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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
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
1900s1-2N/AApproximately 90Minimal seed-oil use
1950s3-4 Approximately 8% Approximately 180Margarine adoption
1980s6-7 Approximately 14%Approximately 310Widespread soybean oil
2000s7-8Approximately 18% Approximately 460Ultra-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 cancerTumor metabolomics + xenograftLA 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]
ProstateDose-response meta-analysis of prospective cohortsNo 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 lungUnited 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]
PancreaticCase-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]
ColorectalMeta-analysis of dietary + biomarker studiesPooled 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]
ColonAnimal + 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 rectumEPIC-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]
KidneyPan-cancer Mendelian randomizationGenetically predicted higher LA levels associated with increased kidney cancer risk. Suggests possible causal effect. No reference to real-world low-LA cohorts[269]
Hepatocellular carcinomaTumor microenvironment analysisLA 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 carcinomaTCGA/ICGC multi-omics prognostic modelingHigh 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 adenocarcinomaEPIC-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]
CervicalRadiotherapy 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-HNEMouse skeletal muscle, 4-HNE adducts rise 3 ×Elevated plasma F2-isoprostanes with high-LA dietsNeed RCTs on LA lowering
Mitochondrial dysfunctionLA-rich cardiolipin increases ETC ROS 2 × in vitroLimited biopsy evidenceHuman tracer studies
Succinate/HIF-1α axisSuccinate rose 2 ×, HIF-1α stabilized in LA-fed ratsNot yet testedClinical metabolomics
Gut dysbiosisHigh-LA diet reduces Faecalibacterium 40% (mouse)Small keto-diet trial shows similar trendLarge 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 kcalLipid peroxidationF2-isoprostanes decreased 20% in 12 weeksRCT-pilot[42,228,274]
Pentadecanoic acid (C15:0)100-200 mg/dayAMPK/SDH restorationSuccinate decreased 30% (rodent)Preclinical[150,229,230]
Low-dose aspirin75-100 mg/dayCOX-2/PGE2 axisSerum PGE2 decreased 50% in 24 hoursObservational + RCT-CV[231-234]
Intermittent fasting16:8 dailyAutophagy inductionLC3-II flux rose 2 × (mouse)Early human[235-238]