Quercetin and tumor microenvironment associated pathways in lung cancer: a network pharmacology and in vitro study

Cancer progression is initiated by genetic mutations but is largely sustained by tumor microenvironment (TME)-mediated epigenetic regulation, which promotes cancer cell survival, adaptation, immune evasion, metabolic adaptation, and therapeutic resistance. This study investigated the potential of Quercetin as a tumor microenvironment-oriented therapeutic agent in non-small cell lung cancer (NSCLC) using network pharmacology, molecular docking, and clonogenic assay. Network pharmacology identified 98 overlapping targets between Quercetin and NSCLC. Pathway enrichment analysis identified key therapeutic targets, particularly hypoxia-inducible factor (HIF)- and cortisol-related pathways involved in TME regulation. Molecular docking demonstrated favorable binding of Quercetin with HIF and cortisol-related targets (CRHR1, NR3C1, EP300, and VHL), supporting its interactions with cortisol signaling, and hypoxia-related pathways. Furthermore, the potential of Quercetin to suppress clonogenic survival associated with cancer relapse was evaluated using the A549 cell line. Simultaneous treatment with 11.73 μg/mL Doxorubicin and 22.98 μg/mL Quercetin reduced colony formation from 39 to 8.5 colonies per field, indicating reduced clonogenic survival and enhanced chemosensitivity. These findings suggest an alternative approach in which Quercetin may complement conventional chemotherapy by targeting tumor microenvironment-associated pathways, with the potential to suppress long-term cancer cell survival and colony formation that usually occur post-chemotherapy.