apoptosis, mitochondrial dysfunction, and oxidative stress in cisplatin-induced acute kidney injury	SYRCLE Low (Risk of bias)	[128]
In vivo. 35 mice		Cisplatin	-Group 1 Negative control group -Group 2 Positive control group, cisplatin (10 mg/Kg intraperitoneal) -Group 3 Treatment with omega-3 6 9 for 7 days orally (50 mg/Kg), 8th day intraperitoneal injection of cisplatin (10 mg/Kg) single dose -Group 4 Treatment with high doses of omega-3 6 9 for 7 days orally (100 mg/Kg), 8th day intraperitoneal injection of cisplatin (10 mg/Kg) single dose -Group 5 Treatment with alpha-tocopherol Vitamin E (AT) 7 days alpha-tocopherol orally (100 mg/Kg), 8th-day intraperitoneal dose of cisplatin (10 mg/Kg) single dose	Intake of ω−3FA was associated with decreased proinflammatory modulators and renal function markers -High dose omega-3–6−9 (100 mg/kg) significantly reduced TNF-α, IL-1β, BUN, and creatinine levels (p < 0.05), low dose was less effective -Positive control group TNF-α and IL-1β levels increased significantly (p < 0.05) after cisplatin administration, indicating the ability of the drug to induce inflammation	SYRCLE Low (Risk of bias)	[130]
In vivo. C57BL/6 J mice		Cisplatin	Vehicle group (n = 6) Cisplatin group (n = 6) Cisplatin and CO group (n = 5) Cisplatin and EPA group (n = 5) Cisplatin and DHA group (n = 5) Cisplatin and EPA/DHA group (n = 5) DHA, EPA, or a combination of EPA/DHA (300 mg/Kg, orally, daily) for 5 days before cisplatin injection	DHA supplementation and EPA/DHA combination showed stronger anti-inflammatory and antioxidant activity than EPA -Administration of EPA/DHA combination decreased serum creatinine, BUN, and NGAL levels in mice(P < 0.001) and was more effective than EPA or DHA alone -Decreased inflammatory response TNF-α(P < 0.01), IL-6(P < 0.05), and IL-1β(P < 0.01) with EPA being interestingly more effective than the EPA/DHA combination -Supplementation with ω−3 PUFA prevented renal failure and cisplatin-induced renal fibrosis through suppression of inflammation and may be an alternative to ameliorate long-term renal injury -EPA, DHA, or their combinations significantly increased antioxidant capacity and GSH level(P < 0.001), and decreased MDA level (P < 0.001) -EPA/DHA significantly increased CAT, SOD, HO-1, GPX4, SLC7A11, NQO1 and SOD1 activity AND COX-2 suppression (P < 0.001)	SYRCLE Low (Risk of bias)	[107]
In vitro. HK-2 cells (proximal tubule epithelial cell line)		Cisplatin	HK-2 cells: Control group Cisplatin group Cisplatin DHA group EPA + cisplatin group DHA + EPA + cisplatin group Pretreated with 50 µM of EPA, 50 µM of DHA, or 50 µM of EPA/DHA (28 µM of EPA and 22 µM of DHA) for 24 h	ω−3FA supplementation positively modulated the p62-Keap1-Nrf2 pathway, promoting the expression of antioxidant enzymes -Significantly increased expression of antioxidant proteins such as HO-1, GPX4, SLC7A11, NQO1, and SOD1 (P < 0.001) -Decrease of proapoptotic proteins Bax and Bak (P < 0.001) -Increased anti-apoptotic proteins of Bcl-2 and Bcl-xL (P < 0.001) -PUFA ω−3 inhibited cisplatin-induced oxidative damage by activating the p62-Keap1-Nrf2 signaling pathway (P < 0.001) -Keap1 level significantly decreased and Nrf2 and p62 levels significantly increased both in vivo and in vitro after treatment with EPA, DHA, or EPA/DHA(P < 0.001) (P > 0.01)	Not applicable	[107]
Cardiotoxicity
Phase 2 clinical trial with 60 children (mean age 8.7 ± 1.9 years) newly diagnosed with ALL		Doxorubicin	Randomly divided into 2 groups Group I (omega 3 treatment) DOX + omega-3 fatty acids 1000 mg/day once daily, 1 week before chemotherapy and maintained for 6 months Group II (control group) DOX alone For 6 months Limitations Small sample size Short-term follow-up Adherence and plasma omega-3 levels were not assessed.	Omega-3 supplementation generated a decrease in oxidative stress by increasing endogenous glutathione SOD levels (p = 0.001) and decreasing MDA levels (p < 0.001) -Group supplemented with omega 3 significantly decreased myocardial injury (early) Echocardiographic parameters such as peak systolic velocity of the left ventricular mitral annulus (P = 0.001) and two-dimensional longitudinal strain (P = 0.003) (associated with systolic function) decreased significantly in group II, and group I showed no significant change from baseline	GRADE Moderate	[131]
In vivo. Male Sprague-Dawley rats		Doxorubicin	Group 1 control n = 8 Group 2 DOX n = 8 Group 3 DOX and fish n-3 fatty acids (400 mg/Kg) for 30 days n = 8 DOX was injected intraperitoneally in a single dose of 30 mg/Kg	Omega-3 fatty acids protect against doxorubicin-induced acute cardiotoxicity due to antioxidant properties Histopathological examination of cardiac tissue, doxorubicin and omega-3 fatty acids group showed improved histological appearance compared to doxorubicin alone (there was severe cardiac damage including disorganization of myocardial muscle fibers, myofibrillar loss and cardiotoxic myocardial fibers with cytoplasmic vacuoles in cardiac tissues) Pretreatment with fish n-3 fatty acids increased GSH-Px and SOD activities, as well as decreased MDA (P < 0.001)	SYRCLE Low (Risk of bias)	[134]
In vivo. 60 male Wistar rats		Doxorubicin	Control group (C; n = 14) Omega-3 fatty acids group (W; n = 14) Doxorubicin group (D; n = 16) Doxorubicin + Omega-3 fatty acids group (DW; n = 16) Groups D and DW were administered doxorubicin (2 weeks after starting Omega-3 fatty acid supplementation) by intraperitoneal injection (3.5 mg/kg), once a week for 4 weeks (total dose: 14 mg/kg) *EPA (360 mg), DHA (240 mg), other fatty acids (350 mg), and DL-alpha-tocopherol (1.6 mg) per 2 week	Attenuated cardiac dysfunction and had an antioxidant effect Omega-3 attenuated the morphological changes induced by doxorubicin, in echocardiography, attenuated morphological changes induced by doxorubicin (improved LV systolic (P = 0.038) and diastolic diameter (P = 0.045)) Group supplemented with omega-3 showed lower carbonylation concentration, associating this to lower oxidative stress (P < 0.021) Omega-3 fatty acid failed to decrease doxorubicin-increased nSMase activity in cardiac tissue or alter nSMase1 expression, so the sphingomyelin/ceramide pathway is not the mechanism by which it attenuates cardiotoxicity (P > 0.05)	SYRCLE Unclear (Risk of bias)	[135]
