Metabolic dysfunction-associated steatotic liver disease (MASLD) [
1], formerly termed nonalcoholic fatty liver disease (NAFLD), has emerged as one of the most prevalent chronic liver diseases worldwide, affecting more than 30% of the global population [
2]. Although the annual incidence of MASLD-related hepatocellular carcinoma (HCC) is low in general, the sheer prevalence of MASLD translates into a substantial and growing disease burden. For example, MASLD is now the fastest rising cause of HCC in the United States and is projected to become the leading etiology of liver cancer in the near future [
3]. An analysis of United Network for Organ Sharing data from 2000 to 2022 demonstrated that nonalcoholic steatohepatitis (NASH) has surpassed chronic hepatitis C as the most common cause of HCC among patients listed for liver transplantation [
4]. These epidemiological trends point to the urgent need for effective strategies to prevent MASLD-related HCC.
In principle, successful treatment of MASLD should reduce the risk of downstream HCC development. Lifestyle modification, particularly sustained weight loss, remains the cornerstone of MASLD management; however, long-term adherence and achievement of therapeutic goals are often challenging. Several pharmacologic agents have shown promise in clinical trials, and resmetirom and semaglutide have recently received approval from the United States Food and Drug Administration [
5,
6]. Nevertheless, their indications are currently limited, primarily to patients with non-cirrhotic NASH and moderate-to-advanced fibrosis. Moreover, long-term safety data and their potential impact on HCC prevention remain to be established. Thus, despite encouraging advances, there remains a pressing need for additional, safe, and broadly applicable preventive strategies.
Aspirin has long been investigated for its chemopreventive properties in malignancies driven by chronic inflammation, most notably colorectal cancer. Similar mechanisms may be operative in the liver. Emerging experimental data suggest that aspirin’s antiplatelet effects can attenuate immune-mediated necroinflammation, reduce fibrosis severity, and inhibit hepatocarcinogenesis [
7,
8]. Consistent with these mechanistic insights, accumulating clinical evidence supports a potential role for aspirin in HCC prevention. Prior studies from our group have demonstrated that aspirin use is associated with a significantly reduced risk of HCC in patients with chronic hepatitis B or C infection [
9,
10]. Beyond viral hepatitis, daily aspirin therapy has been linked to slower fibrosis progression in patients with biopsy-proven NAFLD in a prospective cohort study [
11]. A phase-2 randomized controlled trial in non-cirrhotic MASLD showed that 6 months of low-dose aspirin significantly reduced hepatic fat content compared with placebo [
12]. Importantly, in a large population-based cohort, we further demonstrated that daily low-dose aspirin use was associated with a significantly lower risk of HCC in patients with NAFLD [
13]. Despite these encouraging findings, aspirin has not yet been recommended for HCC prevention in routine clinical practice, largely due to the absence of definitive evidence from well-designed randomized clinical trials.
In the current issue of
Clinical and Molecular Hepatology, the study by Ahn et al. [
14] provides important new evidence supporting the association between aspirin use and reduced HCC risk in patients with MASLD. Using two large, independent datasets, the Korean National Health Insurance Service (NHIS) and the UK Biobank (UKB), the investigators analyzed 1,723,435 and 239,719 patients with MASLD, respectively. After adjustment for multiple potential confounders in the NHIS cohort, aspirin use was associated with a significantly lower risk of HCC in both the overall population and the MASLD subgroup. In the UKB cohort, individuals in the highest 95% of a genomic risk score (GRS) related to aspirin metabolism exhibited a substantially lower risk of HCC compared with those in the lowest 5%, again observed in both the overall population and the MASLD group. By applying the updated MASLD definition, the authors reaffirmed the inverse association between aspirin exposure and HCC risk, despite the substantial overlap between MASLD and the former NAFLD construct. Notably, the use of an aspirin metabolism-related GRS to support the observed association represents a novel approach that strengthens causal inference.
