NQO1 at the crossroads of oxidative stress, cancer, and therapeutic innovation.

NAD[P]H:quinone oxidoreductase (NQO1) is a cytosolic flavoprotein that plays a vital role in cellular defense against oxidative stress through the two-electron reduction of quinones. Beyond its classical antioxidant function, NQO1 has emerged as a multifunctional protein intricately involved in cancer biology, influencing tumor initiation, progression, prognosis and response to therapy. Notably, NQO1 is frequently overexpressed in several solid tumors, where it contributes to redox homeostasis, metabolic adaptation, and protein stability. Contrary to its overexpression, it is suppressed in some solid and liquid tumors either due to NQO1 polymorphism or silencing of upstream regulators, which lend a tumor-specific contextual role for NQO1. Consequences of loss or reduction of NQO1 function are an understudied area of cancer biology. Nevertheless, given the important role NQO1 plays in maintaining redox balance, the lack of fully functional NQO1 has been envisioned to affect cancer development and progression as it relates to redox homeostasis, metabolic adaptation, and protein stability. The unique features of NQO1 biology have positioned NQO1 as both a biomarker and a therapeutic target. This review explores the dualistic nature of NQO1 in cancer, examines its regulation and genetic variability, highlights recent advances in NQO1-targeted therapeutic strategies, including bioactivatable drugs and precision oncology approaches while arguing that one size does not fit all as it relates to assigning a role for NQO1 in cancer biology.