In vivo. 40 Male Sprague-Dawley rats		Doxorubicin	The control group was injected intraperitoneally with a normal saline solution ALA (500 µg/Kg) group. DOX group intraperitoneally injected with 2.5 mg/Kg of DOX DOX plus ALA (500 µg/Kg) group via gastric gavage 1 h before injection with 2.5 mg/Kg of DOX	ALA enhanced endogenous antioxidant enzyme activity ALA contributed to the improvement of cardiac function after DOX administration in rats, as it prevented DOX-induced elevation of serum CK-MB, LDH, and cTnI levels, ameliorated cardiotoxicity-induced histological changes (cardiomyocyte necrosis) (p < 0.05) ALA prevented DOX-induced changes in MDA (prevented its elevation) and significantly increased SOD, GSH-Px, and CAT activity in cardiac tissue (p < 0.05) Significant reduction of Keap1 at the cytosolic level and increase of Nrf2 compared to the control group (p < 0.05) ALA suppressed DOX-induced cardiomyocyte apoptosis and significantly inhibited caspase-3 activation (p < 0.05)	SYRCLE Unclear (Risk of bias)	[136]
In vivo. Albino rats, Wistar adult females		Doxorubicin	5 groups of 7–8 animals each -Groups I and II received distilled water -Groups III, IV, and V received omega-3 (25, 50 and 100 mg/Kg/day, orally) for 4 weeks, respectively 24 h after the last dose of omega-3 each rat in groups II, III, IV, and V received a single intraperitoneal injection of DOX (200 mg/Kg)	Dose-dependent amelioration of cardiorenal toxicity CARDIAC Reduction in cardiac oxidative stress (↓MDA, ↓IL-6, ↑GSH) as well as inflammatory (IL-6) biomarkers (p < 0.05) Improvement in electrocardiographic measurements that were dose-dependent on QTc interval, ST-segment height, and T-amplitude, compared to the positive control group (p < 0.05) Significant suppression of dose-dependent CK-MB levels (p < 0.05) Mild regression of histopathological lesions was demonstrated and the group with the maximum dose of omega (100 mg/kg) cardiomyocyte restored its normal structure and appeared as normal as the control group (p < 0.05) RENAL Decrease of oxidative stress markers (↓MDA, ↑GSH) (p < 0.05). Redox balance, probable association with Nox4-Nrf2, decreased renal levels of Nox4 and renin (p < 0.05) Decrease in serum urea and creatinine levels by approximately 24%, 40%, and 44% respectively, and 36%, 46%, and 59%, respectively (dose-dependent) (p < 0.05) Remarkable improvement in histopathological lesions in the omega-3 treated group (p < 0.05)	SYRCLE Low (Risk of bias)	[137]
In vitro. Cardiomyoblast H9C2		Doxorubicin	H9C2 cells with or without pretreatment for 24 h with EPA or DHA were left untreated or treated with 1 µM of DOX then harvested for analysis, while other cells were co-treated for 24 h with EPA or DHA plus DOX	PUFAs n-3 may be useful in reducing oxidative stress Pretreatment with EPA or DHA prevents doxorubicin-induced decrease in UCP2 protein expression (p < 0.05), as well as ROS production (p < 0,05) (p < 0.01)	Not applicable	[138]
In vivo. 36 female C57BL/6J ovariectomized mice		Anthracycline and cyclophosphamide	-Group 1 vehicle (saline solution) and low n-3 diet.(0 g/Kg of EPA + DHA) for 2 weeks -Group 2: 9 mg/Kg anthracycline + 90 mg/kg cyclophosphamide + Low n-3 diet (0 g/Kg of EPA + DHA) for 2 weeks -Group 3: vehicle and high n-3 diet (12.2 g/Kg of EPA + DHA) for 2 weeks -Group 4: 9 mg/Kg anthracycline + 90 mg/Kg cyclophosphamide + High n-3 diet (12.2 g/Kg of EPA + DHA) for 2 weeks	Fatty acids ω−3 attenuate markers of chemotherapy-induced cardiac damage and fibrosis Supplementation with ω−3 fatty acids attenuated Col3a1 (P < 0.01) and Myh7(P = 0.03) expression significantly Dietary supplementation of n-3 PUFA fatty acids led to significantly higher cardiac EPA, DHA, and arachidonic acid (p < 0,05.) Supplementation with n-3 PUFA may make cardiac mitochondria less prone to apoptosis. Ppargc1a and Nrf1 (involved in mitochondrial biogenesis) were expressed less in the hearts of chemotherapy mice(p = 0.02), and Bcl2 (an apoptotic inhibitor) gene expression increased significantly at the mitochondrial level in supplemented mice (p < 0.01)	SYRCLE Low (Risk of bias)	[142]
In vivo. Fisher344 female rats		Doxorubicin	The reference group not treated with DOX, received saline (n = 10) DOX alone group without any parenteral intervention (n = 10) DOX parenteral control treatment group (n = 12) Treatment with DOX + parenteral glutamine (n = 12) Parenteral DOX + parenteral PUFA ω−3 treatment (n = 12) Combined parenteral treatment with DOX + glutamine/ω−3 PUFA (n = 12) * ω−3 PUFA (0.19 g/Kg/dose EPA and 0.18 g/Kg/dose DHA) parenterally (tail of rats) on alternate days, starting 6 days before the start of chemotherapy and until the end of the study (day 50)	ω−3 PUFA single mitigated the increase in plasma cTnI levels significantly and inhibited cardiac arginase activity, which could lead to a preserved availability of arginine for NO production (P < 0.05) ω−3 PUFA significantly improved DOX accumulation in tumor tissue (p < 0.01). The glutamine combination did not result in a major or additive benefit in cardiac protection and even raises the possibility of being counterproductive	SYRCLE Unclear (Risk of bias)	[143]
Neurotoxicity
In vivo. Male C57BL/6 mice		Oxaliplatin Paclitaxel	→Acute neurotoxicity -Group 1: control received 10 mL/Kg vehicle. -Group 2: Mice received a single injection of oxaliplatin (6 mg/Kg, intraperitoneal) + fish oil 2.3 g/kg, oral route →Chronic neurotoxicity: mice received oxaliplatin (3.5 mg/Kg, intraperitoneal) 2 times per week for 4 weeks, and fish oil was administered in 2 protocols Preventive: fish oil 2.3 g/Kg, oral route with the first oxaliplatin injection and up to 21 days after the last injection Curative: Fish oil 2.3 g/Kg, oral route, 24 h after the last oxaplatin injection, for 21 days →Paclitaxel-induced neuropathic pain: mice received paclitaxel 2 mg/Kg, intraperitoneal, for 5 consecutive days, and fish oil 2.3 g/Kg, oral route was administered starting 30 days before the first injection and up to the last injection *Fish oil (EPA 55.2%, DHA 37.4%)	ω−3FA prevented chemotherapy-induced peripheral neuropathy by reducing inflammation Fish oil supplementation prevented cold hypersensitivity induced by acute oxaliplatin administration (P < 0.05) In the chronic model, preventive and curative treatment significantly reduced oxaliplatin-induced mechanical hypersensitivity (P < 0.05) as well as hypersensitivity to hot stimuli (P = 0.01), and only the preventive protocol was able to interfere with cold hypersensitivity (P < 0.01) It completely prevented paclitaxel-induced mechanical hypersensitivity (p < 0.0001) Reduced levels of proinflammatory cytokines (TNF, IL-1β, and IL-6) in spinal cord and hind paw neuronal tissues (p < 0.05) Reduced levels of neurotrophic factor BDNF, TNF, and IL-1β in brain tissue and spinal cord of mice with oxaliplatin-induced neuropathy (p < 0.05) Reduction in the number of microglia in the spinal cord in oxaliplatin-injected mice (p < 0.05)	SYRCLE Low (Risk of bias)	[149]

