The Mechanisms and Recent Advances in Research on Iron-Mediated Cell Death in Diabetic Cataracts

Abstract

Diabetic cataract (DC) is one of the most common and blinding ocular complications of diabetes mellitus (DM). Its pathogenesis is complex; traditional theories suggest that hyperglycaemia-induced oxidative stress, the accumulation of advanced glycation end products (AGEs) and the activation of the polyol pathway are key mechanisms. However, these mechanisms do not fully account for the rapid progression and unique characteristics of DC. In recent years, a novel, iron-dependent form of programmed cell death—ferroptosis—has attracted significant attention in the pathogenesis of various diseases due to its unique biochemical characteristics. This article aims to provide a systematic review of the core molecular mechanisms of ferroptosis, explore its key role in the pathophysiology of DC, and focus on elucidating the molecular networks underlying iron metabolism imbalance, lipid peroxidation accumulation, and the collapse of the antioxidant defence system in lens epithelial cells under hyperglycaemic conditions. The article provides a detailed analysis of the roles of key signalling pathways such as Nrf2/HO-1, p53, GPX4, in regulating ferroptosis in DCs, and integrates newly identified regulatory axes, such as LCN2 and VDAC3-USP47, discovered in recent studies. Furthermore, this paper outlines the immense potential of targeting ferroptosis as a novel strategy for the prevention and treatment of DC, with the aim of providing a theoretical basis and future direction for elucidating the complete pathological mechanisms of DC and developing innovative drugs.