Olanzapine interacts with Orosomucoid 2 in hepatic steatosis associated with alterations in glucose metabolism and oxidative stress

Olanzapine, a second-generation atypical antipsychotic effective for schizophrenia, induces a distinct metabolic syndrome that increases cardiovascular and other risks. However, the precise molecular mechanisms and targets underlying its metabolic perturbations had remained unclear. In this study, olanzapine exposure significantly increased hepatic lipid accumulation, was accompanied by disruptions in glucose metabolism—particularly glycolysis and TCA cycle, and elicited excessive oxidative stress in vitro. Using DNA-programmed affinity labeling (DPAL), we identified hepatic Orm2 as a direct target of olanzapine, which was further validated by molecular docking, surface plasmon resonance (SPR), and differential scanning fluorimetry (DSF). Olanzapine exposure significantly reduced hepatic Orm2 expression at both mRNA and protein levels. Notably, Orm2 knockdown exacerbated olanzapine-induced disturbances in glucose metabolism and oxidative stress, and aggravated hepatocyte steatosis. Furthermore, olanzapine exposure disrupted hepatic lipid metabolism and down regulated Orm2 in mice. Collectively, these findings identify Orm2 as a key regulator associated with olanzapine-induced metabolic disturbances, potentially linking glucose metabolic alterations and oxidative stress to the observed steatotic phenotype. These results highlight Orm2 as a promising candidate therapeutic target for antipsychotic-associated metabolic syndrome, while the precise causal relationships warrant further functional validation. A schematic summary of the pathophysiological effects of olanzapine on hepatic issues.