4-HNE: 4-hydroxy-2-nonenal; ALA: α-linolenic acid; ALL: acute lymphoblastic leukemia; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BDNF: Brain-Derived Neurotrophic Factor; BI:indirect bilirubin; BT: total bilirubin; BUN: Blood Urea Nitrogen; CK-MB: Creatine Kinase-MB; Cr: Creatinine; cTnI: cardiac troponin I; Cys-C: Cystatin C; DHA: docosahexaenoic acid; DHA-PL:docosahexaenoic acid-enriched phospholipids; DOX: doxorubicin; EPA: eicosapentaenoic acid; EPA-PL: eicosapentaenoic acid-enriched phospholipids; FA: fatty acid; GGT: γ-glutamyl transpeptidase;GPX: glutathione peroxidase; GSH: glutathione; GSK-3β: Glycogen Synthase Kinase 3 beta; HO-1: heme oxygenase 1; IL: Interleukin; KIM-1: Kidney Injury Molecule-1; LV: left ventricle; MDA:malondialdehyde; MTX: methotrexate; NO: nitric oxide; pAKT: Phosphorylated AKT; PI3K: phosphatidylinositol 3-kinase; PUFA: polyunsaturated fatty acids; ROS: reactive oxygen species; SOD:superoxide dismutase; Soy-PL: soy phospholipids; TAC: total antioxidant capacity; TNF: Tumor necrosis factor; ω−3FA: omega-3 fatty acids

