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<p>Mitochondria play a central role in metastatic spread and cancer progression, with the IκBα/NF-κB signaling axis acting as a key regulator of both processes. We suggest that a stable fraction of IκBα localizes to mitochondria, where it escapes proteasomal degradation and acquires oncogenic functions independent of its canonical role in NF-κB inhibition. Using engineered A549 lung cancer cells with enforced mitochondrial localization of IκBα (IκBα-MTS), we show that the IκBα mitochondrial pool promotes increased cell proliferation, enhanced migration, and resistance to chemotherapy-induced apoptosis, along with a metabolic reprogramming characterized by elevated glycolysis and lactate secretion. These changes activated endothelial cells (ECs) and triggered cancer-associated thrombosis (CAT). This prothrombotic state, marked by elevated vWF a potent trigger for platelet adhesion and activation, contributed to an environment favorable for metastatic dissemination. Our findings reveal mitochondrial IκBα as a key mediator in mitochondrial stress, endothelial activation, and thrombo-inflammatory mechanisms that drive lung cancer progression.</p><p></p>

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Mitochondrial IκBα fuels cancer progression through metabolic rewiring, endothelial activation, and thrombotic spread

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Alessio Menga,
  • Jessica Petiti,
  • Roberta Basile,
  • Pietro Poggio,
  • Davide Acquarone,
  • Alfonso Scalera,
  • Lidia Avalle,
  • Francesca Orso,
  • Alessandra Bertoni,
  • Paolo Ettore Porporato,
  • Chiara Riganti,
  • Lukasz Truszkowski,
  • Isaia Barbieri,
  • Mara Brancaccio,
  • Carla Riera Domingo,
  • Federica Cappellesso,
  • Chiara Donno,
  • Maiara Caroline Colombera,
  • Massimiliano Mazzone,
  • Giovanna Carrà,
  • Alessandro Morotti

摘要

Mitochondria play a central role in metastatic spread and cancer progression, with the IκBα/NF-κB signaling axis acting as a key regulator of both processes. We suggest that a stable fraction of IκBα localizes to mitochondria, where it escapes proteasomal degradation and acquires oncogenic functions independent of its canonical role in NF-κB inhibition. Using engineered A549 lung cancer cells with enforced mitochondrial localization of IκBα (IκBα-MTS), we show that the IκBα mitochondrial pool promotes increased cell proliferation, enhanced migration, and resistance to chemotherapy-induced apoptosis, along with a metabolic reprogramming characterized by elevated glycolysis and lactate secretion. These changes activated endothelial cells (ECs) and triggered cancer-associated thrombosis (CAT). This prothrombotic state, marked by elevated vWF a potent trigger for platelet adhesion and activation, contributed to an environment favorable for metastatic dissemination. Our findings reveal mitochondrial IκBα as a key mediator in mitochondrial stress, endothelial activation, and thrombo-inflammatory mechanisms that drive lung cancer progression.