L-Se-methylselenocysteine alleviates iron deposit-induced anxiety- and depression-like behaviors in chronic renal failure rats receiving iron therapy via Nrf2/GPX4 activation

Objective: Iron supplements are routinely administered for renal anemia in patients with end-stage renal disease (ESRD). However, the association between cerebral iron overload and neuropsychiatric symptoms in this patient population remains elusive. This study aimed to investigate these associations and elucidate the potential protective effects and underlying mechanisms of L-Se-methylselenocysteine (L-SeMC). Methods: A human cohort comprised 23 iron-overloaded ESRD patients and 23 healthy controls (HCs), who underwent neuropsychological assessment and quantitative susceptibility mapping (QSM) to evaluate anxiety, depression, and cerebral iron deposition. For animal experiments, 32 rats were divided into Control, CRF (Chronic Renal Failure), CRF + Fe, and CRF + Fe + Se groups. The CRF model was established by adenine gavage, followed by iron sucrose injection for renal anemia. Behavioral tests, magnetic resonance imaging (MRI), histological staining, Western blot, and bioinformatics analysis were performed. Results: In the human cohort, ESRD patients showed significantly higher Beck Depression Inventory scores than HCs (P < 0.001). QSM revealed increased magnetic susceptibility in the ventromedial prefrontal cortex (PFC) and hippocampus, which was positively correlated with depression severity. In animal experiments, L-SeMC intervention reduced serum creatinine and blood urea nitrogen levels in CRF + Fe rats, alleviated renal pathological damage, and decreased hippocampal/PFC iron deposition. Histologically, L-SeMC restored Nissl body content and reduced Fluoro-Jade B (FJB) -positive neuronal cells in hippocampus/PFC (P < 0.05). Behavioral tests showed L-SeMC reversed iron-induced anxiety- and depression-like behaviors. Bioinformatics analysis highlighted erythroid 2-related factor 2 (Nrf2) as a hub gene within the selenium–ferroptosis regulatory network. Western blot confirmed L-SeMC upregulated Nrf2, glutathione peroxidase 4 (GPX4), while concurrently downregulating transferrin receptor 1 (TFR1) expression in the hippocampus and PFC of CRF + Fe rats (P < 0.05). Conclusion: L-SeMC alleviates iron overload-induced anxiety- and depression-like phenotypes in CRF rats by attenuating cerebral iron accumulation and activating the Nrf2/GPX4 pathway, thereby supporting its translational potential as an adjuvant therapy for CRF patients receiving iron supplements.