Mitochondrial IκBα fuels cancer progression through metabolic rewiring, endothelial activation, and thrombotic spread
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.
Authors
- Lukasz Truszkowski (ORCID: https://orcid.org/0000-0001-7816-6092)
- Massimiliano Mazzone (ORCID: https://orcid.org/0000-0001-8824-4015)
- Alessandra Bertoni (ORCID: https://orcid.org/0000-0002-3981-7099)
- Lidia Avalle (ORCID: https://orcid.org/0000-0002-5060-633X)
- Francesca Orso (ORCID: https://orcid.org/0000-0003-4706-6464)
- Paolo E. Porporato (ORCID: https://orcid.org/0000-0001-8519-1552)
- Alessandro Morotti (ORCID: https://orcid.org/0000-0002-8407-2903)
- Isaia Barbieri (ORCID: https://orcid.org/0000-0003-3035-8970)
- Maiara Caroline Colombera (ORCID: https://orcid.org/0000-0002-5718-5865)
- Mara Brancaccio (ORCID: https://orcid.org/0000-0003-2327-6846)
- Alissa Scalera
- Federica Cappellesso (ORCID: https://orcid.org/0000-0002-4610-4222)
- Pietro Poggio (ORCID: https://orcid.org/0009-0006-0118-8107)
- Giovanna Carrà (ORCID: https://orcid.org/0000-0002-6263-6800)
- Chiara Donno
- Jessica Petiti (ORCID: https://orcid.org/0000-0001-8640-2462)
- Carla Riera Domingo
- Davide Acquarone
- Menga Alessio
- Chiara Riganti
- Roberta Basile
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Vrije Universiteit Brussel (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Istituto Nazionale di Ricerca Metrologica (IT)
- VIB-UGent Center for Inflammation Research (BE)
- Ospedale San Luigi Gonzaga (IT)
- Piedmont University (US)
- University of Turin (IT)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2026-03-27
- DOI
- https://doi.org/10.1038/s41420-026-03022-0
- Primary Topic
- NF-κB Signaling Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00