HERV-W Env Induces Neuron Pyroptosis via the NLRP3–CASP1–GSDMD Pathway in Recent-Onset Schizophrenia

HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene <i>HERV-W env</i> (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis-a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as <i>CASP1</i> (Caspase-1), <i>NLRP3</i> (NLR family pyrin domain containing 3), and <i>IL1B</i> (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically <i>CASP1</i>, <i>GSDMD</i> (Gasdermin D), and <i>IL1B</i>, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of <i>CASP1</i>/<i>GSDMD</i>/<i>IL1B</i> in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting <i>NLRP3</i>, <i>CASP1</i>, and <i>GSDMD</i> significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas <i>BID</i> (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces <i>CASP1</i>-<i>GSDMD</i>-dependent pyroptosis through the <i>NLRP3</i>-<i>CASP1</i>-<i>GSDMD</i> signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.