Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD) is characterized by the accumulation of >5% fat in liver tissue without other chronic liver diseases, leading to liver inflammation and potentially progressing to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, or hepatocellular cancer (HCC).1,2 Worldwide prevalence estimates for MAFLD range from 6.3% to 33%, with a median of 20% and MASH ranges from 3% to 5% in the general population.3 MAFLD is included of non-alcoholic fatty liver (NAFL) and MASH.4 Concomitant diseases associated with MAFLD/MASH include obesity (51%), type 2 diabetes (41%), hyperlipidemia (69%), hypertension (39%), and metabolic syndrome in 42% of cases.5,6

Meta-analyses indicate that statins and aspirin use is associated with a significant reduction in HCC risk.7 Aspirin exhibits anti-platelet and anti-inflammatory effects, leading to lower indices of liver fibrosis8. Aspirin also demonstrates a chemopreventive effect on chronic hepatitis B and hepatitis C, as well as the progression of MAFLD/MASH to HCC.9,10 Similarly, statins reported to have a chemopreventive effect on chronic hepatitis B and C, as well as cirrhosis before.11,12 Statin initiators have a 53% lower risk of developing HCC compared to non-users among patients with MAFLD.13 Additionally, a study by Fatima et al suggests that statins may significantly reduce the risk of developing MAFLD by 31% and improve liver histology in patients with MAFLD.14 Statin use might be associated with reducing hepatic decompensation, mortality, and portal hypertension in patients with chronic liver diseases.15

Sarcopenia is closely linked to MAFLD, liver cirrhosis, and HCC. Patients using statins were observed to have a lower likelihood of sarcopenia. Valdivieso et al hypothesized that this association could be attributed to the pleiotropic effects of statins, which enhance endothelial function and subsequently improve muscle perfusion, thereby supporting better neuromuscular fitness. This mechanism may contribute to the prevention of sarcopenia and the progression of MAFLD.16

Newly discovered substances start being considered. These specific stem cells are essential for skeletal muscle regeneration, and a reduction or dysregulation in the mSC pool may accelerate the loss of muscle mass commonly observed in the elderly. Tarantino et al proposed that muscle satellite cells (mSCs) play a crucial role in maintaining muscle health into old age.17

In the metabolic or cardiovascular domain, aspirin use is associated with reducing 20% cancer incidence.18 Historical cohort studies show that statin and aspirin users had significantly lower HCC risk, with reductions of 33% and 19%, respectively, in a nested case-control study.19 Both aspirin and statins have been proposed as anticancer agents due to their anti-inflammatory, anti-proliferative, and pro-apoptotic effects, despite variations in their biological mechanisms of action.20 Early chemoprevention of HCC occurrence or recurrence is crucial.21 Therefore, this study investigates whether daily combined statin and aspirin use is more effective than daily single-drug use (statin or aspirin) in reducing cirrhosis, HCC incidence, and outcomes in MAFLD/MASH patients within a nationwide cohort. This comprehensive discussion highlights the nuanced relationship between MAFLD, cirrhosis, and HCC, as well as the potential benefits of aspirin and statin therapy in mitigating liver disease progression.

Materials and Methods Ethics

Our study was conducted following the protocol approved by the Chang Gung Medical Foundation’s Institutional Review Board (IRB), with approval number: 202100464B0.

Data Sources

All data were collected retrospectively from the National Health Insurance Research Database (NHIRD), covering nearly 99% of the general population in Taiwan. MAFLD/MASH patients (n = 735,574) were identified from the NHIRD between January 1, 2009, and December 31, 2020.

Patients

A cohort of 662,004 cases using aspirin and statins was enrolled, with a follow-up period of 3 years. Exclusion criteria included a diagnosis of cancer, including GI tract cancer, before the index date (n = 408,526), age <18 years old (n = 5191), missing data on sex (n = 3558), diagnosis of outcome before index (n = 6602), follow-up <90 days (n = 9128), duration of statin or aspirin use <90 days after MAFLD/MASH diagnosis (n = 51,948), and index year before 2009 or after 2019 (n = 156,905). After 1:1 propensity score matching by sex, 5-year age group, index year, and each comorbidity, the following groups were analyzed: combined statin with aspirin use (n = 1995), statin alone (n = 1508), aspirin alone (n = 1116), and non-aspirin and non-statin (n = 4619) (Figure 1 and Table 1). The definition of disease and comorbidity followed the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for the period 1997–2015 and International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code for the period after 2016 (Table S1). Drug codes were selected according to ATC (Table S2). Comorbidities were defined as patients having been admitted or visited the outpatient department at least 5 times. The index date was defined as the initial date of diagnosed MAFLD/MASH. Patients were follow-up over 3 years. Charlson comorbidity index was defined concurrent condition such as co-morbidities bases on the ICD-9 and ICD-10.