The ω−3 fatty acids helped maintain normal liver function and oxidant-antioxidant balance

Elbarbary et al. [7], found that patients who received ω−3 fatty acids exhibited significantly lower concentrations of liver enzymes and malondialdehyde, along with higher total antioxidant capacity levels. The dosage used Was 1000 mg per day, which was well-tolerated by the patients without any reported side effects. This finding is consistent with the research conducted by Tulubas et al. [126], who performed an in vivo study on rats. In their study, the group that received ω−3 fatty acids showed a significant increase in the levels of superoxide dismutase and glutathione peroxidase in the serum, liver, and kidneys compared to the group that only received doxorubicin. This was associated with a reduction in oxidative damage to the tissues.

Although various supportive strategies to reduce hepatotoxicity, such as drug dose reduction, hyperhydration, and antioxidant supplementation (e.g., silymarin, N-acetylcysteine), are commonly used to manage chemotherapy-induced hepatotoxicity, none constitutes a definitive or standard treatment. Omega-3 fatty acids have demonstrated promising hepatoprotective effects by modulating oxidative stress and activating signaling pathways such as Nrf2/HO-1 and PI3K/Akt. Although their mechanisms partially overlap with those of standard interventions, no comparisons between these measures and the use of omega-3 fatty acids were found at the time of this review. Given their specific biological profile, omega-3 fatty acids could serve as complementary agents in existing regimens for managing hepatotoxicity, although further validation is required, especially in the pediatric setting. [7, 104, 105, 127].

Omega 3 in the management of nephrotoxicity

In an in vivo study by Shi et al. [128], different fatty acid compositions including soy phospholipids, DHA, EPA, DHA-enriched phospholipids, and EPA-enriched phospholipids were administered to rats, the results showed that in the unsupplemented group, there was a decrease in BCL-2 levels and an increase in the expression of proapoptotic proteins such as BAX, Caspase-3 and Caspase-9 compared to the normal group, and supplementation of DHA-enriched phospholipids attenuated the nephrotoxicity of cisplatin without compromising its antitumor activity in mice. The study also revealed that DHA-enriched phospholipids exert a protective effect by positively regulating the SIRT1/PGC-1α pathway. Inhibition of this pathway leads to mitochondrial dysfunction and cell death. It is important to note that when activated, PGC-1α can translocate to the nucleus, where it activates NRF2, thereby initiating the transcription of nuclear-encoded respiratory chain components and mitochondrial transcription factor A (Tfam). This process results in mitochondrial biogenesis [129] Similarly, Abd et al. [130], found a reduction in pro-inflammatory markers, such as tumor necrosis factor alpha (TNF-α) and IL-1β, that was dependent on the maximum dosage used in their rat model.

Supplementation with omega-3 fatty acids (ω−3FAs) positively modulated the p62-Keap1-Nrf2 pathway by promoting the expression of antioxidant enzymes, according to an in vitro study conducted by Zhang et al. [107]. This research found that omega-3 polyunsaturated fatty acids enhance antioxidant gene expression by activating the p62-Keap1-Nrf2 signaling pathway. Additionally, activating Nrf2 may inhibit the p53 apoptosis signal induced by drugs like cisplatin at the renal level by positively regulating MDM2 expression in renal tubular epithelial cells. This suggests promising effects for omega-3FAs in kidney health (Table 1).

For nephrotoxicity, especially with agents such as cisplatin or ifosfamide, hyperhydration, urinary alkalinization, and occasionally amifostine are preventive strategies. Although omega-3 fatty acids have demonstrated renoprotective effects in preclinical models (through anti-inflammatory modulation and mitochondrial preservation), their role in preventing nephrotoxicity, especially in pediatric patients, has not yet been established or compared with standard measures [108, 109].

Omega 3 in managing cardiotoxicity

The proposed mechanisms for reversing cardiotoxicity include the following:

Decreasing oxidative stress

El Amrousy et al. [131], observed notable improvements in serum markers in children with leukemia who were treated with doxorubicin and supplemented with omega-3 fatty acids. Specifically, they reported increases in glutathione and superoxide dismutase levels, along with a reduction in malondialdehyde levels. This process could be explained by the activation of the transcription factor Nrf2 (nuclear factor erythroid 2), which positively regulates antioxidant enzymes [132]. Omega-3 fatty acids directly interact with Keap1, a negative regulator of Nrf2, leading to the dissociation of Keap1 from Cullin3 and subsequently inducing Nrf2-dependent antioxidant target genes [133].

In vivo studies conducted to assess the cardiotoxicity induced by doxorubicin and omega-3 in rats demonstrated that supplementation with omega-3 fatty acids reduced levels of malondialdehyde and enhanced the activity of antioxidant enzymes, including glutathione peroxidase and superoxide dismutase [134–136].

Saleh et al. [137], conducted a study comparing different doses of omega-3 and found a dose-dependent relationship between omega-3 administration and a reduction in cardiac toxicity. This was evidenced by a significant decrease in creatine kinase-MB (CK-MB) levels, as well as improvements in electrocardiographic and histopathological parameters. Similarly, Monte et al. [135], observed, through echocardiography, a reduction in the morphological changes induced by doxorubicin. Both studies utilized rats as their model.

