Extra Virgin Olive Oil as an Anti-Cytokine Shield: What It Means for Cancer and Muscles

Nutrients has published a large review on how the key components of extra virgin olive oil (EVOO) - hydroxytyrosol, oleocanthal, oleuropein, tyrosol and tocopherols - interfere with inflammatory pathways that link chronic inflammation and cancer. The authors bring together data from cellular and animal experiments and show that EVOO polyphenols suppress proinflammatory cytokines (TNF-α, IL-6), inhibit NF-κB/STAT3, activate the antioxidant response Nrf2 - and against this background, weaken tissue damage, tumor cell proliferation and metabolic breakdowns of skeletal muscle. A special emphasis is on cancer cachexia: systemic inflammation and a "cytokine storm" accelerate the breakdown of muscle protein, and EVOO bioactives potentially shift the balance towards preserving muscle mass.

Background

Chronic “low-grade” inflammation is a common denominator of many tumors and one of the key drivers of cancer cachexia: proinflammatory cytokines such as TNF-α and IL-6 activate NF-κB/JAK-STAT cascades, increase oxidative stress, shift muscle metabolism towards protein breakdown (ubiquitin-proteasome and autophagolysosomal systems), and worsen treatment tolerance. At the other extreme are dietary patterns with a low inflammatory load. The Mediterranean diet traditionally relies on extra virgin olive oil (EVOO) as the main source of fat; unlike refined oils, EVOO retains a rich set of phenolic compounds (hydroxytyrosol, oleocanthal, oleuropein, tyrosol, tocopherols), which in preclinical models reduce TNF-α/IL-6 expression, suppress NF-κB/STAT3, and activate the Nrf2 antioxidant response. In epidemiology and small intervention studies, an olive diet has been associated with lower CRP/IL-6 and a better metabolic profile; in parallel, there is growing interest in whether regular EVOO consumption may attenuate systemic inflammation in cancer patients and thereby protect skeletal muscle from catabolism.

An additional motive is the "gut-liver-muscle" axis. Barrier disturbances and microbial endotoxins enhance hepatic and systemic cytokine release, namely the intestine and liver are the first "targets" of dietary polyphenols. For EVOO, improvement of the red oxidative balance, reduction of TLR4/NF-κB signaling activity and partial normalization of the cytokine profile in models of colitis and metabolic liver damage have been described. Against this background, it is logical to test the extent to which individual EVOO components are able to modify proinflammatory pathways associated with tumor progression and muscle loss. Unresolved issues include dose dependence and bioavailability of phenols (they vary by variety, collection and extraction technology), tolerability in weakened patients, and most importantly, the presence of a clinically significant effect on "hard" cachexia outcomes. It is this context that leads to a review that systematically examines the interaction of EVOO polyphenols with cytokine networks in cancer and their possible impact on skeletal muscle biology.

What is this work and why is it needed?

• Article type: Narrative review focusing on the interactions of EVOO components and proinflammatory cytokines in the context of oncology and skeletal muscle biology.
• Key targets: TNF-α, IL-6, IFN-γ, LIF; NF-κB, JAK/STAT3, p38 MAPK signaling axes; Nrf2 antioxidant pathway.
• Practical context: from reducing inflammation in the intestine and liver to protecting muscle tissue in cachexia, a condition that worsens the prognosis, tolerability of therapy and survival of cancer patients.

In the intestine and liver, the picture is particularly clear. For example, in colon cell culture (Caco-2), oxysterols accelerate ROS and the release of IL-8/IL-6/iNOS - but pre-treatment with a phenolic extract of EVOO dampens this surge. In a model of colitis (DSS), a diet with EVOO reduced mortality and inflammatory markers (TNF-α, iNOS, p38 MAPK) and increased IL-10; enriching the oil with hydroxytyrosol enhanced the effect. In the liver, EVOO polyphenols activate Nrf2, suppress NF-κB and ER stress (PERK), and reduce steatosis and fibrosis; in high-fat diets in mice, hydroxytyrosol reduced the expression of TNF-α and IL-6 and COX-2.

