Photodegradation of Naproxen augment the photosensitization and phototoxicity with attenuated COX-2 binding under ambient UVA and UVB exposure.

Naproxen (NPX) is a widely prescribed non-steroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic, and anti-inflammatory effects. Owing to its structure, NPX is susceptible to photodegradation, a factor of particular concern for topical formulations where exposure to solar UV radiation is inevitable. In this study, we systematically investigated the photodegradation and phototoxic potential of NPX under environmentally relevant UVA and UVB irradiation. NPX underwent faster photodegradation under UVA than UVB. UHPLC and LC-QToF-MS/MS identified two major photoproducts, P1 (1-(6-methoxynaphthalen-2-yl)ethanol) and P2 (2-acetyl-6-methoxynaphthalene), with P1 comprising approximately 90% of the photoproduct profile in both UVA and UVB. Spectroscopic analyses using FTIR and Raman spectroscopy revealed characteristic structural alterations, while LC-QToF-MS, 1H NMR, 13C NMR, and 2D NMR elucidated the photodegradation pathway, dominated by side-chain cleavage and decarboxylation reactions. Computational studies, including molecular docking and molecular dynamics simulations with the COX-2 enzyme, indicated diminished binding efficacy of NPX photoproducts. Further, we checked the COX-2 inhibitory activity, with PGE₂ abundance increasing by 15.6% and 37.4% with degraded NPX (Deg-NPX) relative to NPX at 10 and 50 µg/mL, respectively. Cytotoxicity assays in HaCaT cells demonstrated that NPX is phototoxic but Deg-NPX is both cytotoxic and phototoxic and also induced greater intracellular ROS accumulation, membrane damage, apoptosis, and dsDNA breaks. Collectively, these results highlight that NPX photodegradation generates photoproducts with greater basal cytotoxicity and enhanced phototoxicity and diminished pharmacological activity. The study provides mechanistic insights into their role in cutaneous adverse effects and highlights the importance of evaluating phototoxic risks in the clinical management of NSAID-based topical therapies.