Ferroptosis inhibition via Nrf2/GPX4 activation underlies the broad-spectrum cardioprotection by human α1-antitrypsin.

Abstract

Ferroptosis is a critical contributor to various cardiomyopathies; however, broad-spectrum endogenous inhibitors remain largely undefined. Although human alpha-1-antitrypsin (hAAT) exhibits cytoprotective properties, its involvement in cardiac ferroptosis remains unexplored. To directly assess endogenous hAAT function in vivo, we generated CRISPR/Cas9-mediated humanized knock-in mouse models expressing either functional (SERPINA1WT) or loss-of-function (SERPINA1Q129⁎) hAAT, and subjected them to doxorubicin-induced cardiomyopathy and myocardial infarction. SERPINA1WT mice exhibited robust protection against cardiac dysfunction, fibrosis, and remodeling, whereas SERPINA1Q129⁎ mice conferred no benefit, establishing that protection is strictly dependent on functional protein integrity. This protective effect was mediated through potent suppression of ferroptosis, as evidenced by reduced lipid peroxidation and iron accumulation. Mechanistically, endogenous hAAT activated the Nrf2 signaling pathway, upregulating key anti-ferroptotic effectors including GPX4, HO-1, and xCT; this protection was abolished by the Nrf2 inhibitor ML385. Our findings identify functional hAAT as a novel, broad-spectrum ferroptosis inhibitor operating through the Nrf2/GPX4 axis, highlighting its potential as a therapeutic target for diverse ferroptosis-driven cardiomyopathies.

Key Findings

• Functional human alpha-1-antitrypsin (hAAT) provides robust cardioprotection against doxorubicin-induced cardiomyopathy and myocardial infarction in mouse models.
• The cardioprotective effect is mediated by suppression of ferroptosis, evidenced by reduced lipid peroxidation and iron accumulation.
• Endogenous hAAT activates the Nrf2 signaling pathway, upregulating anti-ferroptotic effectors such as GPX4, HO-1, and xCT, with protection abolished by Nrf2 inhibition.

Clinical Significance

Citation

Li Yanxiao, Chen Hongxia, Abudouwayiti Aihaidanet al.. Ferroptosis inhibition via Nrf2/GPX4 activation underlies the broad-spectrum cardioprotection by human α1-antitrypsin. International journal of biological macromolecules. 2026-Apr-24.