Table 1 Baseline Characteristics of Patients with MAFLD/MASH Across Cohorts of Non-Statin & Aspirin Use, Statin Use, Aspirin Use, and Statin & Aspirin Use

Figure 1 Flow chart.

Main Outcomes

The main outcomes included cirrhosis, HCC, and death. A disease was considered a baseline comorbidity if a patient’s medical records contained the relevant ICD-9-CM or ICD-10-CM code around the index date (Table S1).

Statistical Analysis

A chi-square test was used to assess the difference of the categorical variables such as sex, stratified age, comorbidities and medications between four cohorts. The difference of mean ages between the four cohorts were tested by the student’s t test. Univariate and multivariate Cox regression hazard model analyses were conducted to assess confounding risk factors between patients with MAFLD or MASH who were taking daily statins and/or aspirin versus those who were not. Estimates for crude hazard ratios (cHRs) and adjusted HRs (aHRs), along with their relevant 95% confidence intervals (95% CIs), were derived using Cox proportional hazards regression models, with or without adjusting for age, sex, or confounding factors. Risk factors were analyzed for liver cirrhosis, HCC, and all cause of mortality using forest plots stratification. Three main outcomes were evaluated using a propensity score to determine the correlation between daily statin and/or aspirin use and liver cirrhosis, HCC, and mortality risks. The Kaplan–Meier method investigated the cumulative incidence of liver cirrhosis or HCC and survival rate during follow-up between MAFLD or MASH patients with daily statin and/or aspirin use or not, and the Log rank test examined the differences. Statistical analysis was performed using SAS (version 9.4; SAS Institute, Inc., Cary, NC, USA), with a two-tailed p-value < 0.05 considered statistically significant. Additionally, differences in all variables among the four groups of patients were also compared by the standardized mean difference (SMD), if the SMD value was less than 0.1, the differences among the four groups are considered negligible.

To ensure the robustness of our results, we conducted a proportional hazards assumption test to verify the validity of the Cox regression model. Cox-Snell residuals were utilized, with cumulative hazard function plots against these residuals examined. A close alignment with a 45-degree line indicated that the Cox model met the proportional hazards assumption (Figures S1–S3).

Results Liver Cirrhosis

Compared to non-statin and non-aspirin groups, statins (p = 0.0033, aHR: 0.23, 95% CI: 0.09–0.62), aspirin (p = 0.0147, aHR: 0.23, 95% CI: 0.07–0.75), and combined statin with aspirin use (p < 0.001, aHR: 0.17, 95% CI: 0.06–0.46) all demonstrated the ability to reduce cirrhosis incidence in MAFLD/MASH patients. Conversely, certain comorbidities increased the incidence of liver cirrhosis, such as diabetes mellitus (DM) (p = 0.0218, aHR: 2.01), alcoholism (p < 0.001, aHR: 7.14), and metabolic syndrome (p = 0.0427, aHR: 2.89) (Table 2). According to the Log rank test, the cumulative incidence of liver cirrhosis was significantly lower in the combination of statin and aspirin use cohort than in statin, aspirin, or non-statin and non-aspirin cohort (P < 0.001, Figure 2). Accordingly, combined statin with aspirin use might potentially further reduce cirrhosis development. Comparison between statin alone versus combined statin and aspirin yielded a p-value of 0.65, with an adjusted hazard ratio (aHR) of 1.37 (95% CI: 0.35–5.30). Similarly, the comparison between aspirin alone versus combined statin and aspirin resulted in a p-value of 0.59, with an aHR of 1.52 (95% CI: 0.34–6.90). For further details, refer to Tables 2 and S3.

