Diabetes mellitus is a metabolic disorder with persistent hyperglycemia caused by a variety of underlying factors. Chronic hyperglycemia can lead to diverse serious consequences and diversified complications, which pose a serious threat to patients. Among the major complications are cardiovascular disease, kidney disease, diabetic foot ulcers, diabetic retinopathy, and neurological disorders. Heme oxygenase 1 (HO-1) is a protective enzyme with antioxidant, anti-inflammatory and anti-apoptotic effects, which has been intensively studied and plays an important role in diabetic complications. By inducing the expression and activity of HO-1, it can enhance the antioxidant, anti-inflammatory, and anti-apoptotic capacity of tissues, and thus reduce the degree of damage in diabetic complications. The present study aims to review the relationship between HO-1 and the pathogenesis of diabetes and its complications. HO-1 is involved in the regulation of macrophage polarization and promotes the M1 state (pro-inflammatory) towards to the M2 state (anti-inflammatory). Induction of HO-1 expression in dendritic cells inhibits them maturation and secretion of pro-inflammatory cytokines and promotes regulatory T cell (T_reg cell) responses. The induction of HO-1 can reduce the production of reactive oxygen species, thereby reducing oxidative stress and inflammation. Besides, HO-1 also has an important effect in novel programmed cell death such as pyroptosis and ferroptosis, thereby playing a protective role against diabetes. In conclusion, HO-1 plays a significant role in the occurrence and development of diabetic complications and is closely associated with a variety of complications. HO-1 is anticipated to serve as a novel target for addressing diabetic complications, and it holds promise as a potential therapeutic agent for diabetes and its associated complications. We hope to provide inspiration and ideas for future studies in the mechanism and targets of HO-1 through this review.

Diabetic nephropathy (DN) is one of the common complications of diabetes and the main cause of end-stage renal disease (ESRD) in clinical practice. Schisandrin A (Sch A) has multiple pharmacological activities, including inhibiting fibrosis, reducing apoptosis and oxidative stress, and regulating immunity, but its pharmacological mechanism for the treatment of DN is still unclear. In vivo, streptozotocin (STZ) and a high-fat diet were used to induce type 2 diabetic rats, and Sch A was administered for 4 weeks. At the same time, protein–protein interaction (PPI) networks were established to analyze the overlapping genes of DN and Sch A. Subsequently, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine the hub pathway. In addition, molecular docking was used to preliminarily verify the affinity of hub proteins and Sch A. Further, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, and western blot analysis were used to detect the location and expression of related proteins in DN. This study revealed the multi-target and multi-pathway characteristics of Sch A in the treatment of DN. First, Sch A could effectively improve glucose tolerance, reduce urine microprotein and urine creatinine levels, and alleviate renal pathological damage in DN rats. Second, EGFR was the hub gene screened in overlapping genes (43) of Sch A (100) and DN (2524). Finally, it was revealed that Sch A could inhibit the protein expression levels of EGFR and PTRF and reduced the expression of apoptosis-related proteins, and this effect was related to the modulation of the AKT/GSK-3β signaling pathway. In summary, Sch A has a protective effect in DN rats, EGFR may be a potential therapeutic target, throughout modulating AKT/GSK-3β pathway.

Schisandrin A (SchA), a bioactive lignan that was isolated from the dried fruit of Schisandra chinensis, has attracted much attention because of its diverse spectrum of pharmacological effects. The aim of this study is to clarify the function of SchA in diabetes-related fear memory impairment and its molecular causes. Four rat groups are chosen at random: the control group (Con group), the DM group, the DM + SchA group, and the Con + SchA group. These findings demonstrate that SchA treatment improves insulin sensitivity, reduced blood glucose, and significantly reduced memory impairment. SchA treatment also prevents histological damage, enhances synaptic protein production, and significantly decreases Aβ₄₂ formation in the diabetic prefrontal cortex. Further research reveals that SchA therapy decreases microglial activation and the expression levels of variables linked to inflammation while increasing the phosphorylation of proteins implicated in the insulin resistance signaling pathway. Furthermore, in the prefrontal cortex of diabetic patients, SchA decreases ferroptosis by increasing the protein expression of GPX4, SLC7A11, Nrf2, HO-1, and SIRT1. Overall, our findings suggest that SchA may lessen diabetes-associated fear memory impairment symptoms by, most likely, lowering ferroptosis and inflammatory responses in the prefrontal brain of diabetic patients. SchA may prove to be a useful therapy for diabetes, including for memory impairment.