The ubiquitin-proteasome system (UPS) is composed of E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase, which play a fundamental role in mediating intracellular protein degradation. Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. However, the key pathway for UPS to promote ferroptotic cell death is still poorly understood. Here, we screened 571 UPS-related E1, E2, and E3 genes in a human pancreatic cancer cell line (PANC1) and identified the upregulation of NEDD4-like E3 ubiquitin protein ligase (NEDD4L) as a novel ferroptosis suppressor. Mass spectrometry analysis further showed that lactotransferrin (LTF), an iron-binding transport protein, is a direct NEDD4L-binding protein. Consequently, NEDD4L-mediated LTF protein degradation inhibits intracellular iron accumulation and subsequent oxidative damage-mediated ferroptotic cell death in various cancer cells. These findings establish a new molecular link between UPS and ferroptosis, which may lead to the development of potential anticancer strategies. (C) 2020 Elsevier Inc. All rights reserved.