Arachidonic acid-induced PLIN phosphorylation activates lipophagy and further promotes chemoresistance in colorectal cancer

Resistance to 5-fluorouracil-based chemotherapies presents a major clinical challenge in colorectal cancer (CRC) treatment, leading to elevated recurrence rates. Recent findings indicate that enhanced metabolic plasticity in cancer cells plays a crucial role in drug resistance development, though the exact mechanisms remain uncertain. In this study, we demonstrate that the lipophagy-triggered fatty acid oxidation (FAO) is involved in maintaining the adenosine triphosphate (ATP) levels upon drug administration. Using mass spectrometric imaging, we identified arachidonic acid (AA) as a critical lipid mediator of intracellular selective autophagy and energy balance in resistant cancer cells. The high level of arachidonate metabolism was associated with poor response to chemotherapy in clinical practice. Mechanistically, accumulated AA induced phosphorylation of PLINs via the LOXs/PKCζ pathway and stimulated the production of free fatty acid (FFA) driven by lipophagy. Importantly, we further certified that inhibition of AA-associated lipophagy specifically sensitize drug-resistant colorectal cancer cells to chemotherapy. This study offers insights into the mechanism of acquired chemoresistance, suggesting that targeting AA-associated lipophagy could be a potential therapeutic strategy to overcome drug resistance in colorectal cancer.