Table 2 Incidences and Hazard Ratios of Cirrhosis in Patients with MAFLD/MASH Across Cohorts

Figure 2 Kaplan-Meier curves depict the cumulative incidence rate of liver cirrhosis during the follow-up period among four groups: non-statin and aspirin group, statin group, aspirin group, and combined statin and aspirin group. Comparison between statin alone versus combined statin and aspirin yielded a p-value of 0.65, with an adjusted hazard ratio (aHR) of 1.37 (95% CI: 0.35–5.30). The comparison between aspirin alone versus combined statin and aspirin resulted in a p-value of 0.59, with an aHR of 1.52 (95% CI: 0.34–6.90). For further details, refer to Tables 2 and S3.

Hepatocellular Carcinoma

Compared to non-statin and non-aspirin groups, statin use (p < 0.001, aHR: 0.50, 95% CI: 0.43–0.60), aspirin use (p = 0.0167, aHR: 0.83, 95% CI: 0.72–0.97), and combined aspirin with statin use (p < 0.001, aHR: 0.61, 95% CI: 0.53–0.69) all demonstrated the potential to reduce HCC incidence in NAFLD/NASH patients. Risk factors increasing HCC incidence included male gender (p < 0.001, aHR: 1.36), age over 60 (p < 0.001, aHR: 2.19), cardiovascular disease (p = 0.0044, aHR: 1.20), DM (p < 0.001, aHR: 1.58), viral hepatitis (p < 0.001, aHR: 4.39), alcoholism (p = 0.0144, aHR: 1.25), metabolic syndrome (p = 0.0150, aHR: 1.29), and H2 receptor antagonists (p < 0.001, aHR: 1.24). (Table 3) Univariate and multivariate risk factor stratification analysis are shown in the forest plot of adjusted HRs for the risk of hepatocellular carcinoma (Figure 3). Kaplan–Meier curves illustrating the cumulative incidence of hepatocellular carcinoma during the follow-up between the non-statin-aspirin, statin alone, aspirin alone, and combined aspirin with statin use. As shown in Figure 4, the analysis indicated that statin alone was not inferior to either aspirin alone or combined aspirin and statin in reducing the incidence of HCC. (P < 0.001). The comparison between statin alone and combined statin and aspirin yielded a p-value of 0.07, with an adjusted hazard ratio (aHR) of 0.83 (95% CI: 0.69–1.01). Similarly, the comparison between aspirin alone and combined statin and aspirin resulted in a p-value of <0.001, with an aHR of 1.39 (95% CI: 1.16–1.65). Refer to Tables 3 and S4 for detailed data.

Table 3 Incidences and Hazard Ratios of Hepatocellular Carcinoma in Patients with MAFLD/MASH Across Cohorts

Figure 3 Multivariable stratified analyses were conducted to examine the association between hepatocellular carcinoma and the use of statin and aspirin among individuals in the MAFLD/ MASH groups.

Figure 4 Kaplan-Meier curves illustrate the cumulative incidence rate of Hepatocellular Carcinoma (HCC) during the follow-up period across four groups: non-statin and aspirin, statin alone, aspirin alone, and combined statin and aspirin. The analysis indicated that statin alone was not inferior to either aspirin alone or combined aspirin and statin in reducing the incidence of HCC. The comparison between statin alone and combined statin and aspirin yielded a p-value of 0.07, with an adjusted hazard ratio (aHR) of 0.83 (95% CI: 0.69–1.01). The comparison between aspirin alone and combined statin and aspirin resulted in a p-value of <0.001, with an aHR of 1.39 (95% CI: 1.16–1.65). Refer to Tables 3 and S4 for detailed data.

