Abstract Objective: This study aims to explore the molecular mechanism by which DCI improves MAFLD induced by diabetes by pyroptosis, and to bring new ideas for clinical treatment and reversal of MAFLD.
Methods: In this study, we investigated the effect of DCI on macrophage pyroptosis using a diabetic mouse model (db/db mice) and high glucose (HG) and lipopolysaccharide (LPS) -induced mouse macrophage raw264.7 cells.
Immunohistochemistry (IHC) and immunofluorescence (IF) analysis were used to evaluate the effect of DCI on NLRP3-mediated pyroptosis of macrophages in vitro and in vivo. The binding ability of DCI to nuclear transcription factor NF-κB and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) was investigated by molecular docking experiments.
Results: DCI can reverse the abnormal liver function and hepatic steatosis in db/db mice, and block the release of inflammatory cytokines. These effects were related to the inhibition of NLRP3/NF-κB/Caspase1/GSDMD signaling pathway by DCI. Molecular docking experiments also suggested that NF-κB and NLRP3 are potential targets of DCI.
Conclusion: Using a combination of animal and in vitro experiments, this study is the first to demonstrate that DCI improves MAFLD by targeting NLRP3-activated macrophage pyroptosis. Therefore, DCI may be a potential therapeutic agent for MAFLD.
Keywords: D-chiral inositol, MAFLD, NLRP3, macrophage pyroptosis, db/db mice.