Hsu et al. [138], performed an in vitro study in cardiomyoblasts showing that pretreatment with EPA or DHA increased UCP2 expression, which promotes mild mitochondrial uncoupling and reduces oxidative stress. EPA/DHA also preserved mitochondrial membrane potential and reduced ROS levels in DOX-treated cells effects that were consistent with improved cell viability.

Negative regulation of nuclear factor kappa B

Omega-3 fatty acids can negatively regulate nuclear factor kappa-B (NF-κB) through their inhibitory effects on toll-like receptor 4 (TLR4) and by binding to peroxisome proliferator-activated receptor-γ (PPARγ) [139]. Additionally, Omega-3 may exert a negative regulation on NF-κB by increasing the expression of NRF2 target genes, which helps decrease pro-inflammatory signaling [140, 141]. In various in vivo models, as indicated in Table 1, echocardiographic parameters and markers of myocardial injury were assessed. Significant improvements were noted, and in some cases, these improvements were dose-dependent. Although several studies have reported dose-dependent protective effects of omega-3 fatty acids against chemotherapy-induced toxicity (such as reductions in oxidative stress markers and improvements in histological findings) this relationship is not consistently observed across all models. In some experiments, multiple doses of omega-3s were tested and showed a graded response (e.g., in cardiotoxicity and nephrotoxicity models), whereas in others, all doses provided similar benefits or only a single dose was evaluated. These discrepancies may arise from differences in experimental design (species, strain, and duration), the type and formulation of omega-3s (EPA vs. DHA vs. combinations), and the timing of administration (preventive vs. therapeutic). Future studies should aim to standardize dosing protocols and assess a broader range of doses to clarify the optimal therapeutic window [121, 130, 137].

Decreased markers of cardiac damage and fibrosis

In myocardial tissue, supplementation with ω−3 PUFA attenuated the expression of Myh7 and Col3a1, molecular markers associated with fibrosis, and increased the expression of BCL2 (anti-apoptotic) at the mitochondrial level, which may be related to the fact that these markers are less prone to apoptosis [142].

A controversial finding was reported by Xue et al. [143], where he evaluated the administration of glutamine and omega-3 in rats. The found that treatment of both glutamine and omega-3 separately improved cardiac function, reduced plasma cardiac troponin I (cTnI) levels, decreased cardiac lipid peroxidation, and treatment with ω−3 PUFA alone significantly improved tumor DOX concentration, but combining glutamine with ω−3 PUFA resulted in less accumulation of the drug at the tumor level compared to ω−3 PUFA alone.

It’s also important to consider other factors that could exacerbate or complicate cardiotoxicity, either acutely or chronically. For instance, cardiometabolic issues like dyslipidemia frequently arise in patients with acute promyelocytic leukemia (APL) even before the initiation of anti-APL therapy. This condition has been linked to the secretion of the chimeric oncoprotein PML-RAPα [144].

Dyslipidemia has been observed in children diagnosed with acute lymphoblastic leukemia prior to treatment [145]. Additionally, up to 50% of survivors experience dyslipidemia, which increases their risk of developing metabolic syndrome [146]. A 3-month trial conducted in Mexico aimed to evaluate the impact of long-chain omega-3 polyunsaturated fatty acids (ω3-LCPUFA) on cardiometabolic factors in children undergoing treatment for ALL. The results showed a significantly lower concentration of triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDL-C) in the ω3-LCPUFA group compared to the placebo group. At the time of diagnosis, 82.4% (28 out of 34) of the children presented with hypertriglyceridemia and low levels of high-density lipoprotein (HDL) cholesterol. Furthermore, interleukin-6 (IL-6) levels were found to be significantly lower in the ω3-LCPUFA group than in the placebo group, with a notable reduction in IL-6 levels between the time of diagnosis and after three months of treatment [147].

Compared to established pharmacological strategies for the management of chemotherapy-induced toxicities, omega-3 fatty acids represent an emerging, albeit still experimental, complementary approach. Regarding cardiotoxicity, dexrazoxane remains the only FDA-approved pharmacological agent widely validated in pediatric populations to prevent anthracycline-induced cardiac damage. Omega-3 fatty acids, although direct comparisons with dexrazoxane have not been made, exhibit cardioprotective effects through antioxidant, anti-inflammatory, and mitochondrial mechanisms. Their specific pathways of action suggest a potential adjuvant rather than substitutive role [5, 114, 148].

Omega 3 in the management of neurotoxicity

Melato et al. [149], conducted a study using an in vivo model of male mice to replicate peripheral neurotoxicity. In this study, he administered oral fish oil supplementation both before and during treatment. The results showed a decrease in pro-inflammatory cytokines, specifically TNF, IL-1β, and IL-6, along with reduced microglial activity in both spinal cord and brain tissues.

The peripheral neurotoxicity involves mitochondrial impairment, oxidative stress, and neuroinflammation, which can lead to axonal demyelination and sensory impairment [150].

During the search, no studies were found in the pediatric population. However, there are favorable results from a study conducted in the adult population by Ghoreishi et al. [151]. This randomized, double-blind, placebo-controlled trial involved patients with breast cancer who were treated with paclitaxel. In this study, 70% of the patients receiving supplementation did not develop peripheral neuropathy, compared to 40.7% in the placebo group (p = 0.029).

