In past decades, general cancer-associated morbidity and mortality have grown rapidly and become a major burden for public health management (Sung et al., 2021; Siegel et al., 2022). Thus, early prevention, screening, and diagnosis become the effective strategies for reducing the cancer burden on the population (Rebbeck et al., 2018). As for cancer prevention, especially in terms of chemoprevention, drugs that were frequently prescribed for metabolic and cardiovascular diseases were noticed to have positive effects on the anticancer process (Gronich and Rennert, 2013; Morales and Morris, 2015).

Statins, the inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR), are commonly used as lipid-lowering drugs for atherosclerosis (Ziaeian and Fonarow, 2017). Recently, statins have also received increasing attention owing to the rate-limiting enzyme in the mevalonate pathway (a pathway controlling a range of cell signaling molecules with the potential to regulate carcinogenesis) for cancer prevention (Saka-Herrán et al., 2022; Khazaaleh et al., 2022; Zhang et al., 2019; Longo et al., 2022; Cheung et al., 2023) (Figure 1). Detailly, preclinical research revealed that statins might inhibit the cancer cell proliferation via countering the cell cycle at the G1-S phase and enhancing the cell apoptosis (Ahmadi et al., 2017). Meanwhile, statins could also inhibit Ras/Rho pathways to further inhibit the multiple carcinogenic signaling pathways (Ahmadi et al., 2017; Patel and Kashfi, 2022). Clinically, although numerous population-based studies have described the anticancer properties of statins, the evidence for the anticancer effects of statins is still debatable. Notably, results from one large-scale European population-based study (3,118 biliary tract cancers cases and 15,519 controls), Liu et al. demonstrated that statins use could decrease by nearly 12% (odd ratio (OR) = 0.88), 95% confidence interval (CI): 0.79–0.98) risk of biliary tract cancer (Liu et al., 2019). Similarly, evidence from the Asian population, Chiu et al. determined a protective role of statin use for liver cancer prevention, statins use could significantly reduce the liver cancer risk by 38% (OR = 0.62, 95% CI = 0.42–0.91), compared with no use of statins (Chiu et al., 2011). Conversely, no association between statin use and cancer prevention effects was noticed in recent studies (Baandrup et al., 2015; Wang et al., 2019; Saka-Herrán et al., 2022). Specifically, with a relatively smaller sample size, Chan et al. did not find any beneficial role of statin use on esophageal cancer prevention (Chan et al., 2013). Moreover, evidence from one recent prospective study, the beneficial role of statin use on skin cancer risk was still questionable (Al Rahmoun et al., 2022). More importantly, some researchers even highlighted the potential risk of long-term statins use in developing invasive ductal carcinoma (OR = 1.83) and invasive lobular carcinoma (OR = 1.97) (McDougall et al., 2013). Thus, the disparity results forward us to find a more comprehensive analysis for evaluating the role of statin use in cancers (Ahmadi et al., 2017; Patel and Kashfi, 2022).

Notably, the application of Mendelian randomization (MR) analysis (Sekula et al., 2016; Hemani et al., 2018) based on Genome-wide association studies (GWAS) data was widely used in different fields of public health, which could also help us to investigate the causality by correlating GWAS data of statins use and cancers at the genetic level.

Currently, there are scarce reports in the literature regarding the possible role of statin use in cancer risk based on MR methods. Herein, we aim to evaluate the causal effect of three statin types on multiple cancer risks via the two-sample MR analysis. The results could provide more robust evidence for making clinical decisions.

To the best of our knowledge, this is the only one of few studies on evaluating the genetic association between stain use and pan cancer risk. Detailly, with three frequently used statins and thirteen cancer types involved, this two-sample MR analysis did not show remarkable causality between statin uses and pan-cancer prevention. For the exposure to atorvastatin use, statistically significant relationships were only demonstrated between atorvastatin and colorectal cancer risk (OR = 1.041, by IVW_FE method, OR = 1.086, by weighted median; OR = 1.101, by weighted mode, respectively). Our results were consistent with one recent prospective study explored by Zhang et al. (Zhang et al., 2022). Within 100,300 women and 47,991 men in the Nurses’ Health Study and Health Professionals Follow-Up Study, they demonstrated that there was no significant beneficial effect of statins in decreasing colorectal cancer risk but a higher risk of developing colon cancer was observed in long-term statin use (>15 years, hazard ratio (HR) = 1.85, 95% CI: 1.31–2.61). One recent study with a new target trial design (refers to a more rational analysis method in evaluating the case-control study) was conducted by Dickerman et al. (Dickerman et al., 2020). With linked electronic health records of 752 469 UK adults, the results did not find any significant association between long-term statins use (>5 years) and colon cancer risk (HR = 0.90, 95% 0.71–1.12). Interestingly, studies evaluating the role of stain use on colon cancer survival were consistent (Voorneveld et al., 2017; Yokomichi et al., 2017; Pourlotfi et al., 2022). Notably, as reported by Voorneveld et al. (Voorneveld et al., 2017), statin use after diagnosis was significantly associated with reduced risk of overall and cancer-specific mortality (relative risk (RR) = 0.67, 95% CI: 0.51–0.87, RR = 0.66, 95% CI: 0.49–0.89, respectively). Their tissue microarray results revealed that the protective role of colon cancer survival was remarkably associated with intact BMP signaling pathways, regardless of the K-RAS mutation status. The disparity role of statin uses in colon cancer development and survival indicated the complex interaction of statins and colon cancer was presented. Thus, the deepening of exploring the underlying biological mechanisms is warranted in future works.

