Lung cancer, often diagnosed at advanced stages with limited treatment options, is the leading cause of cancer-related death around the world (Sung et al., 2021). Multiple factors, such as tobacco smoking, air pollution, occupational exposure, and family history, contribute to the high risk of lung cancer (Xia et al., 2022). Although great progress has been made in the diagnosis and treatment of lung cancer, further efforts are still needed to reduce its mortality. For the high-risk populations, chemoprevention may be an effective approach to reducing lung cancer incidence.

β-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione, β-Lap), a natural product extracted from the lapacho tree in South America, possesses various pharmacological activities, including anti-Mycobacterium tuberculosis, anti-Trypanosoma cruzi, antibacterial and antimalarial effects (Gong et al., 2021). Recently, it has gained renewed attention for its special antitumor properties, selectively targeting cancer cells with high expression of endogenous NAD(P)H: quinone oxidoreductase-1 (NQO1) (Blanco et al., 2007; Silvers et al., 2017). NQO1, an important phase II detoxification enzyme in vivo, protects cells from oxidative damage by catalyzing the two-electron reduction reaction of quinones. This process involves the reduction of β-Lap to an unstable hydroquinone form, which can spontaneously react with two oxygen molecules in a two-step reverse reaction to regenerate the original form of β-Lap, thereby mediating a futile redox cycle. A large amount of reactive oxygen species (ROS) rapidly accumulates during this process, triggering a cascade of downstream reactions that ultimately result in cell death (Dou et al., 2022; Huang et al., 2016; Li et al., 2019; Silvers et al., 2017; Zada et al., 2019; Zhang et al., 2017). Therefore, β-Lap has been tested as a potential anticancer drug whose mechanism heavily relies on the presence of NQO1. Multiple phase I and phase II clinical trials of β-Lap and its derivatives (clinical form: ARQ 501, ARQ 761 and MB12066) have been conducted for the treatment of cancer and metabolic syndrome (https://clinicaltrials.gov/) (Beg et al., 2019; Gerber et al., 2018; Hartner et al., 2007; Kawecki et al., 2007; Khong et al., 2007; Kim et al., 2017; Lee et al., 2017; Shapiro et al., 2005). However, its further clinical translation has been significantly hindered by toxicity issues including hemolytic anemia, methemoglobinemia, and other side effects discovered in clinical trials (Gerber et al., 2018; Hartner et al., 2007). Considering the pharmacological potential of β-Lap, extensive efforts have been devoted to optimizing its chemical structure, developing drug delivery systems, and exploring combination strategies to overcome safety concerns (Blanco et al., 2007; Chang et al., 2022; Dou et al., 2022; Huang et al., 2016; Hussain et al, 2017). Nevertheless, no β-Lap derivatives, modified formulations, or combination regimens have been successfully developed.

In this study, we found that the level of NQO1 expression in lung tissue was up-regulated in a time-dependent manner during tumor progression in mouse models of lung cancer, either driven by the oncogenic KrasG12D or induced by tobacco carcinogen NNK. Here, we attempted to prevent lung cancer by using lower dosages (1 mg/kg and 5 mg/kg, oral administration) of β-Lap compared to the clinically therapeutic dose (390 mg/m2 in patients, equivalent to approximately 130 mg/kg in mice, intravenous administration) Gerber et al., 2018; Shapiro et al., 2005; U.S.FDA, 2005), aiming to minimize the potential adverse effects associated with higher therapeutic doses while still achieving the desired preventive outcome.