Another example is a randomized double-blind study involving adults with colon cancer who received oxaliplatin. This study indicated that ω−3 polyunsaturated fatty acids may serve as potential neuroprotectors against peripheral neurotoxicity. In this case, 69.7% of the placebo group developed peripheral neuropathy, while only 52.2% in the supplemented group experienced the same issue, showing a significant difference between both groups (p = 0.017) [152] Table 1.

Despite the growing interest in the neuroprotective properties of omega-3 fatty acids, evidence supporting their role in mitigating chemotherapy-induced neurotoxicity remains limited. Most of the available studies are preclinical or focused primarily on adult models, without data in pediatric populations. This lack of clinical evidence restricts the current depth of analysis but highlights the urgent need for further research in this area.

Regarding neurotoxicity management, symptomatic treatments such as gabapentin, duloxetine, and glutamine are frequently used to alleviate chemotherapy-induced peripheral neuropathy. However, no standard preventive therapy currently exists. Omega-3 fatty acids, through their ability to modulate neuroinflammation and oxidative stress, have shown promising results in preclinical models and limited adult clinical studies. While omega-3 fatty acids offer mechanistic plausibility, their incorporation into pediatric oncology practice will require robust evidence from well-designed controlled trials, either as monotherapy or in combination with existing treatments [151, 153–156].

The Fig. 1 illustrates the proposed mechanisms of action for omega-3 across various models presented in the studies listed in Table 1. EPA and DHA are the most studied ω−3 fatty acids in the context of chemotherapy-induced toxicity and show protective effects, as summarized in Table 1. In contrast, evidence for ALA is more limited.

Fig. 1.

Mechanisms of action of EPA/DHA and ALA on chemotherapy toxicity. a) Situations such as nutritional status, chemotherapy, and the same oxidative stress generated during treatment could affect endogenous DHA/EPA synthesis. However, ALA can stimulate the PI3K/Akt/GSK-3β and NRF2/KEAP1/ARE pathways. b) Proposed mechanism of action of EPA/DHA. 1) Modulation of PI3K/Akt/GSK-3β axis. Increased PI3K production increases AKT activation which could phosphorylate GSK-3β and inhibit its activity (decrease of caspases activation). 2. Modulates activation of antioxidant defense pathway NRF2/KEAP1/ARE. 3. Increased production of oxylipins with anti-inflammatory effect.4. Increased expression of BCL2 and decreased proapoptotic proteins (BAX). 5. Increased mRNA levels of UPC2 and its protein expression.6. Positive regulator of the SIRT1/PGC1α pathway, which increases the protein expression of PGC1α that activates NRF2 for mitochondrial biogenesis

Although ALA is a metabolic precursor of EPA/DHA, its endogenous conversion may be compromised during chemotherapy or under inflammatory/oxidative stress conditions [20]. In terms of mechanisms, the available data for ALA are mainly associated with modulation of the PI3K-Akt-GSK-3β axis and activation of the KEAP1-NRF2-ARE pathway [157].

For EPA/DHA, in addition to involvement in these pathways, studies report anti-inflammatory actions via increased pro-resolving oxylipins, along with reduced mitochondrial ROS, up-regulation of UCP2, and SIRT1–PGC-1α-dependent mitochondrial biogenesis.

Dosage recommendations for the use of omega-3

The recommended daily intake of omega-3 fatty acids varies according to international guidelines. In general terms, an intake of 1 to 2 g of alpha-linolenic acid (ALA) and 250 mg of EPA + DHA per day is suggested. The National Health and Nutrition Examination Survey (NHANES) recommends an ALA intake of 1.55 g for men and 1.32 g for women, children, and adolescents aged 2 to 19 [158]. The European Food Safety Authority establishes an intake of 100 mg/day of DHA and EPA for children over 24 months and 250 mg/day for adults [48].

The National Institutes of Health (NIH) recognizes that the requirements of these nutrients depend on variables such as age, sex, physiological state or disease condition, and the doses proposed by the NIH are shown in Table 2 [159]. Although there is no definitive consensus on the specific doses of EPA and DHA, consuming ALA as a metabolic precursor is recommended in healthy individuals. The dose of omega-3 administered should be individualized, considering age, sex, and body composition.

Table 2.

Dosage recommended by different authors. Taken and modified from Van der Wur et al. [160]

Author	Age (years)	DHA mg/d	EPA mg/d
Kennedy	10–12	1000	20
Kennedy	10–12	400	8
Mc Namara	8–10	1200	---
Mc Namara	---	400	---
Jackson	---	450	90
Jackson	---	900	180
Dalton	7–9	127.3	54.6
Antypa	---	250	1740
Baumgartner	6–11	240	46
Hamazaki	---	1500	1800
Hamazaki	---	200	240
Jackson		200	300
Kirby	8–10	400	56
Long	---	672	93.3
Karr	---	480	720
Montgomery	7–9	600	22.5
Osendarp	6–10	88	22
Parletta	3–10	174	558
Portillo-Reyes	8–12	180	270
Van der Wurff	13–15	280	520
Richardson	7–9	600	---
Benton	---	400	---
Ryan	4	400	---
Muthayya	6–10	86	---

mg/d= miligrams by day

A recent literature review proposes a dose of approximately 84 mg of ALA, 14.8 mg of EPA, 35.6 mg of DHA, 2511.3 mg of linoleic acid (LA) and 6.8 mg of arachidonic acid (AA) per day, administered on a schedule of approximately 4.65 days, accumulating 104 days over six months Table 2 [160].