Overall Mortality

All-cause mortality incidences and hazard ratios were decreased for statin, aspirin, and combined statin with aspirin use compared with non-statin and non-aspirin. Statin (p < 0.001, aHR: 0.41, 95% CI: 0.36–0.46), aspirin (p = 0.026, aHR: 0.85, 95% CI: 0.77–0.95), and combined statin with aspirin use (p < 0.001, aHR: 0.53, 95% CI: 0.48–0.58) all demonstrated the potential to reduce mortality incidence in MAFLD/MASH patients. Risk factors increasing mortality incidence in MAFLD/MASH patients included male gender (p < 0.001, aHR: 1.40), age over 60 (p < 0.001, aHR: 2.15), cardiovascular disease (p < 0.001, aHR: 1.19), stroke (p < 0.001, aHR: 1.51), DM (p < 0.001, aHR: 1.22), and alcoholism (p < 0.001, aHR: 1.51). (Table 4) Univariate and multivariate risk factor stratification analysis showed a reduction in mortality in the forest plot of aHRs for the risk of all-cause mortality (Figure 5). Kaplan–Meier curves showed that both aspirin and statin could reduce mortality incidence. However, the combined use of statin with aspirin was not superior to the use of statin alone in reducing mortality. (Figure 6, p < 0.001). When comparing statin alone versus combined statin and aspirin, the p-value was <0.001, with an adjusted hazard ratio (aHR) of 0.77 (95% CI: 0.67–0.89). Similarly, comparing aspirin alone versus combined statin and aspirin yielded a p-value of <0.001, with an aHR of 1.63 (95% CI: 1.44–1.84). Refer to Tables 4 and S5 for more detailed information.

Table 4 Incidences and Hazard Ratios of All-Cause Mortality in Patients with MAFLD/MASH Across Cohorts

Figure 5 Multivariable stratified analyses were conducted to assess the association between all-cause mortality and the use of statins and aspirin in the MAFLD/MASH groups.

Figure 6 Kaplan-Meier curves display the cumulative incidence rate of all-cause mortality during the follow-up period among four groups: non-statin and aspirin, statin alone, aspirin alone, and statin and aspirin. The combined use of statin with aspirin was not superior to the use of statin alone in reducing mortality. When comparing statin alone versus combined statin and aspirin, the p-value was <0.001, with an adjusted hazard ratio (aHR) of 0.77 (95% CI: 0.67–0.89). Comparing aspirin alone versus combined statin and aspirin yielded a p-value of <0.001, with an aHR of 1.63 (95% CI: 1.44–1.84). Refer to Tables 4 and S5 for more detailed information.

One limitation of our study is the use of propensity score matching (PSM), which addresses only measured confounders, leaving unmeasured confounders unaccounted for. We acknowledge this limitation and recognize its potential impact on the robustness of our findings. To mitigate concerns about overfitting, we initially matched solely on the index year and subsequently conducted an additional matching approach that included index year, sex, and age. Importantly, the results from both matching strategies were consistent with our current findings, further supporting the validity of our conclusions (Tables S6–S13).

Discussion

Many HCC cases develop in cryptogenic cirrhosis, which may be attributable to MAFLD and MASH.22 Most HCC patients are 80–90% correlated with liver cirrhosis.23,24 However, MAFLD-associated HCC may occur in non-cirrhotic patients.23 The prevalence of HCC in non-cirrhotic MASH was 38.0%, significantly higher than in non-cirrhotic patients with others etiologies.23 Liver cirrhosis is an insidious process, making it challenging to accurately determine incidence rates, which may explain why liver cirrhosis incidence is lower than HCC incidence in our findings.

Among 1654 HCC cases, 371 (22%) were non-cirrhotic, with the incidence of non-cirrhotic HCC increasing by 61% between 2009 and 2020. Notably, 39% of non-cirrhotic HCC cases had cryptogenic origins in a Dutch referral center. Advanced stages of cryptogenic non-cirrhotic HCC showed elevated serum interleukin-6 levels compared to non-cirrhotic HCC with known etiologies. Comparative analysis between cryptogenic and MAFLD non-cirrhotic HCC cohorts and controls revealed similar circulating immune biomarker profiles and PNPLA3 polymorphisms.25

MAFLD and ALD share similarities in pathogenesis, with three specific miRNAs (miR-34a, miR-122, and miR-155) implicated in both conditions. This overlap reinforces the notion of a common disease mechanism between MAFLD and ALD, highlighting the pleiotropic effects of these miRNAs.26

