Ghrelin alleviates inflammation and pyroptosis by inhibiting TNF-α /caspase-8/caspase-3/ GSDME signalling pathways in an in vitro model of high glucose induced liver injury.

Diabetic liver injury (DLI) refers to liver injury resulting from prolonged chronic hyperglycemia and represents a significant complication associated with diabetes, The specific pathogenic mechanism of DLI remains incompletely understood. Tumor necrosis factor α (TNF-α) has been demonstrated to play a crucial role in diabetic complications through intricate signalling pathways, including pyroptosis. However, it remains uncertain whether TNF-α mediates pyroptosis in DLI, we initially established an in vitro model of DLI and confirmed the presence of an inflammatory state characterized by TNF-α in DLI. Furthermore, evidence of gasdermin E (GSDME)-mediated pyroptosis and the activation of cysteinyl aspartate specific proteinase (caspase)-8 was observed in AML-12 cell exposed to high glucose concentrations. We subsequently demonstrated that TNF-α can trigger caspase-8 activation, leading to GSDME-mediated cellular pyroptosis. Furthermore, treatment with ghrelin effectively suppressed hepatic cell pyroptosis induced by high glucose concentrations and provided protection against liver injury. Therefore, we propose that the TNF-α/caspase-8/caspase-3/GSDME pathway represents a novel mechanism underlying pyrodeath in DLI cells and to explore the protective role and molecular mechanisms underlying the effects of ghrelin on DLI by this special pathway, These findings may present potential therapeutic implications for the management of DLI.