Risperidone induces osteoporosis and neuropsychiatric treatment resistance via SMPD1-lysosome-mediated ferroptosis: dual rescue by active vitamin D analog ED-71
Abstract
INTRODUCTION: Risperidone (RIS), a second-generation antipsychotic for schizophrenia (SZ), is linked to osteoporosis and suboptimal symptom resolution. The shared cellular mechanisms underlying these cross-tissue toxicities (bone and hippocampus) remain undefined, hindering therapeutic advancement.
OBJECTIVES: To determine if RIS induces toxicity in osteoblasts and hippocampal GABAergic neurons via the acid sphingomyelinase (SMPD1)-lysosome axis, and to evaluate the therapeutic potential of eldecalcitol (ED-71), an active vitamin D analog, in mitigating these effects.
METHODS: Dizocilpine-induced SZ mice were used to evaluate bone loss and psychiatric symptoms. Primary osteoblasts induced from bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 osteoblasts, as well as primary hippocampal neurons and HT22 hippocampal neurons, were treated with RIS to evaluate ferroptosis, lysosomal dysfunction, and SMPD1 activity. Key techniques included micro-CT, histomorphometric staining, behavioral tests, enzyme-linked immunosorbent assay, RNA sequencing, targeted lipidomics analysis, molecular dynamics simulations, and isothermal titration calorimetry assays. Virtual drug screening was used to identify potential RIS-SMPD1 interaction antagonists, with the identified candidate ED-71 further validated thereafter.
RESULTS: RIS targeted lysosomes, causing dysfunction and membrane permeabilization, which drove ferroptosis in osteoblasts and hippocampal GABAergic neurons. Mechanistically,…
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