Copper-dependent autophagic degradation of GPX4 drives ferroptosis

TLDR

Ferroptosis is an iron‑dependent regulated cell death driven by lipid peroxidation, and GPX4 normally blocks this process by reducing phospholipid hydroperoxides, though its regulation is poorly understood. The study investigates how copper promotes ferroptosis by triggering autophagic degradation of GPX4. Copper binds GPX4 cysteines C107 and C148, inducing ubiquitination and aggregation that are recognized by TAX1BP1, which mediates autophagic degradation of GPX4 and drives ferroptosis. Copper chelators diminish ferroptosis sensitivity without affecting apoptosis, necroptosis, or alkaliptosis, whereas exogenous copper promotes GPX4 ubiquitination and aggregation, leading to enhanced ferroptosis‑mediated tumor suppression in pancreatic cancer and reduced acute pancreatitis in mice. These results reveal a novel link between metal stress and autophagy‑dependent cell death.

Abstract

Ferroptosis is a type of iron-dependent regulated cell death characterized by unrestricted lipid peroxidation and membrane damage. Although GPX4 (glutathione peroxidase 4) plays a master role in blocking ferroptosis by eliminating phospholipid hydroperoxides, the regulation of GPX4 remains poorly understood. Here, we report an unexpected role for copper in promoting ferroptotic cell death, but not cuproptosis, by inducing macroautophagic/autophagic degradation of GPX4. Copper chelators reduce ferroptosis sensitivity but do not inhibit other types of cell death, such as apoptosis, necroptosis, and alkaliptosis. Conversely, exogenous copper increases GPX4 ubiquitination and the formation of GPX4 aggregates by directly binding to GPX4 protein cysteines C107 and C148. TAX1BP1 (Tax1 binding protein 1) then acts as an autophagic receptor for GPX4 degradation and subsequent ferroptosis in response to copper stress. Consequently, copper enhances ferroptosis-mediated tumor suppression in a mouse model of pancreatic cancer tumor, whereas copper chelators attenuate experimental acute pancreatitis associated with ferroptosis. Taken together, these findings provide new insights into the link between metal stress and autophagy-dependent cell death.Abbreviations: CALCOCO2, calcium binding and coiled-coil domain 2; GPX4, glutathione peroxidase 4; MAP1LC3A/B, microtubule associated protein 1 light chain 3 alpha/beta; MPO, myeloperoxidase; NCOA4, nuclear receptor coactivator 4; OPTN, optineurin; PDAC, pancreatic ductal adenocarcinoma; RIPK1, receptor interacting serine/threonine kinase 1; ROS, reactive oxygen species; SLC40A1, solute carrier family 40 member 1; SQSTM1, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TM, tetrathiomolybdate.