Metformin improves chronic rhinosinusitis with depressive-like behavior in mice by targeting TCF4 to inhibit the TLR4/NF-κB pathway.

Chronic rhinosinusitis (CRS) frequently co-occurs with depressive disorders. TCF4 aberrant expression is strongly linked to CRS with depression-like behaviors (CRSDB), highlighting the urgent need for TCF4-targeted drugs to treat this complex comorbidity. This study validated the reproducibility and stability of the previously developed mouse model of CRSDB by assessing nasal and hippocampal histopathology via H&E, PAS, and Nissl staining. ELISA determined inflammatory cytokine levels. TCF4's role was explored through lentivirus-mediated in vivo and in vitro microglial knockdown. TLR4/NF-κB pathway regulation by TCF4 was confirmed via immunofluorescence, Western Blot, and RT-qPCR. Metformin's therapeutic effect was tested, with its TCF4 targeting verified by molecular docking and in vitro experiments. The study comprehensively links TCF4 to neuroinflammation in CRSDB, highlighting metformin's potential as a therapeutic agent. The CRSDB model exhibited excellent reproducibility and time-dependent exacerbation of depression-like behaviors, cognitive deficits, and concurrent nasal and hippocampal inflammation. Mechanistically, CRSDB induced TCF4 upregulation, which activated the TLR4/NF-κB signaling pathway, leading to microglial activation and neuroinflammation. Knockdown of TCF4 significantly alleviated behavioral impairments, suppressed microglial activation, and mitigated peripheral inflammation. Furthermore, We identified TCF4 as a direct target of metformin, through which it inhibits the TLR4/NF-κB pathway and subsequent microglial activation. TCF4 has been confirmed as a key regulatory mediator of CRSDB, and it has been demonstrated that metformin exerts its antidepressant effect by specifically targeting TCF4 in microglia to inhibit the TLR4/NF-κB axis.