Carotenoids are powerful antioxidants that can interact with reactive oxygen species through oxidation, reduction, hydrogen atom extraction, or addition reactions, reducing oxidative damage to tissue cells [
53,
54]. They can also lower the risk of gastric cancer by inhibiting cell proliferation, inducing apoptosis, affecting cell communication, and enhancing immune function [
55‐
58]. Among them, lycopene has been found to inhibit the growth of gastric cancer cells, arrest the cell cycle, induce late-stage apoptosis/necrosis, and decrease mitochondrial membrane potential [
59]. Lycopene consists of 89.45% carbon and 10.51% hydrogen, with 11 linear conjugated bonds and 2 non-conjugated double bonds [
60]. This unique structure provides strong antioxidant activity, with an effect that is 100 times greater than α-tocopherol and more than twice that of β-carotene [
61,
62]. In normal cells, it downregulates inflammation, protects DNA, RNA, and lipids from oxidative damage, and prevents genomic mutations that may lead to cancer [
63,
64]. Research has also found that lycopene inhibits the proliferation of Helicobacter pylori-infected gastric adenocarcinoma cells by reducing ROS levels and inhibiting Jak1/Stat3 activation, Wnt/β-catenin signaling, and oncogene expression [
64]. Other carotenoids, including α-carotene, β-carotene, lutein, and β-cryptoxanthin, can also influence the development of gastric cancer. For example, β-carotene exhibits anticancer activity by reducing ROS production mediated by NADPH oxidase, activating NF-κB, and regulating the expression of TRAF1 and TRAF2 genes controlled by NF-κB, while inhibiting excessive proliferation of AGS cells [
65]. β-cryptoxanthin demonstrates anti-proliferative activity by reducing cell viability, migration, and inducing G0/G1 arrest [
66,
67]. Lutein increases the translocation of NADPH oxidase subunit p47Phox to the cell membrane, enhances ROS levels, promotes NADPH oxidase activity, and increases NF-κB activity and apoptotic indices in AGS cells, such as Bax, caspase-3 cleavage, and DNA fragmentation [
68]. However, according to the World Cancer Research Fund, not all carotenoids are beneficial for health. Studies have shown that high-dose supplementation of beta-carotene can increase the risk of lung cancer [
69,
70]. The effects of carotenoid-containing food supplements on other types of cancer have been considered limited and controversial [
71,
72]. In fact, recent research suggests that carotenoids have a dual role in both antioxidant and pro-oxidant activities, making it complex to determine their role in cancer development [
71,
73].
Previous case–control studies exploring the association between carotenoids and gastric cancer incidence have indicated that higher intake of carotenoids significantly reduces the risk of gastric cancer even after adjusting for potential confounding factors such as gender, smoking, and Helicobacter pylori infection [
28]. However, the results of a randomized, double-blind, placebo-controlled clinical trial involving 22,071 healthy males demonstrated that 12 years of continuous beta-carotene supplementation had no beneficial or harmful effects on reducing the incidence of gastric cancer [
74]. These findings are consistent with our research results. Our meta-analysis based on cohort studies revealed no significant correlation between the five types of carotenoids included in the analysis and the occurrence of gastric cancer. In addition, our meta-analysis based on case–control studies showed no significant correlation between beta-cryptoxanthin and lycopene and gastric cancer incidence, while alpha-carotene, beta-carotene, and lutein were negatively associated with gastric cancer incidence. However, it should be noted that except for beta-carotene, the odds ratio values for alpha-carotene and lutein were close to 1, suggesting that their association with gastric cancer occurrence is limited.
Interestingly, when comparing the results of meta-analyses from different study designs, we found that study design appears to have a significant impact on the research outcomes. In contrast to the results of meta-analyses based on case–control studies, the meta-analysis based on cohort studies showed that none of the five carotenoids included in the analysis could reduce the risk of gastric cancer. This is similar to the findings of Friedenreich et al., who found that the correlation between increased intake of vegetables and fruits and reduced cancer risk was only supported by case–control studies, with weaker evidence provided by cohort studies [
75]. In fact, prospective cohort studies involve grouping participants based on their exposure characteristics before the occurrence of the outcomes of interest. This minimizes the impact of baseline characteristics, dietary recall, or selection/participation bias. On the other hand, case–control studies are prone to recall bias and selection bias, which can lead to biased results. Therefore, evidence from cohort studies is generally considered stronger than evidence from case–control studies [
76‐
78]. Furthermore, it is challenging to establish a clear protective effect of a specific compound in the development of chronic diseases within a complex diet influenced by many other risk factors. In such cases, conflicting results may also arise [
79,
80]. Although the studies we included adjusted for age and gender as confounding factors, there is still a possibility of inadequate control for other confounding factors. Additionally, there are variations in the confounding factors across each study, which may lead to biases in the estimation of risks. Moreover, there are significant differences in the quartiles of carotenoid intake across different studies, which can also affect the calculation of effect sizes. Some studies suggest that inconsistent results may be due to variations in consumption levels of phytochemicals, regional differences, dietary and lifestyle variations, sample size limitations, and data acquisition methods [
81‐
83].