Historical rise of cancer and dietary linoleic acid: Mechanisms and therapeutic strategies

Over the past century, dietary intake of linoleic acid (LA), an essential omega-6 fatty acid, has risen markedly in industrialized regions, largely due to industrial seed oils (<i>e.g.</i>, soybean oil). This trend parallels increased cancer incidence, though causality remains unestablished. LA's susceptibility to oxidation may generate reactive species, such as 4-hydroxynonenal, potentially inducing oxidative stress and lipid peroxidation in cellular membranes. Furthermore, excess LA might elevate pro-inflammatory eicosanoid levels (<i>e.g.</i>, prostaglandin E2) and disrupt gut microbiota, fostering dysbiosis and immune dysregulation. Evidence, however, derives primarily from preclinical studies, with limited human data but epidemiological signals are strongest for breast (age-standardized incidence, approximately 130/100000 women), colorectal (approximately 39/100000), prostate (approximately 112/100000 men) and cutaneous melanoma (approximately 26/100000) cancers, where higher LA biomarkers or intakes have been repeatedly observed. Ketogenic diets, historically prioritized for metabolic benefits, reduce blood glucose, an effect possibly beneficial in cancer contexts, but may impair gut health by restricting fermentable fiber, potentially decreasing short-chain fatty acid production. This review explores LA's hypothetical role in cancer-related pathways and the trade-offs of carbohydrate restriction. A proposed "terrain restoration" protocol, emphasizing reduced LA intake, gradual carbohydrate reintroduction to support microbiota, and nutrients like pentadecanoic acid (C15:0) for mitochondrial function, lacks clinical validation. While optimizing diet to bolster metabolic and immune resilience holds promise for cancer prevention, rigorous research is essential.