Ferroptosis-inflammasome crosstalk contributes to hyperglycemia-induced neuronal injury and is modulated by the ferroptosis inhibitor UAMC-3203.

BACKGROUND

Hyperglycemia associated with diabetes and its neurological complications is strongly linked to oxidative stress and chronic inflammation; however, the contribution of ferroptosis to this process remains incompletely understood. Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and glutathione depletion and has recently been implicated in neurodegenerative disorders and diabetic neuropathy. Nevertheless, the interaction between ferroptosis and inflammasome signaling in hyperglycemia-induced neuronal injury remains unclear. This study aimed to investigate the role of ferroptosis in hyperglycemia-induced neuronal damage and to evaluate the potential protective effects of the ferroptosis inhibitor UAMC-3203.

METHODS

SH-SY5Y cells differentiated with retinoic acid were exposed to normoglycemic or hyperglycemic conditions and treated with UAMC-3203. Expression levels of ferroptosis-related proteins (GPX4, ACSL4), inflammatory mediators (NLRP3, Caspase-1), and the antioxidant transcription factor Nrf2 were analyzed by Western blotting. Lipid peroxidation and antioxidant status were assessed by measuring malondialdehyde (MDA) and glutathione (GSH), while apoptosis was evaluated using Annexin V/PI flow cytometry.

RESULTS

Hyperglycemia suppressed GPX4 expression while increasing ACSL4, lipid peroxidation, and NLRP3 inflammasome activation, indicating enhanced ferroptotic and inflammatory stress. UAMC-3203 reduced lipid peroxidation, restored GSH levels, and markedly suppressed NLRP3 expression, particularly at higher concentrations. However, high-dose UAMC-3203 increased apoptotic cell death, suggesting a shift toward alternative cell death pathways when ferroptosis is inhibited.

CONCLUSIONS

Collectively, these findings indicate that hyperglycemia induces neuronal injury through a ferroptosis-associated inflammatory signaling axis and that targeting ferroptosis may represent a promising therapeutic strategy for diabetes-related neuronal damage.