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 that 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. The non-S-palmitoylation form of MTDH-CS enhanced the interaction between MTDH and the ferroptosis enhancer of Acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby reducing ferroptosis sensitivity in breast cancer cells.