Antagonistic SUMOylation and Ubiquitination of ACSL4 Control Ferroptosis in Colorectal Cancer

Abstract Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and represents a therapeutic vulnerability in cancer. ACSL4 is a critical regulator of ferroptosis, yet how its activity is post-translationally regulated remains unclear. Here, we identify a SUMO–ubiquitin switch that controls ACSL4 dimerization, enzymatic activity, and ferroptosis. ACSL4 undergoes both SUMOylation and ubiquitination at K661. SUMOylation suppresses ACSL4 dimer formation and activity, whereas ubiquitination promotes dimerization and ferroptotic function. This antagonistic regulation is driven by competitive binding of the SUMO E3 ligase PIAS1 and the ubiquitin E3 ligase CBL to ACSL4. Inhibition of ACSL4 SUMOylation enhances lipid peroxidation, promotes ferroptosis, and suppresses tumor growth. These findings uncover a post-translational mechanism that precisely regulates ACSL4 activity and ferroptosis, and suggest that targeting ACSL4 SUMOylation may enhance the efficacy of ferroptosis-based antitumor therapy.