Risperidone induces osteoporosis and neuropsychiatric treatment resistance via SMPD1-lysosome-mediated ferroptosis: dual rescue by active vitamin D analog ED-71

Risperidone induces osteoporosis and neuropsychiatric treatment resistance through SMPD1-lysosome-mediated ferroptosis, both of which are dually rescued by the active vitamin D analog ED-71. • In schizophrenia, RIS exacerbates bone loss, inhibits osteogenesis, partially improves psychosis, reduces hippocampal GABA. • RIS directly damages osteoblasts/hippocampal GABAergic neurons via abnormal "SMPD1-lysosome axis", inducing ferroptosis. • RIS impairs lysosomal function, blocks autophagic flux; disrupting lysosomal/mitochondrial iron levels, inducing ferroptosis. • ED-71 blocks RIS-SMPD1 binding, restores SMPD1 activity, reduces lysosomal phospholipids/dysfunction, reverses ferroptosis. • ED-71 reverses RIS-induced bone loss, promotes osteogenesis, synergizes with RIS to combat psychosis, restores GABA levels. 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. 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. 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. RIS targeted lysosomes, causing dysfunction and membrane permeabilization, which drove ferroptosis in osteoblasts and hippocampal GABAergic neurons. Mechanistically, RIS bound to SMPD1 at ARG294, inhibiting its activity and triggering lysosomal phospholipid accumulation and ferroptosis. ED-71 disrupted RIS-SMPD1 interactions, restored lysosomal integrity, mitigated hyperprolactinemia/sympathetic overactivation, and synergized with RIS to enhance antipsychotic efficacy and prevent osteoporosis in SZ models. This study identifies SMPD1 activation as a therapeutic target to counteract RIS-induced ferroptosis in bone and hippocampus. The dual-action mechanism of ED-71 provides a novel strategy for SZ intervention, simultaneously addressing psychiatric symptoms and osteoporotic complications.