Despite these strengths, several limitations warrant careful consideration. First, the authors primarily relied on a 3-year landmark design to mitigate immortal time bias, rather than employing a time-varying exposure model or a target trial emulation framework. Although sensitivity analyses using alternative landmark times (2, 4, and 5 years) were performed, the results in multivariable models for the MASLD subgroup were not entirely consistent. Furthermore, unlike prior aspirin studies [
15,
16], a clear dose-response relationship, whereby longer duration of aspirin use confers greater HCC risk reduction, was not observed. Consequently, while the findings add to the growing body of supportive evidence, the need for confirmatory randomized trials remains unmet. Second, MASLD was defined using a fatty liver index (FLI)≥30, and the protective association of aspirin was not consistently observed in sensitivity analyses applying a more specific and clinically validated cutoff of FLI≥60. Although the authors suggested that higher competing cardiovascular risk may explain the inconsistent findings, further studies employing more robust diagnostic tools, such as controlled attenuation parameter measurements, are necessary. Third, the genetic analysis has inherent limitations. Individuals not receiving aspirin were not fully excluded, and in such individuals, salicylic acid exposure would be absent regardless of genetic predisposition. As a result, the causal relationship between aspirin exposure, genetic variation, and HCC risk cannot be directly established. While the GRS findings imply that higher systemic aspirin levels may enhance chemopreventive effects, prior studies have not demonstrated a clear dosage-dependent relationship for HCC prevention [
16]. In addition, daily low-dose aspirin has consistently been associated with reduced HCC risk [
9,
10,
13,
16]. Thus, although the genetic approach adds novelty and highlights the potential influence of aspirin metabolism, the underlying biological mechanisms linking specific polymorphisms to HCC prevention require further investigation. Additionally, higher effective aspirin levels may increase the risk of adverse events, such as gastrointestinal bleeding, which must be carefully weighed.
As novel therapies for MASLD continue to emerge [
5,
6], concerns regarding long-term safety and effectiveness will require time and rigorous study to resolve. By adopting MASLD as a contemporary diagnostic framework, this large-scale cohort study contributes valuable evidence supporting aspirin use for HCC risk reduction in this growing patient population. Importantly, beyond its potential oncologic benefits, aspirin confers well-established protection against cardiovascular events, a leading cause of mortality among individuals with metabolic dysfunction. When carefully balancing benefits and risks, aspirin may represent an effective, inexpensive, and widely accessible strategy to improve overall clinical outcomes in patients with MASLD. Although pharmaceutical incentives to investigate aspirin are limited, further prospective studies, ideally supported by non-profit-directed funding, are strongly encouraged. Such trials should aim to simultaneously evaluate the impact of aspirin on HCC incidence, cardiovascular events, and all-cause mortality, thereby clarifying its role in the comprehensive management of patients with MASLD.
FOOTNOTES
-
Authors’ contribution
Study conception and design and manuscript drafting: T.Y.L. and C.Y.W. Data acquisition, analysis, and interpretation: T.Y.L. and C.Y.W. Critical revision for important intellectual content: T.Y.L. and C.Y.W. All authors contributed to the revision of final manuscript.
-
Acknowledgements
This work was supported in part by the Ministry of Health and Welfare (MOHW115-TDU-B-221-114006). The funder played no role in the design or conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review or approval of the manuscript.
-
Conflicts of Interest
Teng-Yu Lee: Research support from Gilead, Merck and Roche diagnostics. Consultant of BMS, Gilead, and Astra-Zeneca and speaker of Abbvie, BMS, Eisai, Gilead, Roche and AstraZeneca. Other author has no conflicts to disclose.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis
National Health Insurance Service
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Citations
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- Correspondence to editorial 2 on “Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: nationwide cohort study with genetic risk analysis”
Hyunjae Shin, Moon Haeng Hur, Yoon Jun Kim
Clinical and Molecular Hepatology.2026; 32(3): e381. CrossRef