Additionally, our study observed a slightly protective effect of rosuvastatin use on bile duct cancer (OR = 0.948, by IVW_FE method) prevention. Reviewing recent literature, the conclusions for bile duct cancer prevention with statin use were in conflict. Liu et al. (Liu et al., 2019) reported that statin use was associated with a nearly 12% lower risk of bile duct cancer (OR = 0.88, 95% CI: 0.79–0.98), compared with non-use of statins. Meanwhile, the latest meta-analysis based on eight observational studies also supported this correlation (Cheung et al., 2023). Conversely, from the same European population, the team of Tran et al. (Tran et al., 2020) yielded the benefits role of statin use in liver cancer prevention (OR = 0.48, 95% CI: 0.24–0.94) but not in bile duct cancer (HR = 1.09, 95% CI: 0.45–2.64). In Tran’s work, during the univariate analysis, statin use was associated with an increased risk of developing liver cell cancer (HR = 1.30, 95% CI: 0.80–2.10). However, after adjusting for numerous confounders, the hazard ratio became significant (HR = 0.48, 95% CI: 0.24–0.94). It indicates that the confounders played an important role during the analysis. For this reason, the ignored but pivotal confounders, which were not adjusted during analysis, could hide the real correlations between the statin use and cancer prevention. Besides, findings based on the Asian population, statins use might decrease the liver cell cancer risk by 59% in patients with chronic liver diseases and by 22% in patients without chronic liver diseases (Lai et al., 2013). Although the supplementary MR analyses in our study revealed the statistically significant causality between statin use and liver cell cancer, the protective efforts of stains were limited. And the significance disappeared after changing the analysis method to IVW_MRE owing to the heterogeneity test results. Hereby, our study did not find remarkably decreased liver cell cancer risk in the statin-use population at a genetic level. Future genetic analysis with more comprehensive and latest GWAS datasets could get more robust evidence on this topic.

Regarding skin cancer, especially in terms of non-melanoma cancer, no significant causality was determined during the MR analysis, regardless of the subtype of statins or MR methods. Similar to our findings, one earlier meta-analysis with robust evidence from 29 studies also supported our negative results (Li et al., 2014). By contrast, with a detailed sub-analysis, Arnspang et al. demonstrated there was a positive correlation between simvastatin (OR = 1.10, 95% CI:1.01–1.19) and fluvastatin (OR = 1.59, 95% CI: 1.17–2.16) and basal cell skin cancer (Arnspang et al., 2015). Based on our results and previous studies, limited evidence could support stain use for general skin cancer prevention.

Moreover, there was no causality was detected in statins use and female cancers in our results and we partially validated the results from one recent meta-analysis conducted by Wang et al. (Wang et al., 2019). In their study, statin use and the duration had no impact on the risk of ovarian cancer or endometrial cancer. Studies evaluating the association between statin use and cervical cancer risk were scarce. Nevertheless, one study preliminary evaluated the beneficial role of stain use in the prognosis of cervical cancer (Song et al., 2017). While the results were encouraging that the stains use could remarkably prolong the survival of stages IB to IV patients, the evidence was limited owing to the relatively small sample size and short follow-up time). For these reasons, future well-designed studies with large-scale patients might help confirm our findings on cervical cancer.

During the past few years, the role of statin uses in prostate cancer raised wide concerns (Tan et al., 2011; Alfaqih et al., 2017; Longo et al., 2022). Notably, prostate cancer patients on statins were noticed to have a lower rate of high grade, lower prostate volume, and lower prostate-specific antigen, compared with the non-statins population (Tan et al., 2011). In recent comprehensive review described, the possible mechanisms by which statins could induce the anticancer effect in multiple ways including but not limited to cholesterol-mediated pathways, and apoptosis in prostate cancer cells (Alfaqih et al., 2017; Longo et al., 2022). In contrast, our results showed there was a positive causality between simvastatin use and prostate cancer risk before changing the MR methods (OR = 1.714, 95% CI: 1.085–2.708). By using the IVW_MRE method, this association did not exist. Thus, the MR analysis could not support the beneficial hypothesis of statin use on prostate cancer.

