Role of Transcription Factor Nrf2 in Pyroptosis in Spinal Cord Injury by Regulating GSDMD

Spinal cord injury (SCI) is a prevalent disease that debilitates millions of people. Nuclear factor E2-related factor 2 (Nrf2) is an important regulator of SCI. The current study sought to elaborate on the effects of Nrf2 on gasdermin D (GSDMD)-mediated microglia pyroptosis to repair SCI. The SCI rat model was established via the percussion of the T10 spinal cord and in vitro SCI model was established on BV-2 cells via lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment. Nrf2 expression in SCI rats and BV-2 cells was overexpressed via pcDNA3.1-Nrf2 injection. Functional assays were carried out to evaluate SCI rat pathological injury, BV-2 cell viability, the release of lactate dehydrogenase (LDH), and pyroptotic factors. The binding relations of Nrf2 and microRNA (miR)-146a and miR-146a and GSDMD were verified. BV-2 pyroptosis was analyzed after the combined experiment of miR-146a-inhibitor and pcDNA3.1-GSDMD. Our experiments revealed that Nrf2 was downregulated in SCI, and Nrf2 overexpression relieved SCI pathological injury, promoted BV-2 cell viability, inhibited the release of LDH, and repressed pyroptosis. Mechanically, Nrf2 bound to the miR-146a promoter and promoted miR-146a expression, and miR-146a targeted GSDMD transcription. Rescue experiments revealed that miR-146a knockdown or GSDMD overexpression annulled the inhibitory function of Nrf2 overexpression in LPS/ATP-induced microglia pyroptosis. Overall, our findings initially highlighted that Nrf2 inhibited GSDMD-mediated microglia pyroptosis and accelerated SCI repair by repressing miR-146a.