NRF1 Activates the AMPK/SIRT1/PGC-1α/TFAM Axis to Suppress EMT and Tumor Progression in Lung Adenocarcinoma

<h3>Abstract</h3> <h3>Background/Aim:</h3> Lung cancer is the leading cause of cancer-related mortality globally, emphasizing the need for identifying molecular mechanisms that drive its progression and therapeutic resistance. Nuclear respiratory factor 1 (NRF1) is a transcription factor involved in mitochondrial biogenesis, apoptosis, and epithelial–mesenchymal transition (EMT), all of which contribute to cancer initiation and metastasis. This study investigated the role of NRF1 in lung cancer progression and its potential as a therapeutic target. <h3>Materials and Methods:</h3> A549 lung adenocarcinoma cells were used to evaluate the effects of NRF1 overexpression (pcDNA-NRF1) and silencing (shRNA-NRF1). Moreover, western blotting were used to assess EMT markers (E-cadherin, N-cadherin, vimentin), mitochondrial biogenesis factors (T-fam), and apoptotic markers (caspase-3, caspase-9). Functional assays were performed to measure cell migration, and apoptosis. SCID mice implanted with NRF1-modified tumors were used for <i>in vivo</i> validation. Statistical analyses included analysis of variance (<i>p</i>&lt;0.05). <h3>Results:</h3> NRF1 overexpression increased E-cadherin while reducing N-cadherin and vimentin, inhibiting EMT. It suppressed cell migration while enhancing mitochondrial biogenesis and apoptosis, as indicated by elevated caspase-3 and caspase-9 activity. Conversely, NRF1 silencing promoted EMT, reduced mitochondrial biogenesis, and decreased apoptosis. <i>In vivo</i>, NRF1-overexpressing tumors exhibited higher levels of E-cadherin, T-fam, and caspase-3, supporting NRF1’s role in EMT suppression and mitochondrial and apoptotic pathway enhancement. <h3>Conclusion:</h3> NRF1 acts as a suppressor of EMT and a promoter of mitochondrial biogenesis and apoptosis in lung cancer. Its regulatory role suggests NRF1 as a potential therapeutic target for inhibiting tumor progression and overcoming resistance to conventional therapies.