Which EVOO molecules “work” and what does it look like in experiments

• Hydroxytyrosol/oleuropein/tyrosol
  antioxidant "vacuuming" of free radicals, reduction of oxidative stress in vitro (10-100 μM) and in vivo (10-50 mg/kg/day); attenuation of IL-6/TNF-α release, suppression of iNOS/COX-2, inhibition of NF-κB.
• Oleocanthal
  anti-inflammatory action, crossing pain pathways (ibuprofen-like activity), inhibition of NF-κB and proinflammatory cascades; in the intestine - reduction of MPO activity and local cytokines.
• Systemic effects
  of HFD include decreased LPS load, proportion of TLR4⁺ macrophages in the gut/liver, and circulating TNF-α/IFN-γ.

The authors approach muscles from two sides. In moderate local inflammation (damage, training), TNF-α and IL-6 participate in regeneration and hypertrophy: stimulation of myoblast proliferation, recruitment of immune cells, initiation of differentiation. But in case of systemically high levels of cytokines (cancer, CHF, sepsis, diabetes), they shift the balance to catabolism: NF-κB activates ubiquitin-proteasome and autophagolysosomal protein degradation, and suppression of Akt/mTOR reduces synthesis; at the CNS level - anorexia and hypercorticism. In muscular dystrophy, blockade of the IL-6 receptor improved regeneration; similarly, modulation of IFN-γ changed the balance of "proliferation ↔ differentiation". It is in this picture that it is logical to consider EVOO polyphenols as an adjuvant that reduces the "cytokine background" and oxidative stress.

Figures and facts that set the scale of the problem

• Cachexia: complex hypercatabolic syndrome - loss of weight, fat and muscle mass, increased energy expenditure and mitochondrial dysfunction; occurs in 70-90% of cases in lung, liver and gastrointestinal cancers, and about 30% in breast cancer and "soft" lymphomas. There are still no effective standard therapies.
• Dietary background: A Mediterranean diet (with EVOO as the base fat) in clinical studies reduced TNF-α, CRP and IL-6, improved well-being and exercise tolerance - which indirectly supports the "anti-cytokine" hypothesis.

What this might mean in practice (cautious conclusions, not a treatment guide)

• EVOO is not a “cure-all” but an environmental resource. Incorporating EVOO as a staple cooking fat into a varied diet with a plant “core” is a way to reduce background inflammation, especially in the intestines and liver, where a significant proportion of cancer risks are formed.
• If there is a risk of cachexia (gastrointestinal, lung, liver tumors), it is reasonable to discuss with your doctor an anti-inflammatory dietary pattern (including EVOO, fish, vegetables, legumes) as an adjuvant to standard therapy, rather than a replacement for it.
• The form and dosage of biocomponents matter in experiments, but in real life it is better to focus on whole EVOO oil of guaranteed quality (polyphenol profile), and not on individual hydroxytyrosol “pills”.

Viewing Limitations

• This is a review of experimental and preclinical data supplemented with selected clinical studies; many effects are shown in cells and animals.
• Cytokine interactions are two-faced: IL-6/TNF-α are beneficial in acute repair and harmful in chronic overproduction; the goal is to modulate, not “turn everything off.”
• Cachexia is multifactorial: it cannot be stopped by diet alone; complex strategies are needed (exercise, nutritional support, anti-inflammatory and antitumor therapy).

The main points from the article

• EVOO polyphenols reduce TNF-α/IL-6 activity and downstream inflammatory cascades (NF-κB/STAT3), while activating Nrf2 protection.
• In the gut and liver, this is associated with less inflammation and damage, and in the oncologic context, with a less favorable environment for progression.
• In muscle, against the background of chronic inflammation, EVOO signals help shift the balance from protein breakdown to maintenance of function - an important argument in the risk of cachexia.

Source: De Stefanis D., Costelli P. Extra Virgin Olive Oil (EVOO) Components: Interaction with Pro-Inflammatory Cytokines Focusing on Cancer and Skeletal Muscle Biology. Nutrients 17(14):2334, July 16, 2025. Open access. https://doi.org/10.3390/nu17142334