Objective This study aims to investigate the pathological role and molecular mechanisms of pericyte depletion in neuropsychiatric lupus （NPSLE） and to assess the potential of the PDGFR-β signaling pathway as a novel therapeutic target for NPSLE. Methods NPSLE models were established using 8-week-old female MRL/lpr mice， from which those exhibiting abnormal behaviors were selected for further analysis. The PDGFR-β signaling pathway was modulated using an agonist to promote pericyte proliferation or an inhibitor to suppress pericyte apoptosis. The effects of these treatments on blood-brain barrier （BBB） integrity， eye-signs in blood stasis syndrome， neuronal integrity， and tight junction protein expression were evaluated. Evans blue staining， H&E staining， Nissl staining， and immunofluorescence staining were employed to assess the expression of tight junction proteins （Cadherin， ZO-1）， endothelial cell markers （CD31）， and pericyte markers （NG2）. Results Mice in the NPSLE group exhibited significant anxiety， depression， and cognitive impairment. In the PDGFR-β inhibition group， eye-signs in blood stasis syndrome scores were significantly elevated （P < 0.01）， BBB permeability was markedly increased （P < 0.001）， neuronal numbers were significantly reduced， tight junction protein expression was diminished， and pericyte depletion was aggravated. Conversely， the PDGFR-β agonist group showed a significant reduction in eye-signs in blood stasis syndrome scores （P < 0.01）， improved pericyte survival， enhanced expression of tight junction proteins， reduced neuronal damage， and restoration of BBB function （P < 0.001）. Immunofluorescence staining further confirmed that PDGFR-β activation significantly protected pericytes. Conclusions Pericyte depletion is closely associated with increased BBB permeability and exacerbation of eye-signs in blood stasis syndrome. Modulation of the PDGFR-β signaling pathway may provide a promising therapeutic strategy for NPSLE.