The proportion of fibrosis progression and mean annual rate of progression in MASH were 40.76% (95% CI: 34.69–47.13) and 0.09 (95% CI: 0.06–0.12),6 respectively. Aspirin and other anti-platelet agents inhibiting platelet aggregation provided protection against hepatic fibrosis and were associated with a 32% decreased odds of hepatic fibrosis (adjusted pooled OR 0.68; CI 0.56–0.82, p = 0.0001).8,27 In chronic liver diseases, portal hypertension develops as a result of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells and hepatic stellate cells.28 The anti-inflammatory action of some anti-platelet agents like aspirin inhibits the transcription of NF-κB in endothelial cells, preventing the adhesion of macrophages and T-lymphocytes and reducing levels of inflammatory cytokines including interleukin-6, tumor necrosis factor-β, and PDGF.27,29 Antiplatelet agents can prevent injury to sinusoidal endothelial cells by inhibiting platelet aggregation, thereby reducing chemotherapy-induced sinusoidal lesions.27,30

Studies have shown that statins may significantly reduce the risk of developing MAFLD and decrease ALT/AST levels, as well as significant fibrosis.14 Statins also reduce portal pressure, improve liver sinusoidal endothelial and hepatic microvascular dysfunction, decrease fibrogenesis, and offer protection against ischemia/reperfusion injury, among other benefits.12 In the Cox proportional hazard model, chronic hepatitis B patients receiving statin therapy exhibit a dose-dependent reduction in the risk of cirrhosis and its decompensation.31

In our study, statins (p = 0.0033, aHR: 0.23), aspirin (p = 0.0147, aHR: 0.23), and combined statin with aspirin use (p < 0.001, aHR: 0.17) all demonstrated the potential to reduce cirrhosis incidence in MAFLD/MASH patients. Combined statin and aspirin use seemed to potentially have an additional effect, warranting further validation studies.

HCC incidence among MAFLD patients was 0.44 per 1000 person-years, HCC increases up to 5.29 per 1000 person-years after MAFLD-to- MASH transition.6

Statins and aspirin have various mechanisms of action that potential to reduce HCC incidence. Statins have anti-inflammatory, anti-tumor, and immunomodulatory properties. It has been shown that statins can affect the 5′-adenosine monophosphate-activated protein kinase (AMPK) pathway in differing physiological and pathological ways, resulting in anti-cancer and cardio-protective effects.32 Statin data suggests that statin use was associated with a 20–43% lower risk of HCC compared to statin nonusers.33,34 Aspirin’s mechanism includes anti-inflammation and anti-platelet effects, inhibiting platelet coagulopathy, hemostasis, and reducing tumor development, recurrence, and metastasis. Aspirin use alone was associated with a decreased incidence of HCC.35,36 In the Cancer and Cause of Death registries in Swedish adults with chronic hepatitis B or hepatitis C infection. A reduction of the estimated cumulative incidence of HCC was 31% at 7.9 years of follow-up aspirin users versus nonusers.37,38

Singh et al reported that the combined use of statin with aspirin was associated with a decreased hazard of HCC, statistically significant in the multivariable model [HR (CI): 0.113 (0.026–0.483); p = 0.0033] in a prospective cohort of patients with liver cirrhosis.39 I In a large cohort study, it is evident that overweight and obesity significantly increase the risk of HCC in Koreans,40 Non-cirrhotic patients with nonalcoholic fatty liver disease and hyperlipidemia show a significant association with the development of HCC.41 Obesity and hyperlipidemia were significantly in reducing HCC associated with statin and aspirin use compared to non-use in our study. We hypothesize that statin and aspirin use may confer a stronger chemopreventive effect in high-risk populations.

Statin use was associated with an overall reduced risk of HCC (HR: 0.52; 95% CI: 0.37–0.72), including in subgroup analyses for cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease, as well as in studies that accounted for concurrent use of aspirin, metformin, and lipophilic statins. Similarly, aspirin use was linked to a reduced overall risk of HCC (HR: 0.48; 95% CI: 0.27–0.87). Although both statin and aspirin use were associated with a decreased HCC risk, only statin use remained statistically significant in subgroup analyses that considered concurrent medication use.7

Our results indicate that statin use alone is not inferior to the combined use of statins and aspirin in reducing HCC in patients with MAFLD/MASH. We hypothesize that statins may offer a more significant anti-inflammatory effect, decrease hyperlipidemia, and provide greater protection against HCC than aspirin in patients with non-alcoholic fatty liver and chronic hepatitis.

