ZBP1-medicated PANoptosis-related signaling contributes to PD-1 inhibitor-associated cardiotoxicity.

BACKGROUND

The growing use of PD-1 inhibitors has led to an increased incidence of immune-related cardiotoxicity, a condition associated with high mortality. Understanding its underlying mechanisms is critical for early detection and targeted treatment.

METHODS

This study integrated transcriptomic and single-cell transcriptomic data to identify potential pathways involved in immune-related cardiotoxicity. BMS-1- and anti-PD-1 antibody-induced mouse models were established for in vivo validation. In vitro, AC16 cardiomyocytes were co-cultured with Jurkat cells in the presence of the PD-1 inhibitor pembrolizumab. Cardiac function, myocardial injury, cell death, inflammatory cytokines, PANoptosis-related signaling, mitochondrial function, and cytosolic mtDNA were assessed.

RESULTS

Bioinformatic analyses identified activation of PANoptosis-related pathways and increased ZBP1 expression in immune-related cardiotoxicity. Pembrolizumab induced cardiomyocyte injury and increased IFN-γ and TNF-α production. Anti-PD-1 antibody treatment caused cardiac dysfunction and myocardial injury in mice, accompanied by increased ZBP1 and apoptosis-, pyroptosis-, and necroptosis-related markers. ZBP1 overexpression aggravated, whereas ZBP1 knockdown attenuated, cardiomyocyte injury and PANoptosis-related signaling. Cardiac ZBP1 knockdown also improved cardiac function and reduced myocardial injury in anti-PD-1-treated mice without suppressing inflammatory cytokine levels. Furthermore, PD-1 inhibition induced mitochondrial dysfunction, altered mitochondrial dynamics, and increased cytosolic mtDNA accumulation, with enhanced ZBP1 association with Z-DNA-associated signals.

CONCLUSION

ZBP1-associated PANoptosis-related signaling may contribute to PD-1 inhibitor-associated cardiotoxicity, potentially linking inflammatory activation and mitochondrial/mtDNA stress to cardiomyocyte injury.