Alpha-linolenic acid in cancer: a predictive fate-switch framework for tumor lipid reprogramming.

Alpha-linolenic acid (ALA) is the major plant-derived omega-3 fatty acid in human diets, yet its relevance to cancer is often narrowly interpreted as a precursor to eicosapentaenoic acid and docosahexaenoic acid. Here we propose a predictive fate-switch framework that treats ALA as a dietary lipid input whose biological output is dictated by tumor-intrinsic routing after uptake. Five competing fates are identified-membrane phospholipid incorporation; elongation and desaturation mediated by fatty acid desaturases (FADSs) and elongases of very-long-chain fatty acids (ELOVLs); lipid-droplet buffering; mitochondrial β-oxidation; and peroxidation-prone phospholipid enrichment-each governed by distinct molecular checkpoints. We organize these routes into three dominant but potentially overlapping tumor metabolic states: conversion-prone, storage-buffered, and peroxidation-vulnerable, which yield specific and testable predictions. For example, ALA is expected to exert stronger oxidative or ferroptosis-related effects in tumors with high polyunsaturated fatty acid (PUFA)-phospholipid incorporation and weak peroxide defense, but weaker effects where it is sequestered into neutral lipid pools. Accordingly, future studies should prioritize direct assessment of ALA fate through lipidomics, isotope tracing, and redox profiling rather than relying on intake or exposure alone. We recognize that direct ALA-specific evidence remains uneven across mechanisms-most notably in ferroptosis. Rather than undermining the framework, this unevenness defines its priority testing ground, transforming evidence gaps into actionable explorations.