PSMD14 reduced microglial M2 polarization to promote ferroptosis and aggravate traumatic brain injury through the induction of BMP6/SMAD3 pathway

Abstract

The present study aimed to investigate the functional role of proteasome 26S subunit non-ATPase 14 (PSMD14) in traumatic brain injury (TBI) and further elucidate its molecular mechanisms linking ferroptosis to microglial M2 polarization. A total of 52 clinical samples from TBI patients and 52 matched healthy volunteers samples were collected in this study. Both clinical specimen validation and in vivo animal experiments demonstrated significant upregulation of PSMD14 at both mRNA and protein levels in TBI patients and TBI mouse models. Immunohistochemistry and immunofluorescence staining further confirmed elevated PSMD14 expression primarily in microglia of TBI mouse brain tissues. In vivo functional evaluation showed that genetic inhibition of PSMD14 effectively alleviated brain pathological injury in TBI mice. In terms of inflammatory cytokine profiling, shRNA-mediated PSMD14 knockdown reduced the secretion of pro-inflammatory factors IL-6 and TNF-α, while increasing the levels of anti-inflammatory cytokines IL-10 and TGF-β in TBI model mice. Consistent with the altered inflammatory phenotype, PSMD14 inhibition decreased the proportion of M1-type microglia (IL-6/CD86) and increased the abundance of M2-type microglia (IL-10/CD206) in TBI brain tissues. Mechanistic exploration revealed that PSMD14 overexpression aggravated reactive oxygen species (ROS) accumulation, oxidative stress activation, and mitochondrial structural and functional damage in microglia, thereby facilitating microglial ferroptosis under TBI pathological conditions. Moreover, PSMD14 prominently activated the BMP6/SMAD5/SMAD3 signaling axis in microglia following TBI injury. In conclusion, PSMD14 suppresses microglial M2 polarization during TBI progression by promoting mitochondrial oxidation-induced ferroptosis through the activation of the BMP6/SMAD3 pathway. Targeted inhibition of PSMD14 may serve as a promising therapeutic strategy for TBI treatment.