Approximately 10–20% of MAFLD patients may progress to MASH, potentially leading to cirrhosis and liver-related mortality.6 Overall mortality among MAFLD and MASH were 11.77 per 1000 person-years (range, 7.10–19.53), and 25.56 per 1000 person-years (range, 6.29–103.80), respectively. Incidence risk ratios for overall mortality for MAFLD were 1.05 (range, 0.70–1.56).6 In a meta-analysis, statin use was associated with a lower risk of all-cause mortality in HCC compared to non-use, with an HR of 0.80 (95% CI 0.68–0.94, P < 0.0001).34 Statins could reduction of oxidative stress, inflammation, improvement in vascular function, and reorganization of the extracellular matrix in cirrhosis, increase in nitric oxide products (NOx) in the hepatic vein, decreasing portal pressure, and the hepatosinusoidal-protective effects has been strongly correlated with improved outcomes.12 The risk of overall mortality was significantly lower in MAFLD patients using statins compared to those not using statins (HR: 0.87, 95% CI: 0.76–0.99, p = 0.04). Similarly, cancer-related mortality was also significantly lower in statin users (SHR: 0.73, 95% CI: 0.54–0.99, p = 0.04).42

Aspirin, anti-platelet, and anti-inflammation effect, that could prevent thromboembolism for reducing cardiovascular death, and also prevent cancer develop, recurrent, and metastasis.43–45 In the Cancer and Cause of Death registries among Swedish adults with chronic hepatitis B or C, liver-related mortality was found to be reduced by 27% in aspirin users compared to non-users.37,38

Statin use was particularly associated with a significant decrease in mortality rates than aspirin use, combined statin and aspirin use in our study. We suppose statins had a much more significant greater chemopreventive effect on mortality rates, and the others effect than aspirin use in patients with MAFLD/MASH.

Limitations

Our study has several limitations, including its retrospective design and dependence on administrative databases, which lack clinical examination results. This reliance makes it challenging to access detailed socioeconomic information, lifestyle factors, health behaviors, and potentially unhealthy habits. The NHIRD’s strict privacy regulations further restrict the ability to link de-identified data with external sources, which limits comprehensive data analysis. Despite these constraints, our findings emphasize the potential of aspirin and statins in mitigating liver disease burden in MAFLD/MASH patients. Combined statin and aspirin therapy may offer additional benefits for cirrhosis prevention but does not appear to provide incremental advantages in reducing HCC incidence or mortality. Future research should aim to explore the mechanisms at play and optimize treatment strategies to improve patient outcomes in MAFLD/MASH.

Conclusion

Both aspirin and statins could reduce the incidence of cirrhosis, HCC, and mortality. However, combining statin with aspirin use might potentially offer additional reduction in cirrhosis development, but not in reducing HCC and mortality in MAFLD/MASH patients. It appears that statins may have a more pronounced chemopreventive effect compared to aspirin in these patients. Our findings underscore that the combined use of statin and aspirin was not superior to statin use alone for preventing HCC and mortality in MAFLD/MASH patients. This highlights a promising therapeutic strategy in this high-risk population.

Data Sharing Statement

The data supporting the findings of this study are available upon reasonable request from the corresponding author.

Informed Consent Statement

As this was a retrospective study based on the assessment of existing data, the committee waived the requirement for informed consent from the patients. All personal data were only available to investigators and were secured by delinking the recognition information from the main dataset.

Acknowledgments

We acknowledge the support of the NHIRD and funding agencies for their contributions to this study. The authors declare no conflicts of interest, and the datasets used are available upon request. Ethical approval was obtained, and informed consent was waived due to the retrospective nature of the study. The contributions of the authors to the study are outlined, and relevant ORCID identifiers are provided for reference.

Funding

This work was supported by grants from Chang Gung Memorial Hospital (CFRPG3L0081), OMRPG3M0011) and the National Health Research Institute (NHRI-EX113-11217BI).

Disclosure

The authors declare no conflicts of interest in this work.

