Mechanisms and therapeutic strategies of ferroptosis in Diabetic-Associated Cognitive Dysfunction: focus on the crosstalk with apoptosis, autophagy, and pyroptosis

Jan 13, 2026Molecular biology reports

How Iron-Driven Cell Death May Affect Diabetes-Related Thinking Problems and Its Link to Other Cell Death Processes

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Abstract

Ferroptosis is identified as a core pathogenic mechanism in diabetes-associated cognitive dysfunction (DACD).

Diabetes-associated cognitive dysfunction is linked to complex cellular processes involving programmed cell death.
Hyperglycemia disrupts iron balance in the brain, leading to mitochondrial damage and oxidative stress.
Inhibition of glutathione peroxidase 4 (GPX4) activity results in the buildup of lipid peroxides and triggers ferroptosis.
Ferroptosis affects neurons, glial cells, and the blood-brain barrier, contributing to cognitive decline.
A network of interactions exists between ferroptosis and other forms of programmed cell death, such as autophagy and pyroptosis.
Various intervention strategies targeting ferroptosis have shown promise in improving cognitive function in preclinical studies.

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Diabetes-associated cognitive dysfunction (DACD), a serious central nervous system complication of diabetes mellitus, poses a heavy global burden due to its intricate pathogenesis and lack of effective therapies. Mounting evidence identifies programmed cell death (PCD) as a pivotal driver of DACD progression. This review systematically elaborates on the molecular mechanisms of various PCD modalities (including apoptosis, autophagy, pyroptosis, and ferroptosis) in DACD, with a particular focus on the role of ferroptosis as a core pathogenic mechanism. Hyperglycemia disrupts cerebral iron homeostasis, induces mitochondrial dysfunction and oxidative stress, leading to inhibition of glutathione peroxidase 4 (GPX4) activity and accumulation of lipid peroxides. This cascade ultimately triggers ferroptosis in neurons, glial cells, and the blood-brain barrier, resulting in impaired synaptic plasticity and cognitive decline. Furthermore, the review delineates the complex interactive regulatory network between ferroptosis and other PCD forms (e.g., autophagy, pyroptosis), which can converge into the coordinated cell death program of PANoptosis. Intervention strategies targeting ferroptosis, such as iron chelators (deferoxamine), antioxidants (N-acetylcysteine), GPX4 activators, natural products (resveratrol, curcumin), repurposed traditional medicines (liraglutide, metformin), and non-pharmaceutical interventions (exercise, electroacupuncture), have demonstrated significant potential in improving cognitive function in preclinical models. This review aims to provide novel insights into the pathophysiology of DACD and establish a theoretical foundation for developing precise therapeutic strategies centered on targeting ferroptosis.

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Mechanisms and therapeutic strategies of ferroptosis in Diabetic-Associated Cognitive Dysfunction: focus on the crosstalk with apoptosis, autophagy, and pyroptosis

Abstract

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