3-hydroxyanthranilic acid analog mitigates ischemia-reperfusion injury by inhibiting cardiomyocyte ferroptosis through the activation of Nrf2/HO-1/GPX4.

Myocardial ischemia-reperfusion injury (MIRI) is a widespread condition that causes cardiac dysfunction, myocardial cell loss, and fibrosis. It is associated with substantial global morbidity, disability, and mortality, placing a considerable strain on healthcare systems and economies. 3-Hydroxyanthranilic acid (3-HA), an endogenous intermediates of tryptophan metabolism, exhibits modest anti-ferroptotic effects; however, its limited efficacy hinders its clinical applicability. Here, we report ethyl 3-hydroxydiaminobenzoate (E3-H), a novel analog of 3-HA, which demonstrates a striking 100-fold increase in efficacy in the RSL3-induced ferroptosis model. E3-H exhibits broad-spectrum efficacy, effectively suppressing ferroptotic cell death across multiple cell types and diverse ferroptosis inducers. In vivo, E3-H provides superior protection against myocardial ischemia-reperfusion injury (MIRI) compared to 3-HA, mitigating ferroptosis, reducing cardiac damage, and enhancing anti-inflammatory responses. Mechanistically, E3-H inhibits ferroptosis by upregulating the Nrf2/HO-1/GPX4 signaling axis, a critical regulator of cellular antioxidant defense and ferroptosis. These findings highlight the potential of E3-H as a promising therapeutic strategy for treating MIRI and suggest a new avenue for ferroptosis-targeted interventions.