APEX1 attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis via the Nrf2/GPX4 signaling pathway.

Abstract

BACKGROUND: Myocardial ischemia reperfusion injury (MIRI) is a primary cause of poor prognosis in patients with myocardial infarction, with ferroptosis being a significant form of cell death in this process. Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein involved in DNA repair and redox activation of transcription factors and has shown therapeutic potential in ischemic heart disease. This study aims to investigate whether APEX1 protects against MIRI by inhibiting ferroptosis and to explore the underlying mechanisms. METHODS: A rat model of myocardial ischemia/reperfusion (I/R) and a H9c2 cell model of hypoxia/reoxygenation (H/R) were established. APEX1 protein levels were assessed in both models. The protective effects of APEX1 against ferroptosis were evaluated by measuring ferroptosis-associated proteins, Fe²⁺ levels, and lipid peroxidation markers. To explore the mechanistic pathway, the Nrf2 inhibitor ML385 was employed to examine whether the protective effects of APEX1 were mediated through the Nrf2/GPX4 signaling axis. RESULTS: APEX1 protein levels were significantly reduced in both the rat I/R model and the H9c2 cell H/R model. APEX1 mitigated MIRI-induced ferroptosis through exogenous pathways, including inhibition of iron transporters TfR1 and FTH1, and endogenous pathways, such as GPX4 activity. Inhibition of Nrf2 using ML385 partially reversed the protective effects of APEX1 against ferroptosis and reduced GPX4 expression, indicating the involvement of the Nrf2/GPX4 signaling pathway. CONCLUSION: This study demonstrates that APEX1 protects against MIRI by inhibiting ferroptosis through activation of the Nrf2/GPX4 signaling pathway. These findings identify APEX1 as a promising therapeutic target for the treatment of MIRI.

Key Findings

• APEX1 protein levels are significantly reduced in myocardial ischemia/reperfusion injury models.
• APEX1 mitigates myocardial ischemia-reperfusion injury-induced ferroptosis by inhibiting iron transporters TfR1 and FTH1 and enhancing GPX4 activity.
• Inhibition of Nrf2 partially reverses the protective effects of APEX1, indicating that APEX1 acts through the Nrf2/GPX4 signaling pathway.

Clinical Significance

Citation

Wu Liuxin, Yin Xiaomeng, Yang Linet al.. APEX1 attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis via the Nrf2/GPX4 signaling pathway. Molecular biology reports. 2026-Jul-18.