Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation; however, how selective autophagy regulates ferroptotic sensitivity remains incompletely understood. Here, we identify RAB8A as a selective autophagic substrate and negative regulator of ferroptosis. Quantitative proteomic analyses reveal that ferroptotic stress induces ATG5- and ATG7-dependent degradation of RAB8A. Mechanistically, ferroptotic stimuli induce RNF126-dependent polyubiquitination of RAB8A and subsequent SQSTM1-mediated autophagic degradation. Functionally, loss of RAB8A sensitizes cancer cells to ferroptosis, whereas expression of the degradation-resistant active mutant RAB8AQ67L suppresses ferroptotic cell death. RAB8A interacts with TFRC and facilitates stress-induced redistribution of TFRC from the plasma membrane toward endolysosomal compartments. RAB8A deficiency impairs TFRC clearance, enhances transferrin-dependent iron uptake, and increases intracellular Fe2+ accumulation and lipid peroxidation. In fibrosarcoma and pancreatic cancer xenograft models, RAB8A depletion enhances the antitumor efficacy of ferroptosis-inducing therapy. Clinically, RAB8A is upregulated and associated with poor prognosis and ferroptosis resistance in pancreatic cancer. Collectively, these findings establish an autophagy-RAB8A-TFRC axis that regulates ferroptotic sensitivity.
