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Despite the disappointing findings of the human intervention trials that were conducted to determine the chemoprotective effect of β-carotene on the incidences of lung cancer in smokers found no protective effects or even harmful effects in 1990s, there is supporting evidence that indicates a protective role of fruits and vegetables rich in carotenoids in prevention of lung cancer that continues to be reported in human epidemiological studies and small intervention trials, as well as in mechanistic studies using cell culture and animal models over the past 20 years.The earlier unexpected findings also brought carotenoid researchers back to experimental research in animal and cell culture models in an attempt to better understand the roles of carotenoids and their derivatives in the process of these chronic diseases, with special attention to their metabolism and biological actions, molecular targets, dose effects, and organ-specific effects.My laboratory has recently demonstrated that β-cryptoxanthin, a xanthophyll that is strongly associated with a reduced risk of lung cancer in the data analysis pooled from seven large cohorts, can inhibit lung inflammation, emphysema and tumor development in animal models (ferret and mice).We provided an evidence-based scientific verification of β-cryptoxanthin as a preventive agent independent of vitamin A activity.We demonstrated that βcryptoxanthin treatment increased Sirtuin 1 (SIRT1, a NAD+-dependent protein/histone deacetylase),increased survival probability;and decreased the levels of lung IL-6 and phosphorylation of AKT.Targeting the SIRT1 pathway with carotenoids, will provide new opportunities for future human studies involving carotenoids for the prevention of lung cancer and smoking-related complications.