References

1. Athyros VG, Tziomalos K, Daskalopoulos GN, Karagiannis A, Mikhailidis DP. Statin-based treatment for cardiovascular risk and non-alcoholic fatty liver disease. Killing two birds with one stone? Ann Med. 2011;43(3):167–171. doi:10.3109/07853890.2011.561363

2. Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An expert panel statement. Metabolism. 2017;71:17–32. doi:10.1016/j.metabol.2017.02.014

3. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–285. doi:10.1111/j.1365-2036.2011.04724.x

4. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005–2023. doi:10.1002/hep.25762

5. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156(5):1264–1281.e1264. doi:10.1053/j.gastro.2018.12.036

6. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431

7. Zeng RW, Yong JN, Tan DJH, et al. Meta-analysis: chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin. Aliment Pharmacol Ther. 2023;57(6):600–609. doi:10.1111/apt.17371

8. Jiang ZG, Feldbrügge L, Tapper EB, et al. Aspirin use is associated with lower indices of liver fibrosis among adults in the United States. Aliment Pharmacol Ther. 2016;43(6):734–743. doi:10.1111/apt.13515

9. Guidotti LG, La Vecchia C, Colombo M. Low-dose aspirin reduces the risk of HBV-associated HCC even when administered short-term: too good to be true? Hepatology. 2022;76(2):300–302. doi:10.1002/hep.32445

10. Liao YH, Hsu RJ, Wang TH, et al. Aspirin decreases hepatocellular carcinoma risk in hepatitis C virus carriers: a nationwide cohort study. BMC Gastroenterol. 2020;20(1):6. doi:10.1186/s12876-020-1158-y

11. Facciorusso A, Abd El Aziz MA, Singh S, et al. Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis. Cancers. 2020;12(4):874. doi:10.3390/cancers12040874

12. Bosch J, Gracia-Sancho J, Abraldes JG. Cirrhosis as new indication for statins. Gut. 2020;69(5):953–962. doi:10.1136/gutjnl-2019-318237

13. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2023;21(2):435–444.e436. doi:10.1016/j.cgh.2022.01.057

14. Fatima K, Moeed A, Waqar E, et al. Efficacy of statins in treatment and development of non-alcoholic fatty liver disease and steatohepatitis: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2022;46(4):101816. doi:10.1016/j.clinre.2021.101816

15. Kim RG, Loomba R, Prokop LJ, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2017;15(10):1521–1530.e1528. doi:10.1016/j.cgh.2017.04.039

16. Valdiviesso R, Sousa-Santos AR, Azevedo LF, et al. Statins are associated with reduced likelihood of sarcopenia in a sample of heart failure outpatients: a cross-sectional study. BMC Cardiovasc Disord. 2022;22(1):356. doi:10.1186/s12872-022-02804-5

17. Tarantino G, Sinatti G, Citro V, Santini SJ, Balsano C. Sarcopenia, a condition shared by various diseases: can we alleviate or delay the progression? Intern Emerg Med. 2023;18(7):1887–1895. doi:10.1007/s11739-023-03339-z

18. Carrat F. Statin and aspirin for prevention of hepatocellular carcinoma: what are the levels of evidence? Clin Res Hepatol Gastroenterol. 2014;38(1):9–11. doi:10.1016/j.clinre.2013.09.007

19. Choi WM, Kim HJ, Jo AJ, et al. Association of aspirin and statin use with the risk of liver cancer in chronic hepatitis B: a nationwide population-based study. Liver Int. 2021;41(11):2777–2785. doi:10.1111/liv.15011

20. Goh MJ, Sinn DH. Statin and aspirin for chemoprevention of hepatocellular carcinoma: time to use or wait further? Clin Mol Hepatol. 2022;28(3):380–395. doi:10.3350/cmh.2021.0366

21. Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. 2012;12(9):1129–1159.

22. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51(5):1820–1832. doi:10.1002/hep.23594

23. Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther. 2018;48(7):696–703. doi:10.1111/apt.14937

24. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50. doi:10.1053/j.gastro.2004.09.014

25. Beudeker BJB, Guha R, Stoyanova K, et al. Cryptogenic non-cirrhotic HCC: clinical, prognostic and immunologic aspects of an emerging HCC etiology. Sci Rep. 2024;14(1):4302. doi:10.1038/s41598-024-52884-w

26. Tarantino G, Citro V. What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver? Lipids Health Dis. 2024;23(1):41. doi:10.1186/s12944-024-02031-1

