An Integrative Approach to Lung Cancer Therapy: Linking the TGF-β (+869 C/T) Polymorphism to a Structurally Validated Natural Inhibitor

OBJECTIVE: This study aimed to create a genetic and clinical roadmap for the TGF-β pathway in an Iraqi population, focusing on the TGF-β1 (+869 C/T) polymorphism. METHODS: A structure-guided approach was used to identify a natural compound, quercetin, as a potential inhibitor of its primary receptor, ALK5. The clinical aspect evaluated the biochemical profile of each patient by measuring serum levels of TGF-β and IL-17, while assessing the genetic predisposition of each individual using ARMS-PCR to genotype the TGF-β1 (+869C/T) polymorphism. Following the evaluation of clinical findings, a molecular docking study was conducted to investigate how quercetin interacts with the ALK5 kinase domain (PDB: 1VJY). RESULT: The study demonstrated a two-fold signature of risk among the patients. First, the levels of serum TGF-β and IL-17 were significantly elevated (P < 0.05) in lung cancer patients compared to healthy individuals. Second, patients exhibited a genetic predisposition to lung cancer-specifically, those with the "TT" genotype had a higher risk of developing the disease than individuals with the protective "CC" genotype. Furthermore, the model illustrated that quercetin forms key hydrogen bonds with the ALK5 kinase hinge residues Glu245 and Lys232, which are essential for inhibitory binding. CONCLUSION: This study established a strong connection between the activity of the TGF-β pathway, the +869C/T polymorphism, and lung cancer susceptibility in the Iraqi population. Additionally, it provided conclusive structural evidence supporting quercetin as a highly promising natural inhibitor of ALK5.