Dysregulation of the GPX4/ACSL4 axis mediates ferroptosis in neurons of T2DD rats

Introduction Diabetes mellitus complicated with depression (T2DD) is different from a single disease. It leads to more severe damage to nerve cells and cognitive dysfunction, and has a poor prognosis. Existing evidence indicates that ferroptosis—a form of programmed cell death driven by iron accumulation and lipid peroxidation—is involved in both diabetes and depression. Glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase family member 4 (ACSL4) are key regulators of ferroptosis, but their roles in T2DD-associated neural damage remain unclear. Methods In this study, we established a T2DD rat model using a high-fat diet combined with streptozotocin injection and chronic unpredictable mild stress and performed behavioral tests to assess depressive-like behaviors. Meanwhile, HT22 hippocampal neuronal cells were exposed to high glucose and corticosterone to simulate an in vitro model of T2DD. We investigated the role of the GPX4/ACSL4 axis in ferroptosis in the primary somatosensory cortex. Results In vivo , T2DD rats exhibited reduced spontaneous activity, aggravated neuronal damage, Fe 2+ accumulation in the cortical region, elevated oxidative stress, upregulation of CSL4/NCOA4 expression, and downregulation of GPX4/SLC7A11 expression, indicating that T2DD exacerbates neural damage. In vitro , high glucose (50 mM) and corticosterone (200 μM) synergistically reduced HT22 cell viability, increased reactive oxygen species (ROS) levels, and induced JC-1 and Ca 2+ alterations suggesting mitochondrial depolarization and aggravated mitochondrial damage, further complementing the above conclusions. Notably, treatment with the ACSL4 inhibitor AS252424 reversed the abnormalities in reactive oxygen species, Fe 2+ , and malondialdehyde levels induced by RSL3 (a GPX4 inhibitor), while restoring glutathione (GSH) levels and Adenosine Triphosphate suggesting that dysregulation of the GPX4/ACSL4 axis may be the central mechanism underlying ferroptosis and neuronal damage in T2DD. Conclusion This study reveals the role of ferroptosis in the T2DD model and provides new insights into therapeutic interventions targeting lipid metabolism pathways.