TXNIP Suppresses Lung Cancer Progression by Inhibiting TRAF6-Mediated NF-κB Activation and Autophagy

Thioredoxin-interacting protein (TXNIP) functions as a tumor suppressor, but its role in lung cancer remains poorly defined. This study identifies TXNIP as a negative regulator of TNF receptor-associated factor 6 (TRAF6)-mediated NF-κB activation and autophagy, key pathways in tumor progression. TXNIP directly binds TRAF6 via its C-terminal arrestin domain, inhibiting TRAF6 dimerization and auto-ubiquitination. This, in turn, reduces ubiquitination of downstream targets TGF-β-activated kinase 1 and beclin 1 (BECN1), thereby suppressing NF-κB signaling and autophagic activity. TXNIP expression is significantly reduced in lung adenocarcinoma and lung squamous cell carcinoma, as demonstrated by public datasets and patient tissue analysis. Gene set enrichment analysis shows that non-small cell lung cancer patients with TXNIP^DOWN and TRAF6^UP expression exhibit increased metastasis-associated gene signatures and poorer survival outcomes. Functionally, <i>TXNIP</i>-knockout lung cancer cells show enhanced TRAF6 and BECN1 ubiquitination, increased LC3 puncta, and elevated NF-κB activity and cytokine production after TLR3/4 stimulation. These cells also display increased proliferation, migration, invasion, and colony formation in vitro across multiple lung cancer cell lines (A549 and H1299). Collectively, this study highlights TXNIP as a critical suppressor of TRAF6-driven oncogenic pathways in lung cancer, suggesting that its downregulation contributes to disease progression through enhanced TLR-induced signaling.