KNK437 Suppresses the Growth of Non‐Small Cell Lung Cancer Cells by Targeting Heat Shock Factor 1

ABSTRACT Heat shock factor 1 (HSF1) has emerged as a promising therapeutic target in various solid tumors. However, its specific role in non‐small cell lung cancer (NSCLC) and the potential efficacy of HSF1 inhibitors in this context remain largely unexplored. The current data showed that HSF1 is overexpressed in NSCLC cells and is positively associated with poorer survival outcomes in NSCLC patients. Moreover, the HSF1 inhibitor KNK437 markedly suppresses NSCLC cell proliferation and induces dose‐dependent cell cycle arrest and apoptosis. In addition, KNK437 significantly alters the expression of HSF1 and its downstream target genes in HSF1‐overexpressing NSCLC cells, while HSF1 knockdown markedly attenuates the anti‐proliferative effects of KNK437, indicating that its therapeutic efficacy is largely mediated through HSF1 inhibition. Finally, molecular docking simulations revealed that KNK437 engages in hydrophobic interactions and forms two critical hydrogen bonds with HSF1, potentially underpinning its inhibitory activity. Collectively, these findings support HSF1 as a compelling molecular target for NSCLC treatment and highlight KNK437 as a promising therapeutic candidate.