Nab-paclitaxel exacerbates PD-1 antibody-associated immune myocarditis via the STAT1/Egr-1/Trp53-mediated ferroptosis...

Combination therapy with immune checkpoint inhibitors and chemotherapy heightens cardiovascular toxicity, yet the mechanism of exacerbated cardiac injury is poorly understood. Here, we investigated the cardiotoxicity of anti-PD-1 antibody plus nab-paclitaxel, focusing on ferroptosis and the role of Egr-1 as a therapeutic target. In tumor-bearing C57BL/6J mice, the combination caused more severe left ventricular dysfunction, myocardial inflammation, and ferroptotic features than either agent alone. In NRVMs, IFN-γ dose-dependently triggered ferroptosis through STAT1 phosphorylation. Activated STAT1 bound the Egr1 promoter to drive Egr-1 expression; Egr-1 then translocated to the nucleus and upregulated Trp53, leading to p53 accumulation that suppressed SLC7A11/xCT, impaired glutathione synthesis, and caused lethal lipid peroxidation. Cardiac-specific Egr-1 knockout markedly alleviated cardiac dysfunction, inflammation, and SLC7A11 loss induced by anti-PD-1 alone or combined with nab-paclitaxel, effectively attenuating ferroptosis and toxicity. These findings reveal the IFN-γ/STAT1/Egr-1/Trp53/xCT axis as a key driver of cardiomyocyte ferroptosis, positioning Egr-1 as a key driver linking immune activation to ferroptosis and a promising target for preventing ICI-chemotherapy cardiotoxicity.