Ferroptosis and pyroptosis in diabetes mellitus: emerging therapeutic potential of GLP-1 receptor agonists

Ferroptosis and pyroptosis are two emerging forms of regulated cell death. The former encompasses cell death by excessive accumulation of lipid hydroperoxides in an iron-dependent way. The latter pertains to inflammation-associated cell death following activation of caspase-1, caspase-11/4/5 through gasdermin D (GSDMD). Recent evidence confirms the implication of ferroptosis and pyroptosis in diabetes mellitus (DM) and its complications, notably diabetic kidney disease (DKD), and also in metabolic-dysfunction associated liver disease (MASLD). The aim of this narrative review was to summarise current experimental evidence on the potential beneficial actions of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in DM and diabetic complications via reduction of ferroptosis and pyroptosis. Data points to their therapeutic potential in DKD and MASLD. Treatment with GLP-1RAs was comparable with ferrostatin-1 (Fer-1), a well-known-ferroptosis inhibitor: ferroptosis-associated markers (e.g. Acyl-CoA Synthetase Long Chain Family Member 4, ASCL4) were decreased and factors alleviating ferroptosis were increased. Similarly, caspase-1, GSDMD, interleukin-1β (IL-1β) and/or nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor-containing pyrin domain 3 (NLPR3), which induce pyroptosis, were restored following GLP-1RAs therapy. The pleiotropic effects of GLP-1RAs included improvements in inflammatory markers, fibrosis-associated indices, mitochondrial ultrastructure and oxidative stress. Nevertheless, these positive effects mediated by GLP-1RAs are almost exclusively based on experimental models. Therefore, clinical trials are required to explore these promising outcomes in clinical practice.