Repurposing Diphenhydramine in Non-Small Cell Lung Cancer: A Mitochondrial Redox Mechanism and a Derived Prognostic Gene Signature

Diphenhydramine (DIPH) is a widely used first-generation H1 antihistamine. While multiple antihistamines have recently shown noteworthy anticancer potential, the therapeutic efficacy of DIPH in non-small cell lung cancer (NSCLC) and its underlying mechanisms of action remain unreported. Here, we demonstrate that DIPH potently suppresses the viability, clonogenicity, migration, and invasion of non‑small cell lung cancer (NSCLC) cells. Mechanistically, DIPH induces mitochondrial dysfunction and consequent redox imbalance, culminating in DNA damage and activation of the intrinsic apoptotic pathway—a cascade further validated in patient‑derived lung cancer organoids. To investigate the potential clinical implications of DIPH, we examined DIPH‑related genes (DRGs) in The Cancer Genome Atlas (TCGA) cohort of lung adenocarcinoma (LUAD, the predominant NSCLC subtype). This analysis revealed two DRG‑based molecular subtypes with significantly distinct survival outcomes and enabled the construction of a robust DRG‑derived prognostic signature. The signature served as an independent predictor of survival and was associated with specific alterations in the tumor immune microenvironment. Collectively, our findings not only report the first evidence of DIPH’s antitumor efficacy in NSCLC but also delineate its underlying mitochondria–redox–DNA damage axis, thereby establishing a translational framework that links this drug‑induced pathway to a clinically actionable molecular signature in LUAD.