Key result
Anti-PD-1 plus nab-paclitaxel exacerbates immune myocarditis and LV dysfunction via ferroptosis in preclinical models.
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Why the study?
Combination therapy with immune checkpoint inhibitors and chemotherapy increases cardiovascular toxicity, but the mechanisms of exacerbated cardiac injury remain poorly understood.
Identifies the IFN-γ/STAT1/Egr-1/Trp53/xCT axis as a mechanistic driver of ICI-chemotherapy-associated cardiotoxicity and highlights Egr-1 as a potential therapeutic target.
Egr-1 inhibition may mitigate ferroptosis in ICI-chemo cardiotoxicity; leaves open translation beyond animal models.
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.
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Meng et al. (2026) studied PD-1 antibody-associated immune myocarditis. Anti-PD-1 antibody plus nab-paclitaxel vs. Either agent alone was evaluated. The combination of anti-PD-1 antibody and nab-paclitaxel exacerbated immune myocarditis and left ventricular dysfunction via STAT1/Egr-1/Trp53-mediated ferroptosis in mouse and cellular models.
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