A novel small-molecule inhibitor TD6 targets prohibitin 1 (PHB1) and suppresses colorectal cancer pulmonary metastasis by destabilizing mitochondrial complex I.

Given the limited efficacy of existing therapies for metastatic colorectal cancer (mCRC), there is an urgent need for novel strategies. Prohibitin 1 (PHB1) is significantly upregulated in CRC, where it plays a critical role in oxidative phosphorylation (OXPHOS) to meet the heightened energy demands of rapid tumor growth and metastasis. Here, we discover that PHB1 interacts with NADH: ubiquinone oxidoreductase core subunit S1 (NDUFS1), a subunit of the OXPHOS complex, thereby modulating mitochondrial respiratory function. Based on these insights, we developed TD6, a highly potent and selective small-molecule inhibitor of PHB1. In a mouse model of colorectal cancer pulmonary metastasis (CRPM), TD6 treatment significantly prolonged animal survival. Mechanistically, TD6 binds to PHB1 and induces a conformational change in the PHB complex, which reduces PHB-mediated stabilization of NDUFS1. Disruption of the PHB-NDUFS1 interaction promotes NDUFS1 degradation via the lysosomal pathway, leading to impaired activity of mitochondrial complex I (MCI) and reduced OXPHOS function. In summary, PHB1 maintains MCI stability and OXPHOS activity through its interaction with NDUFS1. By targeting PHB1, TD6 effectively disrupts this regulatory axis, demonstrating therapeutic potential against CRPM. This study presents a novel drug candidate and a theoretical foundation for PHB1-based interventions targeting cancer energy metabolism.