Targeting TAK1 to overcome cisplatin resistance in lung adenocarcinoma by rewiring the NF-κB and p53 signaling.

Acquired cisplatin resistance limits the efficacy of chemotherapy in advanced non-small cell lung cancer (NSCLC). Identifying key resistance regulators is clinically important. Although TAK1 (transforming growth factor-beta-activated kinase 1) has been implicated in drug resistance, its role in cisplatin-resistant lung adenocarcinoma remains unclear. Bioinformatic analysis of Gene Expression Omnibus (GEO) data identified TAK1 as a resistance-related gene. TAK1 expression was elevated in resistant clinical samples and cell lines (A549R, PC9R), positively correlating with the upregulation of drug-efflux proteins P-glycoprotein (P-gp) and ATP-binding cassette subfamily G member 2 (ABCG2). The TAK1 inhibitor (5Z)-7-oxozeaenol (5Z7) synergized with cisplatin to suppress proliferation and epithelial-mesenchymal transition, induce apoptosis, cause G0/G1 arrest, and promote senescence in resistant cells. Genetic TAK1 inhibition produced similar trends. Mechanistically, 5Z7 inhibited the TAK1-IκB kinase (IKK) axis, blocking inhibitor of κBα (IκBα) phosphorylation and nuclear factor kappa-B (NF-κB) p65 nuclear translocation, while upregulating p53 and its downstream effectors p21/p16-effects that were reversible by an NF-κB activator or p53 inhibitor. In vivo, 5Z7 plus cisplatin suppressed resistant tumor growth without notable organ toxicity. This study establishes TAK1 as a key hub in cisplatin resistance and shows that 5Z7 reverses resistance by targeting TAK1 to coordinately regulate NF-κB/p53 signaling, providing a foundation for potential clinical translation.