Natural Products Targeting Ferroptosis in Type 2 Diabetes Mellitus and Its Complications

Type 2 diabetes mellitus (T2DM) and its associated complications represent major global health challenges, significantly affecting multiple vital organs. Ferroptosis-a distinct form of regulated cell death, separate from apoptosis, necroptosis, pyroptosis, and autophagy-has garnered increasing attention in the pathogenesis of T2DM and its complications. Emerging evidence suggests that ferroptosis is closely linked to β-cell dysfunction and insulin resistance-key features of the disease-making it a promising therapeutic target. This review summarizes current evidence on how natural products inhibit ferroptosis and alleviate T2DM and its complications. These compounds exert protective effects primarily by enhancing the antioxidant defense system, often through activation of NRF2, which upregulates downstream targets such as HMOX1 and GPX4. This regulatory axis counters iron overload, lipid peroxidation, oxidative stress, and mitochondrial damage-hallmarks of ferroptosis. Natural products have demonstrated efficacy across various diabetic complications, including nephropathy, retinopathy, cardiovascular disease, encephalopathy, impaired wound healing, reproductive dysfunction, and other less common conditions. Their actions involve modulation of several key signaling pathways, such as AdipoR1/AMPK, TXNIP/NLRP3, SIRT1/HMGB1, HIF-1α/HMOX1, PPARγ/TXNIP, PRDX2/MFN2/ACSL4, and SIRT3. By regulating these pathways, they suppress ferroptosis, mitigate tissue damage, modulate iron metabolism-related proteins, reduce oxidative stress, preserve mitochondrial integrity, and promote cell survival. These outcomes suggest promising therapeutic avenues for managing T2DM and its complications. However, despite encouraging preclinical findings, clinical validation remains lacking. Further research is needed to clarify underlying mechanisms, optimize therapeutic applications, and evaluate safety in human trials.