How walnuts combat inflammation and oxidative stress in the body

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Nov 3 2025

From protecting brain cells to modulating immunity, walnut bioactives demonstrate remarkable antioxidant and anti-inflammatory potential; however, scientists caution that human evidence remains sparse, and more translational work is needed.

A Review of Antioxidant Activity, Anti-Inflammatory Properties, Apoptosis-Regulatory Effects, and Immune System Modulation of Juglans regia L. (Walnut). Image Credit: Steidi / Shutterstock

In a recent review published in the journal Food Science & Nutrition, researchers summarized the immunomodulatory, antioxidant, and anti-inflammatory properties of walnuts. Most of the evidence synthesized in this review derives from in vitro and animal studies, with limited and heterogeneous human data, meaning that clinical relevance remains to be established. The authors also noted that walnuts can provoke allergic reactions in sensitive individuals, particularly due to the Jug r 2 allergen.

Inflammation, Oxidative Stress, and Disease Development

Chronic inflammation, oxidative stress, and immune dysregulation contribute to the development of various diseases. These factors have garnered substantial attention in recent years, warranting the development of new therapies. Herbal medicine is a promising area of medical research, offering potential treatments for inflammation, immune dysregulation, and oxidative stress.

Traditional Uses and Emerging Research on Walnuts

Juglans regia L. (walnut) is a deciduous tree native to regions in Eastern Asia, North America, and Southeastern Europe, and it has been a part of folk medicine across various countries. Walnuts possess diverse pharmacological effects, including immunomodulatory and antioxidant properties. In the present study, researchers reviewed the anti-inflammatory, immunomodulatory, and antioxidant properties of walnuts. They also summarized emerging findings on gut microbiota modulation by walnut components, such as the increased abundance of Lactobacillus and Akkermansia, which may contribute to anti-inflammatory activity.

Neuroprotective and Antioxidant Mechanisms of Walnuts

A study reported that rat primary hippocampal neurons pretreated with walnut extracts before exposure to lipopolysaccharide (LPS) were protected from calcium dysregulation and cell death. Similarly, pretreating pheochromocytoma 12 cells with walnut extracts before exposure to amyloid-β was found to reduce DNA damage, reactive oxygen species (ROS) generation, lactate dehydrogenase release, and cell death. These antioxidant effects have been partly linked to activation of the Nrf2 signaling pathway, which regulates cellular redox balance.

Further, a walnut-derived polypeptide was found to prevent mitochondrial bioenergetic deficits and reduce the opening of mitochondrial permeability transition pores in HT-22 cells (a hippocampal cell line) subjected to oxidative stress. One study demonstrated that pretreating human neuroblastoma cells with a walnut-derived tetrapeptide before exposure to hydrogen peroxide increased cell viability and reduced oxidative stress.

Metabolic and Cognitive Benefits Linked to Antioxidant Activity

Treatment of U937 cells, a human monocytic cell line, with walnut oil under hyperglycemic conditions increased their antioxidant capacity and superoxide dismutase (SOD) activity, although it did not protect against DNA or protein oxidative damage. Oral administration of walnut protein hydrolysates and low-molecular-weight fractions enhanced behavioral performance by increasing catalase, glutathione peroxidase, and SOD levels, while reducing malondialdehyde in the brains of rats with memory deficits.

Similarly, another study showed that a walnut suspension ameliorated memory function in rats with memory impairments. Furthermore, oral administration of the polyphenol fraction from walnuts was found to reduce an oxidative stress biomarker, 8-hydroxy-2′-deoxyguanosine, in mice with type 2 diabetes. Additionally, walnut leaf extracts have been found to lower triglycerides, low-density lipoprotein cholesterol, total cholesterol, and fasting blood glucose in diabetic rats. However, findings from acute human feeding trials have been mixed, with some studies reporting post-prandial improvements in oxidized LDL and tocopherol levels, while others found no consistent effects on triglycerides or endothelial function.

Anti-Inflammatory Pathways and Cellular Protection

A study demonstrated that the ethyl acetate fraction of walnuts was protective against cytotoxicity in HT-22 cells by ameliorating inflammatory responses. In human keratinocytes exposed to t-butyl hydroperoxide or tumor necrosis factor α (TNF-α), treatment with walnut extracts decreased the expression of inflammation-related genes. Notably, walnut oil exhibits both anti-inflammatory and pro-inflammatory effects in U937 cells depending on concentration and incubation time, highlighting the complexity of its biological response.

Further, walnut kernel extracts were found to decrease lung edema in rats with lung injury and acute inflammation. Treatment with glansreginin A, derived from walnut extracts, was found to ameliorate abnormal behavior in mice with LPS-induced inflammation. Moreover, walnuts were found to reduce hepatic triglycerides, pro-inflammatory gene expression, and macrophage infiltration in mice on a high-fat diet.

Moreover, a peptide derived from walnuts was found to decrease symptom severity during the development of colitis and restore gut dysbiosis in mice. Walnut leaf extracts were reported to ameliorate arthritis and acute inflammation in rats by attenuating TNF-α, interleukin (IL)-6, prostaglandin E2, cyclooxygenase 2, and IL-16.

Apoptosis Regulation and Anticancer Potential of Walnuts

Another study showed that a phenolic extract of walnut hulls increased caspase activity and apoptosis and reduced cell migration, proliferation, intracellular ROS, and mitochondrial membrane potential in bone tumor cells. Further, walnut green husk extracts inhibit proliferation and promote apoptosis in PC-3 cells (human prostate cancer cells). Similarly, walnut leaf extracts demonstrated anti-proliferative effects in breast cancer cells. These effects are partly mediated through the upregulation of pro-apoptotic Bax and the downregulation of anti-apoptotic Bcl-2 proteins, consistent with the activation of the intrinsic apoptosis pathway.

Green walnut husks have been reported to reduce tumor growth and induce apoptosis in CT26 cells, a mouse colon cancer cell line. In addition, treatment with walnut oligopeptides increased antioxidant defenses, facilitated hematopoietic recovery, and reduced weight loss in mice with intestinal injury induced by γ-irradiation; oligopeptide treatment was found to be crucial in decreasing intestinal barrier dysfunction and limiting radiation-induced apoptosis.

Immunomodulatory Effects and Immune System Enhancement

Treatment with walnut polyphenol extracts increased the proliferation of mouse splenocytes exposed to 3-methyl-4-nitrophenol or 4-pentylphenol, which are major constituents of car emissions, resulting in increases in the proportions of T cell subsets, as well as the production of cytokines and granzymes. In a mouse leukopenia model, walnut septa extracts were found to restore the inhibited myelopoiesis.

Furthermore, the administration of walnut oligopeptides led to substantial increases in humoral and cell-mediated immune responses, macrophage phagocytosis, and natural killer cell activity in mice. Walnut leaf extracts have been found to decrease arthritic progression, paw swelling, and improve various tissue outcomes in rodents.

Summary of Therapeutic Promise and Research Gaps

Taken together, walnuts exhibit substantial anti-inflammatory, apoptosis-regulatory, antioxidant, and immunomodulatory properties. The rich phytochemical profile of walnuts contributes to their therapeutic potential against inflammation and oxidative stress. In addition to these benefits, the review highlights that most evidence remains preclinical, and further mechanistic and translational studies are necessary to clarify pathways, assess microbiome interactions, and confirm safety, including allergenicity, in human populations.