Selective autophagy in type 2 diabetes-associated cognitive dysfunction: Insightful mechanisms and therapies

Type 2 diabetes-associated cognitive dysfunction (TDACD) is an escalating yet underestimated global health challenge, reflecting a complex convergence of metabolic dysregulation and neurodegenerative pathogenesis. Despite increasing concern, its underlying neuropathogenesis remains partially elucidated. It should be noted that T2DM and neurodegenerative diseases exhibit a high degree of overlap in pathological mechanisms, including impaired insulin signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and autophagy dysregulation, and these shared mechanisms constitute the neuropathogenesis of TDACD. Accumulating findings have identified selective autophagy as a pivotal mechanism in preserving neuronal integrity and mitigating cellular stress under diabetic conditions. Distinct from non-selective autophagy, selective autophagy enables the precise degradation of specific subcellular substrates, mitochondria, endoplasmic reticulum, lysosomes, ferritin, lipid droplets, and glycogen, each of which contributes uniquely to neuroprotection or pathology. This review comprehensively synthesizes current mechanistic insights into how these selective autophagic subtypes modulate neural function in the context of TDACD, underscoring their respective roles in mitochondrial quality control, ER stress resolution, iron homeostasis, lipid metabolism, and energy regulation. Furthermore, we summarize potential therapeutic strategies targeting specific autophagic pathways, offering a novel perspective for the prevention or treatment of TDACD. By positioning selective autophagy as a critical interface between neurodegeneration and metabolic stress responses, this review proposes a pathway-specific and precision-based framework for mitigating cognitive decline in type 2 diabetes.