27. Iqbal U, Dennis BB, Li AA, et al. Use of anti-platelet agents in the prevention of hepatic fibrosis in patients at risk for chronic liver disease: a systematic review and meta-analysis. Hepatol Int. 2019;13(1):84–90. doi:10.1007/s12072-018-9918-2

28. Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: pathophysiological mechanisms and therapy. JHEP Rep. 2021;3(4):100316. doi:10.1016/j.jhepr.2021.100316

29. Muhlestein JB. Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost. 2010;103(1):71–82. doi:10.1160/th09-03-0177

30. Brouquet A, Benoist S, Julie C, et al. Risk factors for chemotherapy-associated liver injuries: a multivariate analysis of a group of 146 patients with colorectal metastases. Surgery. 2009;145(4):362–371. doi:10.1016/j.surg.2008.12.002

31. Huang YW, Lee CL, Yang SS, et al. Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a nationwide cohort study. Am J Gastroenterol. 2016;111(7):976–985. doi:10.1038/ajg.2016.179

32. Dehnavi S, Kiani A, Sadeghi M, et al. Targeting AMPK by statins: a potential therapeutic approach. Drugs. 2021;81(8):923–933. doi:10.1007/s40265-021-01510-4

33. Khazaaleh S, Sarmini MT, Alomari M, et al. Statin use reduces the risk of hepatocellular carcinoma: an updated meta-analysis and systematic review. Cureus. 2022;14(7):e27032. doi:10.7759/cureus.27032

34. Wang J, Li X. Impact of statin use on the risk and prognosis of hepatocellular carcinoma: a meta-analysis. Eur J Gastroenterol Hepatol. 2021;33(12):1603–1609. doi:10.1097/meg.0000000000002040

35. Tan JL, Sidhu-Brar S, Woodman R, Chinnaratha MA. Regular aspirin use is associated with a reduced risk of hepatocellular carcinoma (HCC) in chronic liver disease: a systematic review and meta-analysis. J Gastrointest Cancer. 2023;54(2):325–331. doi:10.1007/s12029-022-00842-y

36. Ricciotti E, Wangensteen KJ, FitzGerald GA. Aspirin in hepatocellular carcinoma. Cancer Res. 2021;81(14):3751–3761. doi:10.1158/0008-5472.Can-21-0758

37. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382(11):1018–1028. doi:10.1056/NEJMoa1912035

38. Ballerini P, Contursi A, Bruno A, Mucci M, Tacconelli S, Patrignani P. Inflammation and cancer: from the development of personalized indicators to novel therapeutic strategies. Front Pharmacol. 2022;13(838079). doi:10.3389/fphar.2022.838079

39. Singh J, Wozniak A, Cotler SJ, et al. Combined use of aspirin and statin is associated with a decreased incidence of hepatocellular carcinoma. J Clin Gastroenterol. 2022;56(4):369–373. doi:10.1097/mcg.0000000000001546

40. Jun BG, Kim M, Shin HS, Yi -J-J, Yi S-W. Impact of overweight and obesity on the risk of hepatocellular carcinoma: a prospective cohort study in 14.3 million Koreans. Br J Cancer. 2022;127(1):109–115. doi:10.1038/s41416-022-01771-0

41. Phan J, Ng V, Sheinbaum A, et al. Hyperlipidemia and nonalcoholic steatohepatitis predispose to hepatocellular carcinoma development without cirrhosis. J Clin Gastroenterol. 2019;53(4):309–313. doi:10.1097/mcg.0000000000001062

42. Ng CH, Teng ML, Chew NW, et al. Statins decrease overall mortality and cancer related mortality but are underutilized in NAFLD: a longitudinal analysis of 12,538 individuals. Expert Rev Gastroenterol Hepatol. 2022;16(9):895–901. doi:10.1080/17474124.2022.2119128

43. Morris T, Stables M, Hobbs A, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183(3):2089–2096. doi:10.4049/jimmunol.0900477

44. Ji X, Hou M. Novel agents for anti-platelet therapy. J Hematol Oncol. 2011;4(44). doi:10.1186/1756-8722-4-44

45. Elwood P, Protty M, Morgan G, Pickering J, Delon C, Watkins J. Aspirin and cancer: biological mechanisms and clinical outcomes. Open Biol. 2022;12(9):220124. doi:10.1098/rsob.220124