Mitochondrial IκBα fuels cancer progression through metabolic rewiring, endothelial activation, and thrombotic spread
Year: 2026
Type: article
Abstract: 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.
Source: Cell Death Discovery
Authors: 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
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W7140841666