ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains cell survival and promotes cancer metastasis in cancer cells. Ferroptosis is a type of cell necrosis caused by an overload of lipid oxidation, which has been demonstrated to be involved in cancer cell metastasis. However, the mechanism by which fatty acid metabolism regulates the anti-ferroptosis signaling pathways is not fully understood. The formation of ovarian cancer spheroids helps to counteract the hostile microenvironment of the peritoneal cavity with low oxygen, shortage of nutrients, and subjected to platinum therapy. Previously, we demonstrated that Acyl-CoA synthetase long-chain family member 1 (ACSL1) promotes cell survival and peritoneal metastases in ovarian cancer, but the mechanism is still not well elucidated. In this study, we demonstrate that the formation of spheroids and under exposure to platinum chemotherapy increased the levels of anti-ferroptosis proteins as well as ACSL1. Inhibition of ferroptosis can enhance spheroid formation and vice versa. Genetic manipulation of ACSL1 expression showed that ACSL1 reduced the level of lipid oxidation and increased the resistance to cell ferroptosis. Mechanistically, ACSL1 increased the N-myristoylation of ferroptosis suppressor 1 (FSP1), resulting in the inhibition of its degradation and translocation to the cell membrane. The increase in myristoylated FSP1 functionally counteracted oxidative stress-induced cell ferroptosis. Clinical data also suggested that ACSL1 protein was positively correlated with FSP1 and negatively correlated with the ferroptosis markers 4-HNE and PTGS2. In conclusion, this study demonstrated that ACSL1 enhances antioxidant capacity and increases ferroptosis resistance by modulating the myristoylation of FSP1.

Automated summary

Reprogramming of lipid metabolism affects energy utilization and cell signaling in cancer cells, contributing to cell survival and metastasis. Ferroptosis, a form of necrosis caused by lipid oxidation overload, has been implicated in cancer metastasis. However, the mechanism by which fatty acid metabolism regulates anti-ferroptosis signaling pathways is not fully understood. This study demonstrates that the formation of ovarian cancer spheroids and exposure to platinum chemotherapy increase levels of anti-ferroptosis proteins, including ACSL1. Inhibition of ferroptosis enhances spheroid formation, while genetic manipulation of ACSL1 expression reduces lipid oxidation and increases resistance to ferroptosis by modulating the myristoylation of FSP1.