MTF1 attenuates ferroptosis and cuproptosis synergistic potentiation in gastric cancer.

The recent discovery of cell death mediated by metal ions has aroused significant interest in harnessing this novel mechanism of cell death for cancer therapy. As the two identified metal ion-based regulated cell death forms, ferroptosis and cuproptosis were initially studied separately, while increasing evidences underscored their intricate connections. Gastric cancer (GC) is one of the most severe malignant tumors of the digestive system. Targeting the complex interplay between ferroptosis and cuproptosis, and understanding their intrinsic mechanisms may offer approaches for developing innovative therapies in GC. Here, we identified that metal-regulatory transcription factor 1 (MTF1) was the key gene blocking the sensitivity of ferroptosis and cuproptosis enhanced by the combination treatment with FINO2 and ES-Cu in vitro and in vivo. Mechanistically, MTF1 suppressed FINO2/ES-Cu induced ferroptosis through upregulating FTH1 to reduce Fe2+ levels. In addition to direct transcriptional upregulation of FTH1, MTF1 activated TRIM31. Subsequently, TRIM31 catalyzed ubiquitination of NCOA4 and also promoted the expression of FTH1. On the other hand, it also activated iron-sulfur cluster assembly 2 (ISCA2)-mediated iron-sulfur cluster (ISC) assembly and iron starvation response to inhibit cuproptosis and ferroptosis. Collectively, our findings indicated the mechanism of the synergistic effect of ferroptosis and cuproptosis in the treatment of GC and presented a prospective therapeutic strategy through elucidating the molecular mechanism of ferroptosis and cuproptosis mediated by MTF1.