OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, plays a significant role in pancreatic β-cell failure associated with diabetes. In this study, we investigated how 2-deoxy-d-ribose (dRib) induces ferroptosis in β-cells and identified the OTUB1-SLC7A11 axis as a critical regulatory mechanism. Using rat insulinoma-derived RIN5mF cells and isolated rat islets, we found that dRib exposure markedly impaired cystine uptake via system χc^-, resulting in intracellular glutathione (GSH) depletion, accumulation of lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal, and increased lipid reactive oxygen species (ROS). Although SLC7A11 mRNA levels were upregulated, its protein levels were reduced due to increased ubiquitination and proteasomal degradation. Further analysis revealed that dRib suppressed the expression of OTUB1, a deubiquitinating enzyme that directly interacts with SLC7A11 and inhibits its ubiquitination. Overexpression of either OTUB1 or SLC7A11 restored cystine transport, replenished GSH levels, reduced lipid ROS and cell death, supporting their protective roles against ferroptosis. Transmission electron microscopy confirmed that dRib induced mitochondrial morphological changes consistent with ferroptosis, such as shrinkage and cristae loss. These findings demonstrate that the loss of OTUB1 promotes ferroptosis in pancreatic β-cells through destabilization of SLC7A11. Targeting the OTUB1-SLC7A11 pathway may offer a novel therapeutic approach for preserving β-cell survival and preventing the progression of diabetes.