The autophagy-ferroptosis axis as a critical factor in diabetic-associated cognitive dysfunction

Diabetic-associated cognitive dysfunction (DACD) is a critical complication of diabetes mellitus, characterized by progressive cognitive decline and neurodegeneration. This review synthesizes emerging evidence on the interplay between autophagy and ferroptosis, highlighting their roles in DACD pathogenesis. We emphasize the unique contribution of the autophagy-ferroptosis axis, particularly under hyperglycemic and insulin-resistant conditions, in driving iron overload, oxidative stress, and lipid peroxidation in brain tissue. The brain's vulnerability to ferroptosis is underscored by its high energy demand, low coenzyme Q (CoQ) content, and abundant polyunsaturated fatty acids (PUFAs), which collectively exacerbate oxidative damage. Key signaling pathways, the DNA damage inducible transcript 4 (DDIT4)-Tuberous Sclerosis Complex (TSC)-mammalian target of rapamycin (mTOR) axis are discussed as potential therapeutic targets. Notably, the DDIT4-TSC-mTOR axis links autophagy dysregulation to ferroptosis induction through iron metabolism imbalance. This review uniquely integrates these mechanisms to propose novel intervention strategies, such as ferroptosis inhibitors and natural compounds, which may mitigate DACD by restoring redox homeostasis and autophagic flux. By bridging molecular pathways with clinical implications, this work advances our understanding of DACD and provides innovative directions for therapeutic development.