USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer

Gastric cancer (GC) ranks as the third leading cause of cancer-related mortality. Chemoresistance poses a major obstacle to successful treatment for GC patients. Here, we demonstrate that ferroptosis suppressor protein 1 (FSP1) enables chemoresistance in GC by inhibiting ferroptosis, resulting in diminished chemotherapy response and reduced patient survival rate. USP29 and SMURF1 are subsequently discovered as the deubiquitinase and E3 ligase of FSP1, respectively, orchestrating the ubiquitination of FSP1 to modulate ferroptosis and chemoresistance in GC. In the ubiquitination process, SMURF1 is observed to interact with and polyubiquitinate FSP1 within K63/K193 sites. Notably, pharmacological inhibition of FSP1 by iFSP1 is shown to synergize with chemotherapeutic agents across chemoresistant cellular and mouse models. Our findings thus underscore the pivotal role of the USP29 and SMURF1 in regulating GC chemoresistance via FSP1-mediated ferroptosis suppression. FSP1 inhibition may represent a promising therapeutic avenue to overcome chemoresistance in GC. Regulated cell death and its dysregulation may contribute to chemoresistance. Here, the authors show that Ferroptosis Suppressor Protein 1 (FSP1) promotes chemoresistance in gastric cancer in part by suppressing ferroptosis.