Copyright
©The Author(s) 2025.
World J Clin Oncol. Sep 24, 2025; 16(9): 110686
Published online Sep 24, 2025. doi: 10.5306/wjco.v16.i9.110686
Published online Sep 24, 2025. doi: 10.5306/wjco.v16.i9.110686
Table 1 Twentieth-century surge in dietary and adipose linoleic acid with parallel rise in United States cancer incidence
Decade | Per-capita linoleic acid intake (% kcal) | Adipose-tissue linoleic acid (% fatty acid) | Age-adjusted total cancer incidence (per 100000) | Key dietary milestone |
1900s | 1-2 | N/A | Approximately 90 | Minimal seed-oil use |
1950s | 3-4 | Approximately 8% | Approximately 180 | Margarine adoption |
1980s | 6-7 | Approximately 14% | Approximately 310 | Widespread soybean oil |
2000s | 7-8 | Approximately 18% | Approximately 460 | Ultra-processed foods |
Table 2 Associations between linoleic acid and cancer risk or progression
Cancer type | Study design | Key findings/interpretation | Ref. |
Breast (ER+/ER-) | Mendelian randomization (United Kingdom Biobank) | Genetically elevated plasma LA was associated with increased risk of ER+ breast cancer. This suggests a potential causal relationship, though dietary intake thresholds were not assessed. No control population consuming < 5% LA of total daily energy | [263] |
Triple-negative breast cancer | Tumor metabolomics + xenograft | LA served as a key metabolic substrate driving tumor progression via upregulated β-oxidation and PPARα signaling. In vivo, LA supplementation accelerated triple-negative breast cancer tumor growth. Effect not observed under low-LA feeding | [13] |
Prostate | Dose-response meta-analysis of prospective cohorts | No consistent association between dietary or biomarker LA and prostate cancer risk. Studies lacked low-LA intake arms (< 5% of daily calories), limiting ability to detect nonlinear effects | [31] |
Non-small-cell lung | United Kingdom Biobank (plasma LA) | Higher circulating LA associated with significantly reduced incidence of non-small-cell lung. LA was inversely associated with time to diagnosis and overall risk. Relationship limited to biomarker data; dietary LA thresholds not stratified | [264] |
Lung (all histologies) | Prospective cohort (plasma fatty acids) | Circulating LA inversely associated with lung cancer risk across histologic subtypes. No evidence of U-shaped risk or high-LA threshold effects. No low-intake (< 5% energy) group included | [265] |
Pancreatic | Case-control (PanC Consortium) | Slight inverse association between LA intake and pancreatic cancer risk. Association was non-linear, with attenuation at higher intakes. No stratification by low-LA consumption | [266] |
Colorectal | Meta-analysis of dietary + biomarker studies | Pooled analysis found modestly increased colorectal cancer risk with higher LA intake. Effect stronger for dietary LA vs plasma biomarker. Studies lacked representation of < 5% LA intake groups | [29] |
Colorectal (sub-site stratified) | Pooled analysis (54 studies + 4 Mendelian randomization) | Increased risk particularly for rectal cancer. No protective effect observed. Sub-group analysis suggests dose-response relationship, but low-LA intake not studied | [11] |
Colon | Animal + human tissue (CYP- epoxyoctadecenoic acids mechanism) | LA-rich diets led to higher levels of pro-inflammatory epoxyoctadecenoic acids via CYP metabolism, promoting colonic tumorigenesis. Effects confirmed in human samples. No low-LA comparator group included | [267] |
Colon and rectum | EPIC-InterAct (plasma phospholipid LA) | Plasma LA not significantly associated with colorectal cancer risk. Null finding, but biomarker variability may mask associations. No data on dietary intake below 5% energy from LA | [268] |
Kidney | Pan-cancer Mendelian randomization | Genetically predicted higher LA levels associated with increased kidney cancer risk. Suggests possible causal effect. No reference to real-world low-LA cohorts | [269] |
Hepatocellular carcinoma | Tumor microenvironment analysis | LA uptake enhanced tumor cell proliferation via upregulation of LINC01116 and fatty acid metabolism genes. Supported LA’s role as an oncometabolite in hepatocellular carcinoma | [270] |
Hepatocellular carcinoma | TCGA/ICGC multi-omics prognostic modeling | High LA metabolic activity (gene expression signature) correlated with reduced survival and more aggressive tumor phenotypes. LA-related metabolic pathways proposed as therapeutic targets | [271] |
Gastric adenocarcinoma | EPIC-EURGAST (plasma phospholipids) | No significant association between plasma LA and gastric cancer risk. Very limited range of dietary intake in cohort; < 5% energy LA group not present | [272] |
Cervical | Radiotherapy cohort (serum + fecal metabolomics) | Patients with low serum and fecal LA at baseline showed poorer nutritional status and worse treatment response. Unclear if LA was causally protective or a marker of overall intake | [273] |
Table 3 Mechanistic evidence linking high dietary linoleic acid metabolic and microbial dysregulation, and the remaining research gaps
Mechanism | Preclinical finding (model, effect size) | Corresponding human data | Evidence gap |
Lipid peroxidation and 4-HNE | Mouse skeletal muscle, 4-HNE adducts rise 3 × | Elevated plasma F2-isoprostanes with high-LA diets | Need RCTs on LA lowering |
Mitochondrial dysfunction | LA-rich cardiolipin increases ETC ROS 2 × in vitro | Limited biopsy evidence | Human tracer studies |
Succinate/HIF-1α axis | Succinate rose 2 ×, HIF-1α stabilized in LA-fed rats | Not yet tested | Clinical metabolomics |
Gut dysbiosis | High-LA diet reduces Faecalibacterium 40% (mouse) | Small keto-diet trial shows similar trend | Large human cohorts |
Table 4 Candidate strategies to mitigate linoleic acid-driven metabolic stress: Doses, biomarkers, and evidence landscape
Intervention | Proposed human dose | Primary target | Expected biomarker change | Evidence level | Ref. |
Dietary LA reduction | ≤ 3% total kcal | Lipid peroxidation | F2-isoprostanes decreased 20% in 12 weeks | RCT-pilot | [42,228,274] |
Pentadecanoic acid (C15:0) | 100-200 mg/day | AMPK/SDH restoration | Succinate decreased 30% (rodent) | Preclinical | [150,229,230] |
Low-dose aspirin | 75-100 mg/day | COX-2/PGE2 axis | Serum PGE2 decreased 50% in 24 hours | Observational + RCT-CV | [231-234] |
Intermittent fasting | 16:8 daily | Autophagy induction | LC3-II flux rose 2 × (mouse) | Early human | [235-238] |
- Citation: Mercola J. Historical rise of cancer and dietary linoleic acid: Mechanisms and therapeutic strategies. World J Clin Oncol 2025; 16(9): 110686
- URL: https://www.wjgnet.com/2218-4333/full/v16/i9/110686.htm
- DOI: https://dx.doi.org/10.5306/wjco.v16.i9.110686