Safety and drug interactions

Long-chain polyunsaturated fatty acids are not altered in the oral or gastric cavity; their digestion begins in the small intestine with the aid of bile salts and pancreatic enzymes. In patients with cancer, such as acute lymphoblastic leukemia, 500 mg capsules (equivalent to 0.1 g/kg/day during the first three months) have been used as a complementary treatment. This approach aims to utilize omega-3 long-chain polyunsaturated fatty acids to help reduce certain adverse cardiometabolic and inflammatory risk factors in children with ALL [136].

Omega-3 fatty acids can interact with certain medications, potentially leading to adverse effects. In vitro studies have shown that they can induce coagulopathy by inhibiting platelet aggregation, which in turn affects thrombin generation. In patients taking long-chain polyunsaturated fatty acids (PUFAs) without other medications, the coagulopathy effect is weak, and symptoms typically do not develop. However, when omega-3s are combined with antiplatelet therapies—such as daily aspirin (a non-steroidal anti-inflammatory drug that inhibits COX-2 cyclooxygenase), anticoagulants like warfarin, clopidogrel (a P2Y12 receptor inhibitor), or factor Xa inhibitors—adequate coagulation may be compromised [141, 161, 162]. At doses of 3 to 6 g per day, omega-3 fatty acids have not shown significant anticoagulant activity, making this dosage generally considered safe. Nonetheless, to minimize the risk of hemorrhage, it is important to consider the half-lives of eicosatetraenoic acid and docosahexaenoic acid, which are approximately 37 h and 48 h, respectively [141]. Among the beneficial interactions of omega-3, notable effects can be observed when they are combined with vitamin B12, folic acid, or lutein—all of which possess antioxidant properties. When acting together, these nutrients can improve overall cognitive function [163].

To date, no serious side events have been reported; however, when exceeding 3 g daily, they may have the potential to trigger inflammation and oxidative stress while exerting antioxidant effects at low concentrations; another point to take into account is their antithrombotic role since high doses have been reported to prolong bleeding time [164]. Allergic reactions to Omega-3, particularly in individuals with fish allergies, are an important consideration when deciding to consume it. Since fish and shellfish are common sources of Omega-3, those who are allergic to these foods should exercise caution when taking fish-derived Omega-3 supplements.

Omega-3 fatty acids and other antioxidants

Omega-3 fatty acids (n-3 FAs) play a crucial anti-inflammatory role by modulating eicosanoid synthesis and membrane fluidity, distinguishing them from other antioxidants, such as vitamin C, vitamin E, and polyphenols. Common antioxidants act primarily by directly decreasing reactive oxygen species (ROS); omega-3 fatty acids exert more complex bioactive effects, including down-regulation of inflammatory cytokines and also serve as precursors of essential lipid mediators, in particular specialized pro-resolving mediators (SPMs) such as resolvins, protectins and maresins. These mediators play a crucial role in the management and resolution of inflammation. Recent studies have shed light on the protective functions of SPMs, which can regulate and inhibit the activity of inflammatory agents, inducers of neoplastic transformation and tumor progression. Consequently, SPMs have become an attractive therapeutic target to improve conventional treatments and reduce adverse effects [165, 166].

Other antioxidants, like N-acetylcysteine, act as a potent antioxidant precursor by replacing intracellular glutathione, the body’s principal endogenous antioxidant. In contrast, traditional antioxidants often have more immediate but less sustained effects on oxidative balance, omega-3 fatty acids complement, rather than replace, the antioxidant defense system, acting through different molecular pathways with implications for cardiovascular, neurological, and metabolic health [167–169]. Water-soluble B vitamins serve as essential cofactors in various biochemical processes, including DNA synthesis, repair, methylation, and energy metabolism [170]. Recent observations indicate that certain chemotherapy drugs and specific types of cancer can lead to deficiencies in these vitamins, increasing the risk of complications [171–173]. Deficiencies in vitamins such as thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), and biotin (B7) have been associated with reduced ATP production by disrupting the citric acid cycle and the electron transport chain [170, 174].

Supplementation with thiamine and its derivatives (such as benfotiamine and oxythiamine) may have beneficial effects, including inhibiting tumor growth, reducing oxidative stress, preventing NF-κB-mediated inflammatory signaling, decreasing glycolytic activity, and promoting oxidative phosphorylation. Riboflavin (B2) also plays a significant role by regulating reactive oxygen species (ROS) to inhibit tumor growth, promote apoptosis, and reduce inflammation, thereby enhancing the efficacy of chemotherapy drugs like cisplatin and gemcitabine [170].

Vitamins B2, B3, B6, and B12 are crucial for maintaining redox homeostasis, as they are involved in the metabolism of glutathione (GSH) [175]. Pyridoxine (B6) has been shown to augment antioxidant responses, potentially by upregulating the expression of the nuclear gene Nrf2, while also decreasing mitochondrial ROS levels [176]. Therefore, we can conclude that supplementation with vitamin B and Omega-3 may help maintain better mitochondrial function and reduce the toxic effects of cancer treatments.

