Berberine's antihyperglycemic effects via modulation of pancreatic ferroptosis and the CDC42-AR/PTGS2/ESR1 signaling pathway: A genomic and network pharmacology approach

Abstract

Diabetes mellitus (DM) is a prevalent metabolic disorder. The increase in lethality associated with ferroptosis, a novel form of programmed cell death in pancreatic tissues at the molecular level, arises from the accumulation of reactive molecules, such as oxygen species, generated through lipid metabolism, which is linked to the cells' reduced capacity to manage oxidative stress. Recent studies have highlighted that ferroptosis plays a crucial role in the onset, progression, and development of DM and its various complications. A thorough understanding of the molecular mechanisms governing iron metabolism and its contribution to ferroptosis in DM could enhance disease management strategies. To address this, a bioinformatics approach was employed to investigate the antidiabetic potential of key target genes, including CDC42, AR, PTGS2, and ESR1, using a polyherbal extract (PHE) enriched with berberine (BBR), offering a novel perspective in DM treatment. Findings revealed that BBR (constituting 6.442 % in PHE and 0.399 % in Berberis aristata) was identified at retention times of 7.14 in PHE and 6.80 in BA, respectively, as the most significant compound in the positive mode of HR-MS analysis. The antihyperglycemic effect of PHE resulted in a notable decrease in fasting blood glucose (FBG) levels within 30 min of glucose loading in different experimental rat groups. The outcomes suggest that the target genes CDC42 and AR/PTGS2/ESR1 could be downregulated by BBR-enriched PHE, potentially modulating pancreatic ferroptosis in DM. © 2024 Elsevier B.V.