Aspirin has a long history, originating from its use as an analgesic and antipyretic in ancient civilizations and later evolving into a cornerstone therapy for cardiovascular disease prevention [
1]. Beyond its antithrombotic effects, interest in the anticancer potential of aspirin emerged in 1988, when Kune et al. [
2] first reported a reduced incidence of colorectal cancer among regular aspirin users. Since then, accumulating evidence has suggested that aspirin may reduce the incidence and mortality of several cancer types [
3-
5].
In hepatocellular carcinoma (HCC), aspirin’s chemopreventive potential was first highlighted in 2012 by the NIHAARP Diet and Health Study, which reported a substantially lower risk of HCC among aspirin users [
5]. Building on this work, subsequent studies have primarily focused on individuals with established HCC risk factors [
6-
10]. Although viral hepatitis has historically been the dominant cause, metabolic dysfunction-associated steatotic liver disease (MASLD) is now emerging as an increasingly important contributor worldwide [
11].
In this issue of
Clinical and Molecular Hepatology, Ahn et al. [
12] suggested a potential protective association between aspirin use and HCC risk in patients with MASLD, using a nationwide cohort along with complementary genetic analyses. Although a prospective randomized controlled trial would represent the ideal approach, the practical implementation of such trials is limited by various factors. Recognizing these limitations, the authors employed multiple analytical approaches and analyzed two independent population-based cohorts: the Korean National Health Insurance Service database and the UK Biobank cohort. From an editorial perspective, a major strength of this study lies in its large-scale, population-based design, which substantially enhances the generalizability of the findings. In the Korean cohort, aspirin use was associated with a 14% lower risk of HCC compared with non-use among patients with MASLD. In addition, the use of landmark analysis represents an effort to minimize immortal time bias. This analysis differs from those of a previous Taiwanese nationwide cohort study, which reported that aspirin therapy was associated with a 52% reduction in HCC risk among patients with non-alcoholic fatty liver disease (NAFLD), using the 90th day after aspirin initiation as the index date [
13]. Furthermore, by integrating Mendelian randomization analysis, the authors provide complementary genetic evidence supporting a potential causal relationship between aspirin use and reduced HCC risk.
Despite these analyses, several important issues still need to be addressed before aspirin can be recommended for HCC prevention. The foremost ethical principle in clinical practice is to do no harm [
14]. Although aspirin use is well known to be associated with an increased risk of bleeding, this study did not provide detailed data on bleeding complications. Nevertheless, prior studies have provided important insights into the bleeding risk associated with aspirin use in patients with liver disease [
6-
8,
10,
13]. A previous Taiwanese cohort study in patients with NAFLD demonstrated that while aspirin use was associated with a reduced risk of HCC, this benefit was associated with an increased risk of peptic ulcer bleeding over long-term follow-up [
13]. Similarly, a Korean cohort study of patients with hepatitis B virus (HBV)-related cirrhosis reported a 16% reduction in incidence of HCC associated with low-dose aspirin use, accompanied by a 20% increase in gastrointestinal bleeding [
6]. In contrast, a nationwide Swedish study of patients with chronic hepatitis B (CHB) or hepatitis C found a significantly lower risk of HCC among aspirin users, without a corresponding increase of gastrointestinal bleeding [
7]. Likewise, a Taiwanese cohort study in patients with CHB showed no significant difference in the 5-year cumulative incidence of peptic ulcer bleeding between aspirin-treated and untreated patients, irrespective of cirrhosis [
8]. Another Korean study stratified by cirrhosis reported a higher bleeding risk among aspirin users without cirrhosis, but similar risks in those with cirrhosis [
10]. However, it should be noted that patients in the treated groups were selected based on their ability to tolerate aspirin therapy for at least 90 days; the risk of bleeding may have been underestimated. Therefore, even if the clinical benefit of low-dose aspirin for primary prevention is established, it must be carefully balanced against the risk of major bleeding.
