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.