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

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.