S-palmitoylation of MTDH regulates ferroptosis resistance in breast cancer cell

S -palmitoylation is a dynamic and reversible post-translational modification that plays crucial roles in cancer progression. Here, we found the oncogene of metadherin (MTDH) modulates lipid metabolism and ferroptosis by its S -palmitoylation. We demonstrate that MTDH is S -palmitoylated at Cys-75 in the endoplasmic reticulum by ZDHHC1/9 and S -depalmitoylated by APT1. The flexible loop and the α-helix length in the MTDH N-terminus affect its S -palmitoylation level. In addition, metabolomics analysis found that the S -palmitoylated MTDH increases intracellular levels of triglycerides, phosphatidylethanolamines, and phosphatidylcholines. However, the non- S -palmitoylation form of MTDH-CS enhanced the interaction of between MTDH and the ferroptosis enhancer of Acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby reducing ferroptosis sensitivity in breast cancer cell. Taken together, targeting MTDH S -palmitoylation may represent a novel strategy for breast cancer therapy.