Strengths and limitations

In this narrative review article, we comprehensively summarize the effect of omega-3 fatty acids on the management of chemotherapy toxicity and highlight their potential to prevent these toxicities in different systems. However, one of the most important limitations is heterogeneity of the study populations, including disease type, tolerance to treatment, dose of DHA and EPA, timing and duration of DHA and EPA supply, EPA to DHA ratio, initial EPA and DHA status, intake of other nutrients such as vitamins, clinical status, and concomitant use with medications. More well-designed interventional clinical studies are needed to address the relevance of these different variables and adequately identify the effect of DHA and EPA in specific patient populations. It is important to take into consideration that consumption of food with Omega3 high content, is low in pediatric patients, even in some countries this type of food has low availability, so the supplementation is the way to catch the recommended daily intake.

Conclusions

We provide initial evidence from in vitro and in vivo models indicating that n-3 polyunsaturated fatty acid (PUFA) supplementation could help reduce toxicity. Data on appropriate dosing and studies involving pediatric cancer patients remain limited. Recommendations for this population are unclear, and nearly all meta-analyses conclude that more evidence is needed. Omega-3 fatty acids have been shown to be effective in pediatric oncology patients by reducing the cardiotoxicity associated with certain chemotherapy treatments. However, additional research is still necessary to reinforce these findings. It is crucial to note that while ALA is the only essential omega-3 that the body cannot synthesize, EPA and DHA are of vital importance for health, even if their conversion from ALA is limited.

Research must include dietary fatty acid profiling and genotyping. Omega-3 diet in-take should be taken into consideration, as almost 85% of the world’s countries do not meet the omega-3 intake recommendation. The supplementation and diet recommendations, including the clinical trials, should address global access and product quality. There is an urgent need to analyze different mechanisms of action using preclinical models and epigenetic or inflammatory biomarkers, especially across subpopulations (e.g., by sex, age, genotype). Personalized dosing strategies could enhance efficacy and safety. With specific doses, evaluating long-term benefits and the risk of high doses should be a focus of future studies.

To establish robust recommendations, future studies should focus on key factors that will enhance the available evidence: (1) clearly defined n-3 interventions (EPA versus DHA), (2) precise dosing based on preliminary clinical trials, (3) expansion of the evaluated results to larger cohorts, and (4) improved reporting of findings.

Abbreviations

ALA

Alpha-linolenic acid

EPA

Eicosapentaenoic acid

DHA

Docosahexaenoic acid

PUFAs

Polyunsaturated fatty acids

ω-3FA

Omega-3 fatty acids

ROS

Reactive oxygen species

AA

Arachidonic acid

TXA2

Thromboxane A2

COX-1

Cyclooxygenase-1

COX-2

Cyclooxygenase-2

LTB4

Leukotriene B4

FDA

Food and drug administration

BMI

BMI

IL-18

Interleukin-18

IL-6

Interleukin-6

TNF-α

Tumor necrosis factor alpha

NF-κB

Nuclear factor-kappa B

TLR4

Toll-like receptor 4

PPARγ

Peroxisome proliferator-activated receptor gamma

TG

Triglycerides

VLDL-C

Very-low-density lipoprotein cholesterol

HDL

High-density lipoprotein

4-HNE

4-hydroxy-2-nonenal

ALA

α-linolenic acid

ALL

Acute lymphoblastic leukemia

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

BDNF

Brain-derived neurotrophic factor

BI

Indirect bilirubin

BT

Total bilirubin

BUN

Blood urea nitrogen

CK-MB

Creatine kinase-MB

Cr

Creatinine

cTnI

Cardiac troponin I

Cys-C

Cystatin C

DHA

Docosahexaenoic acid

DHA-PL

Docosahexaenoic acid-enriched phospholipids

DOX

Doxorubicin

EPA

Eicosapentaenoic acid

EPA-PL

Eicosapentaenoic acid-enriched phospholipids

FA

Fatty acid

GGT

γ-glutamyl transpeptidase

GPX

Glutathione peroxidase

GSH

Glutathione

GSK-3β

Glycogen synthase kinase 3 beta

HO-1

Heme oxygenase 1

IL

Interleukin

KIM-1

Kidney injury molecule-1

LV

Left ventricle

MDA

Malondialdehyde

MTX

Methotrexate

NO

Nitric oxide

pAKT

Phosphorylated AKT

PI3K

Phosphatidylinositol 3-kinase

PUFA

Polyunsaturated fatty acids

ROS

Reactive oxygen species

SOD

Superoxide dismutase

Soy-PL

Soy phospholipids

TAC

Total antioxidant capacity

TNF

Tumor necrosis factor

ω-3FA

Omega-3 fatty acids

NIH

National institutes of health

Author contributions

Conceptualization, T.E.L., C.S.S., and V.H.L.; methodology, M.S.R., C.L.M, and A.G.A.; investigation, T.E.L., C.S.S, M.S.R, M.C.H, P.V.C., and A.P.N.; resources, M.C.H, P.V.C., and A.P.N.; data curation, G.G.A., V.H.L., and A.G.A.; writing—original draft. preparation, M.S.R, T.E.L; writing— review and editing; C. L.M., A.G.A., V.H.L., G.G.A and P.V.C., A.P.N., M.C.H; visualization; A.G.A., C.S.S., M.C.H. All authors have read and agreed to the published version of the manuscript.

Funding

This paper is supported by program E022 of the National Institute of Pediatrics.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.