<p>The pathophysiology of depression is associated with inflammation. This study aims to investigate the mechanism by which Yin Yang 1 (YY1) participates in microglial inflammatory activation and M1 polarization in depression. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) mRNA in serum from depressed patients and healthy controls. A chronic unpredictable mild stress (CUMS) depression mouse model was established, and proteins were detected by Western blot (WB). Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of TRAF6 for depression. Depressive-like behaviors were assessed by behavioral tests. Inflammatory factors were detected via Enzyme-linked immunosorbent assay (ELISA), M1 polarization markers were analyzed via flow cytometry, and WB, respectively. CHX stability and WB-based ubiquitination assays were used to examine the regulatory effect of Ubiquitin-Specific Protease 19 (USP19) on TRAF6 ubiquitination. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to verify the transcriptional activation effect of YY1 on USP19. TRAF6 was highly expressed in patient serum and mouse hippocampi, with potential diagnostic value for depression. Silencing TRAF6 improved depressive-like behaviors and reduced inflammation. USP19 was highly expressed in mouse hippocampi, and stabilized TRAF6 via deubiquitination. TRAF6 overexpression reversed inflammation and M1 polarization inhibition from USP19 silencing. YY1 was also highly expressed in mouse hippocampi and activated USP19 transcription. USP19 overexpression reversed the inhibition from YY1 silencing. YY1 activates USP19 to promote TRAF6 deubiquitination and its stabilization, thereby enhancing microglial inflammation and M1 polarization that exacerbates depression progression. This axis may provide a novel direction for depression diagnosis and treatment.</p>