Targeting Ferroptosis With Natural Products to Treat Diabetes and Its Complications: Opportunities and Challenges

ABSTRACT Diabetes mellitus (DM) is a common chronic metabolic disorder, and the recommended pharmacotherapies in DM guidelines can effectively alleviate symptoms of DM, but some drugs may have certain side effects. In contrast, natural products and their derivatives have shown promising therapeutic effects on DM with fewer side effects. Additionally, ferroptosis, as a form of cell death, is involved in the normal physiological and pathological regulation of the body. Numerous studies have demonstrated the crucial role of ferroptosis in the occurrence and progression of diabetes and its complications. Furthermore, there is evidence that natural compounds can play a role in the prevention and treatment of diabetes and its complications by inhibiting ferroptosis. This review aims to enhance the understanding of the role and iron death mechanism of natural compounds in the treatment of diabetes and its complications. It also emphasizes the significance of utilizing natural products for managing diabetes and its complications. We conducted a systematic literature search using PubMed, Web of Science, and Clinical Trials: The search used keywords including natural products, natural compounds, oxidative stress, diabetes mellitus, and diabetic kidney disease. Comprehensive research and compilation of existing literature were conducted. Ferroptosis is a newly discovered form of cell death that is caused by an excess of iron and the buildup of reactive oxygen species (ROS) and lipid peroxides (LPO). These factors can affect ferroptosis through various signaling pathways, including the system Xc − /GSH/GPX4 axis, AMPK, and the E‐cadherin‐NF2‐Hippo‐YAP pathway. Additionally, p53 has been identified as a regulator of ferroptosis. In the development of type 2 diabetes mellitus (T2DM) and its complications, ferroptosis has been found to play a crucial role in numerous studies. These studies have also elucidated the specific pathways of ferroptosis in diabetes‐related conditions such as diabetic cardiomyopathy (DCM), diabetic kidney disease (DKD), diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), and diabetic foot ulcers (DFU). Natural products have been widely used to treat diabetes and its complications, and some have been found to have inhibitory effects on ferroptosis. This article also provides a detailed overview of the toxicity, side effects, and current research progress of natural products in this context. Ferroptosis plays a crucial role in the development of T2DM and its associated complications, with multiple signaling pathways involved in its regulation. Natural compounds have been shown to have an impact on diabetes and its complications by inhibiting ferroptosis and regulating the associated signaling pathways. As such, natural products hold great potential for the treatment of diabetes and its complications.