Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype.

While proteins facilitate fatty acid (FA) partitioning into plasma membranes, movement between membrane leaflets occurs through a "flip-flop" mechanism. This study provides evidence that biological acidosis, as encountered in tumors and ischemic diseases, promotes FA protonation, thereby enhancing neutral, non-ionized FA uptake. This positions the altered lipid metabolism in acid-exposed cells as a consequence, rather than a cause, of preferential FA uptake. Cancer cell vulnerability, independent of their genetic background, directly stems from this paradigm shift, as detoxifying the overload of very long-chain FA (VLCFA) becomes highly dependent on peroxisomal activity. Inhibition of peroxisomal function in acid-exposed cancer cells leads to the rerouting of these fatty acids into triglycerides within lipid droplets, but also into phospholipids, contributing to membrane alterations, triggering ER stress, and ultimately supporting cytotoxicity. Using patient-derived tumor organoids and sera from human volunteers supplemented with polyunsaturated FA (PUFA), it is shown that inhibiting peroxisomal ACOX1 selectively kills acid-exposed cancer cells, an effect exacerbated by pharmacological stimulation of glycolysis. Similar acid-driven FA uptake is observed in endothelial cells and cardiac myocytes, opening new therapeutic avenues not only cancer but also cardiovascular diseases.