A second key principle relevant to clinical interventions is beneficence: who should be treated and for how long. Ahn et al. [
12] defined steatotic liver disease using a fatty liver index (FLI)≥30; although widely used in the literature, this cutoff may not precisely reflect true hepatic steatosis. If a substantial proportion of relatively healthy individuals with a low baseline HCC risk is included, the protective effect of aspirin may be overestimated. A recent Taiwanese multiinstitutional cohort study evaluated the impact of daily aspirin on liver-related outcomes over a 3-year period in patients with MASLD, in whom the diagnosis was confirmed by abdominal ultrasonography or histopathological evidence [
15]. In that study, daily aspirin use alone was not associated with a significant reduction in mortality or HCC incidence over 3 years. This discrepancy may not necessarily be attributable to differences in disease definition but could instead reflect the relatively short duration of aspirin exposure. In the study by Ahn et al. [
12], sensitivity analyses using alternative landmark intervals of 2 and 5 years did not demonstrate a significant protective effect of aspirin in patients with MASLD. The lack of significance at the 2-year landmark likely reflects the limited number of HCC events and insufficient exposure duration. At the 5-year landmark, the apparent reduction in events in the non-aspirin group, despite continued event accumulation in the aspirin group, is well explained by the selection of event-free individuals under follow-up in landmark analyses, which likely contributed to the lack of statistical significance. Importantly, growing evidence suggests that the duration of aspirin use is a critical determinant of its chemopreventive effect. Data from two Korean cohort studies consistently showed a significant reduction in HCC risk among patients who continued aspirin therapy for ≥3 years, in HBV-related cirrhosis and CHB.6,9 Similarly, a Taiwanese cohort study in patients with NAFLD demonstrated a significantly lower HCC risk with aspirin use for ≥3 years compared with short-term use [
13]. A Danish nationwide 20-year cohort study reported that long-term aspirin use (≥5 or ≥10 years) was associated with a risk reduction for several cancers, and a 20-year longitudinal cohort study from Hong Kong similarly demonstrated a stronger cancer-preventive association among individuals using aspirin for more than 10 years [
3,
4]. These findings indicate that the preventive effect of aspirin on HCC requires long-term use, implying that patients must maintain therapy over an extended period to achieve meaningful benefit.
Another important consideration is the optimal timing for starting aspirin and the stage of disease at which it remains effective. In the present study, aspirin did not demonstrate a protective effect in patients with a FLI≥60 or those classified as having metabolic dysfunction-associated alcohol-related liver disease, suggesting that aspirin may be less effective in patients with progressive hepatic fibrosis [
12]. This finding is consistent with the notion that earlier intervention, before substantial fibrosis develops, may be more beneficial. Nevertheless, evidence from previous studies in patients with cirrhosis has been conflicting: some studies reported no significant association between aspirin use and HCC risk in HBV-related cirrhosis [
8,
10], whereas others observed a significantly lower risk of HCC among patients with chronic viral hepatitis regardless of cirrhosis [
6,
7,
9]. These findings highlight the need to carefully consider both the duration of aspirin therapy and the underlying stage of liver disease when evaluating its potential role in HCC prevention.
This large nationwide cohort study suggested a possible protective association between aspirin use and HCC in patients with MASLD. As is well recognized, patients with MASLD are also at increased risk of developing cardiovascular disease [
16]. Therefore, antiplatelet therapy, including aspirin, might not only help prevent cardiovascular events but could also potentially slow disease progression, including the development of HCC. Nevertheless, more robust evidence is required before long-term aspirin therapy can be recommended in patients with MASLD, and its clinical adoption should be guided by careful patient selection, disease stage, and long-term safety considerations rather than enthusiasm alone.
FOOTNOTES
-
Authors’ contribution
Yang-Hyun Baek contributed to analysis of data, concept of design and writing the manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
non-alcoholic fatty liver disease
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Citations
Citations to this article as recorded by
- Correspondence to editorial 1 on “Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: nationwide cohort study with genetic risk analysis”
Moon Haeng Hur, Hyunjae Shin, Yoon Jun Kim
Clinical and Molecular Hepatology.2026; 32(3): e378. CrossRef - Reply to correspondence on “Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: nationwide cohort study with genetic risk analysis”
Yang-Hyun Baek
Clinical and Molecular Hepatology.2026; 32(3): e439. CrossRef
