Synergistic Promotion of Ferroptosis in Cardiomyocytes by Tumor Cell Secretory Factors and PD-1 Blockade.
- 1Department of Cardiovascular, The Fourth People's Hospital of Jinan, Jinan, Shandong, China.
Abstract
Immune checkpoint inhibitors (ICIs) targeting PD-1 frequently cause severe cardiotoxicity, yet the mechanisms involving tumor-host crosstalk remain poorly defined. Emerging evidence implicates ferroptosis, an iron-dependent regulated cell death, in cardiac injury during cancer immunotherapy. Primary neonatal murine ventricular cardiomyocytes (NMVCs) were exposed to lung cancer-derived tumor-conditioned media (TCM; tumor-conditioned media) enriched with exosomes, anti-PD-1 antibody, or both. Ferroptotic markers, mitochondrial bioenergetics, inflammatory signaling, and exosomal microRNA cargo were systematically evaluated using standardized biochemical assays, quantitative PCR, and targeted pharmacological rescue experiments. TCM primed cardiomyocytes for ferroptosis by downregulating the GPX4/SLC7A11/Nrf2 antioxidant axis, depleting glutathione, and elevating labile iron and lipid peroxidation. Anti-PD-1 treatment alone induced minimal oxidative stress but synergized with TCM to amplify ferroptosis > 4.7-fold, triggering profound mitochondrial depolarization and upregulating pro-ferroptotic enzymes ACSL4/LPCAT3. Tumor-derived exosomal miR-214-3p and miR-23a-3p directly suppressed GPX4 and Nrf2, mediating cellular vulnerability. The combined insult hyperactivated NF-κB and STING pathways in a mitochondria-dependent manner, markedly increasing pro-inflammatory cytokine secretion. Co-treatment with ferrostatin-1, deferoxamine, or Nrf2 activators effectively reversed ferroptotic markers and restored mitochondrial function. Tumor-derived exosomal factors and PD-1 blockade synergistically drive ferroptotic cardiomyocyte death by crippling antioxidant defenses and amplifying inflammatory signaling. Targeting ferroptosis or its upstream regulators presents a promising cardioprotective strategy for patients receiving cancer immunotherapy.
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BibTeX
@article{ma2026synergistic,
title = {{Synergistic Promotion of Ferroptosis in Cardiomyocytes by Tumor Cell Secretory Factors and PD-1 Blockade.}},
author = {Xiaohua Ma and Xiufeng Li and Fuchao Qu and Hao Cheng and Yifei Liu and Chenhui Liu},
journal = {Journal of biochemical and molecular toxicology},
year = {2026},
month = oct,
doi = {10.1002/jbt.71064},
url = {https://europepmc.org/article/MED/42949492},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synergistic Promotion of Ferroptosis in Cardiomyocytes by Tumor Cell Secretory Factors and PD-1 Blockade.
AU - Xiaohua Ma
AU - Xiufeng Li
AU - Fuchao Qu
AU - Hao Cheng
AU - Yifei Liu
AU - Chenhui Liu
PY - 2026
DA - 2026/10/28
JO - Journal of biochemical and molecular toxicology
DO - 10.1002/jbt.71064
UR - https://europepmc.org/article/MED/42949492
AB - Immune checkpoint inhibitors (ICIs) targeting PD-1 frequently cause severe cardiotoxicity, yet the mechanisms involving tumor-host crosstalk remain poorly defined. Emerging evidence implicates ferroptosis, an iron-dependent regulated cell death, in cardiac injury during cancer immunotherapy. Primary neonatal murine ventricular cardiomyocytes (NMVCs) were exposed to lung cancer-derived tumor-conditioned media (TCM; tumor-conditioned media) enriched with exosomes, anti-PD-1 antibody, or both. Ferroptotic markers, mitochondrial bioenergetics, inflammatory signaling, and exosomal microRNA cargo were systematically evaluated using standardized biochemical assays, quantitative PCR, and targeted pharmacological rescue experiments. TCM primed cardiomyocytes for ferroptosis by downregulating the GPX4/SLC7A11/Nrf2 antioxidant axis, depleting glutathione, and elevating labile iron and lipid peroxidation. Anti-PD-1 treatment alone induced minimal oxidative stress but synergized with TCM to amplify ferroptosis > 4.7-fold, triggering profound mitochondrial depolarization and upregulating pro-ferroptotic enzymes ACSL4/LPCAT3. Tumor-derived exosomal miR-214-3p and miR-23a-3p directly suppressed GPX4 and Nrf2, mediating cellular vulnerability. The combined insult hyperactivated NF-κB and STING pathways in a mitochondria-dependent manner, markedly increasing pro-inflammatory cytokine secretion. Co-treatment with ferrostatin-1, deferoxamine, or Nrf2 activators effectively reversed ferroptotic markers and restored mitochondrial function. Tumor-derived exosomal factors and PD-1 blockade synergistically drive ferroptotic cardiomyocyte death by crippling antioxidant defenses and amplifying inflammatory signaling. Targeting ferroptosis or its upstream regulators presents a promising cardioprotective strategy for patients receiving cancer immunotherapy.
SN - 1095-6670
SN - 1099-0461
ER -