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

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

4-HNE: 4-hydroxynonenal; HIF-1α: Hypoxia-inducible factor-1α; LA: Linoleic acid; RCTs: Randomized controlled trials; ETC: Electron transport chain; ROS: Reactive oxygen species.