On the other hand, there was a trend to be significant in atorvastatin use and head and neck cancer risk (p = 0.052). And evidence from different ethnicity-based studies also demonstrated the inverse correlation between statins and head and neck cancer risk (Kao et al., 2019; Getz et al., 2021). Interestingly, evidence from the large-scale SEER-Medicare linked datasets highlighted the protective role of statin use in the survival outcome of head and neck cancer patients (Gupta et al., 2019). The optimal findings among statin use and the prolonged survival probabilities in cancer survivors might be due to the unique effects of statin on promoting the apoptosis of cancer cells and inhibiting the cell proliferation as well as the invasion in cancer related metabolism (Wang et al., 2000; Wong et al., 2002; Chan et al., 2003; Nübel et al., 2004; Kidera et al., 2010). Furthermore, recent clinical and preclinical studies also demonstrated the statin could be the radio-sensitizers in cancer therapy (Wei et al., 2022). Thus, these findings help to reveal the potential mechanisms of the beneficial role of statin use in cancer therapy (Duarte et al., 2021).

As for other frequent solid tumors, like breast cancer, lung cancer, bladder cancer, as well as oesophageal cancer, our MR analysis results confirmed the results in previous studies that there was no association between statin use and the risk of these mentioned cancers (Setoguchi et al., 2007; Kuo et al., 2012; Undela et al., 2012; Chan et al., 2013; Chan et al., 2014). Interestingly, however, recent works suggested that statins might improve the survival probabilities in these cancer types like the results observed in liver cell cancer (Alexandre et al., 2016; Manthravadi et al., 2016; Richard et al., 2017; Borgquist et al., 2019; Chen et al., 2019). Emerging evidence even revealed that statins users appeared to have substantially better survival outcomes than nonusers in different observational studies. However, some scholars speculated that the inverse association between statin use and cancer mortality might be owing to data collection and selection bias, and immortal-time bias (Emilsson et al., 2018). Thereby, the confirmatory works done by Emilsson et al. (Emilsson et al., 2018) demonstrated that the bias existing in previous observational studies could be reduced by using the inverse-probability weighting method in data censoring. Compared with the positive findings in previous observational studies, neither 3-year cancer-specific survival nor overall survival was improved in patients who started the statin therapy within 6 months during postdiagnosis (Emilsson et al., 2018). Nevertheless, although this emulated trial yielded the negative influence of selection bias on evaluating the statin use and cancer survival, it should not discourage the enthusiasm for conducting trials of statins in cancer prevention and survival since statin repurposing was expected to be a more cost-effective way compared to some other newly modalities of cancer treatment (Ahern et al., 2018; Chan et al., 2018).

There are some strengths of our study that need to be mentioned. First, to our knowledge, this is the first comprehensive analysis in evaluating the three different statins use and pan-cancer risk via the two-sample MR analysis, which could provide more insightful evidence for future investigation. Second, compared with previous clinical observational or case-control studies, the GWAS datasets maintain stability in the same ancestry population. The data stability could help to reduce the bias during the outcome comparisons. Third, there is no horizontal pleiotropy observed during the MR analysis and the leave-one-out analysis proved the stability of the MR analysis. While there are some heterogeneities existed in several cancers, the changed MR method could help to reduce this bias.

Nonetheless, several limitations are existed in this study, which should be noticed in the interpretation and generalization of our findings. First, although the study population in this work eliminates the race discrepancy, it is unknown whether the findings could be generalized to other different race and regions. Thus, GWAS studies from different regions could provide more robust evidence on statin use and cancer risk. Moreover, the GWAS data on statins and cancer are updated periodically, and future datasets with comprehensive SNPs results could provide more significant results. While our results only determine a slightly beneficial role of statin use in some particular cancers, future well-designed double-blind randomized controlled trials with matched participants enrollment, the same dosage of statin use, the same duration of medication of statin therapy, and long-term follow-up information, are warranted to validate these findings and provide more robust evidence in evaluating the feasibility of lipid-lowering therapy in the anti-cancer process. Regarding the nonrandomized trials, subgroup analyses can be considered in specific populations with a high risk of cancer occurrence, which could assist clinicians to find the most suitable population to receive the statin therapy for cancer-related chemoprevention.

Generally, results from this large-scale pan-cancer MR analysis, the statistical significance causalities are only observed in atorvastatin use and colorectal cancer and rosuvastatin use and bile duct cancer in European ancestry population. For this reason, we could not provide sufficient evidence to support that statin use could remarkably reduce the risk of different cancers. The role of statin use in cancer prevention remains debatable and there is still a long way to go before considering devoting the stains as chemo-preventive drugs into clinical practice. On the one hand, there are still existing disparities between remarkably anticarcinogenic effects in preclinical models and negative results in real-world observational studies. On the other hand, the potential confounding factors that existed in observational studies could also overlap the real influence of statin use in cancers. Therefore, future well-designed double-blind randomized controlled trials are warranted to validate the existing correlations we determined.