2. Academic Validation
  3. Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype

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

  • Adv Sci (Weinh). 2025 Jul 29:e05436. doi: 10.1002/advs.202505436.
Sébastien Ibanez 1,  Maria Virginia Giolito 1,  Sultan Al-Siyabi 1,  Kristian Serafimov 1 2,  Florine Laloux 1,  Emeline Dierge 1 3,  Léo Aubert 1,  Céline Guilbaud 1,  Selena Kaye 1,  Paula Varon 1,  Dorothée Marchand 1,  Hanne Vlieghe 4,  Emmanuel Hermans 5,  Caroline Bouzin 6,  Davide Brusa 7,  Christiani Andrade Amorim 4,  Barabara Pachikian 8,  Yvan Larondelle 3,  Cyril Corbet 1 9,  Chantal Dessy 1,  Olivier Feron 1 2 9
Affiliations

Affiliations

  • 1 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, B-1200, Belgium.
  • 2 IREC Metabolomics Core, UCLouvain, Brussels, B-1200, Belgium.
  • 3 Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, B-1348, Belgium.
  • 4 Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, B-1200, Belgium.
  • 5 Group of Neuropharmacology, Institute of Neuroscience, UCLouvain, Brussels, B-1200, Belgium.
  • 6 Imaging Platform 2IP, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, B-1200, Belgium.
  • 7 CytoFlux-Flow Cytometry and Cell Sorting Platform, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, B-1200, Belgium.
  • 8 Center of Investigation in Clinical Nutrition, UCLouvain, Louvain-la-Neuve, B-1348, Belgium.
  • 9 Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) department, WEL Research Institute, Wavre, B-1300, Belgium.
PMID: 40726407 DOI: 10.1002/advs.202505436
Abstract

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.

Keywords

acidosis; cancer; fatty acid; lipid metabolism; peroxisome.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z