The evidence hierarchy separates direct randomized clinical evidence for reduction of HCC incidence from indirect clinical evidence, surrogate histological evidence in MASLD/Metabolic Dysfunction-Associated Steatohepatitis (MASH) or fibrosis trials, and preclinical or mechanistic plausibility. At present, most chemoprevention signals for HCC are observational rather than randomized and should therefore be interpreted as hypothesis-generating unless supported by prospective HCC-endpoint trials. Figure 2 summarizes the levels of evidence in HCC chemoprevention by pharmacological class.

A meta-analysis updated as of 2022 found that both statin and aspirin use were associated with a reduced risk of HCC [statins: Hazard ratio (HR) 0.52, 95%CI: 0.37-0.72; 10 studies; 1,774,476 participants; aspirin: HR 0.48, 95%CI: 0.27-0.87; 11 studies; 2,190,285 participants]^[23]. This evidence is almost entirely observational, although higher-quality analyses increasingly restrict inclusion to propensity-score-matched or inverse probability-weighted cohorts to reduce confounding by indication, immortal-time bias, and differences in baseline liver disease severity. However, in subgroup analyses accounting for concurrent medications, only statin use remained significantly associated with lower HCC risk. By contrast, metformin use was not significantly associated with reduced HCC risk (HR 0.57, 95%CI: 0.31-1.06; 3 studies; 125,458 participants). Thus, these agents should not be interpreted as equivalent chemopreventive options: statins have the most consistent epidemiologic signal, aspirin has a plausible but more confounded association, and metformin has the weakest and most diabetes-dependent evidence base.

A more recent study evaluated whether metformin and statins may reduce HCC risk in patients with chronic hepatitis C from the T-COACH cohort who did not respond to antiviral therapy^[34]. The findings suggest that both drugs may have a chemopreventive effect in this setting. Importantly, the higher HCC risk associated with non-use of metformin was mainly observed in non-cirrhotic patients, whereas statins were associated with lower HCC risk in both cirrhotic and non-cirrhotic patients. These etiology- and stage-specific findings are important because the apparent benefit of metformin may be driven partly by metabolic risk modification in diabetic or insulin-resistant patients rather than by a direct antineoplastic effect across all causes of chronic liver disease. In HCV, particularly before sustained virologic response was widely achievable, residual inflammation and metabolic cofactors may have amplified any protective signal; in HBV, MASLD, and alcohol-related liver disease, evidence remains less uniform and is more dependent on cohort design, medication duration, and adjustment for diabetes, obesity, antiviral therapy, and cirrhosis.

Statins should be viewed not only as cholesterol-lowering agents, but also as drugs with the strongest retrospective evidence for HCC prevention. Meta-analyses of observational studies suggest that statin use is associated with an approximately 46% reduction in HCC risk^[35-38]. The association has been reported across several high-risk populations, including chronic HBV, chronic HCV, cirrhosis, and MASLD, and appears more reproducible for lipophilic statins and for longer cumulative exposure. Nevertheless, causality has not been established, and the available data cannot fully exclude healthy-user bias, better cardiometabolic care among statin users, or differential surveillance for HCC.

The biologically plausible chemopreventive effect of statins against HCC is most evident in patients at high risk for liver cancer, particularly Asians, those with underlying cirrhosis, MASLD, or chronic viral hepatitis^[21,39-41]. The risk reduction, which requires prospective evaluation, appears to be dependent on the chemical properties and dose of statins, with lipophilicity, long-term use, and higher cumulative daily doses conferring greater benefits^[42-45].

The chemopreventive effect of aspirin in HCC is likely to vary by disease etiology, reflecting differences in the inflammatory, thrombotic, and carcinogenic pathways that drive viral, metabolic, alcohol-related, and other forms of chronic liver disease^[10]. Low-dose aspirin is an appealing candidate for modifying MASLD pathobiology, but current data do not justify routine use, especially in cirrhosis. In a single-center phase 2 trial, daily 81 mg aspirin for 6 months reduced hepatic fat content vs. placebo in adults with non-cirrhotic MASLD, but the study was small, short, and not powered for fibrosis, decompensation, HCC, or bleeding outcomes^[46]. Observational meta-analyses link aspirin exposure to lower HCC incidence, yet estimates remain vulnerable to confounding, immortal-time bias, heterogeneous exposure definitions, and residual differences in liver disease severity^[47]. Benefit was not significant in cirrhosis, whereas bleeding risk increased; in compensated HBV-related cirrhosis, aspirin was associated with lower HCC risk but higher gastrointestinal bleeding risk^[48]. Any chemopreventive signal must therefore be weighed against portal-hypertensive bleeding, thrombocytopenia, anticoagulant use, and decompensation risk pending adequately powered prospective trials. Statins are generally usable in compensated chronic liver disease when clinically indicated, but require caution in decompensated cirrhosis, frailty, interacting drug regimens, and patients at risk of myopathy or hepatotoxicity. Metformin remains attractive in type 2 diabetes, yet its preventive role is uncertain after adjustment for statin use, glycemic control, and liver disease stage, and it should be avoided or used cautiously in severe renal impairment, hypoxic illness, sepsis, or unstable decompensated cirrhosis. Overall, these agents support risk-stratified investigation, not routine prescription solely for HCC chemoprevention.

Semaglutide is currently a major focus of HCC chemoprevention research, particularly for patients at risk of MASLD-HCC. Current evidence is confined largely to weight loss, metabolic improvement, MASH resolution, and observational class-level associations, with no prospective trials powered for HCC endpoints. While not yet Food and Drug Administration (FDA)-approved specifically for cancer prevention, semaglutide may reduce HCC risk in patients with MASLD and type 2 diabetes based on recent observational evidence^[49].

Several putative mechanisms may be involved, although current data should be distinguished as indirect risk-reduction evidence rather than evidence of direct anti-tumor effects. Phase III trials, such as the ESSENCE trial, have shown that semaglutide (2.4 mg) can lead to the resolution of steatohepatitis (MASH) in up to 63% of patients^[50], potentially slowing the progression to cancer through this pathway. Moreover, a large-scale meta-analysis of over 2.3 million patients indicated that Glucagon-like peptide-1 (GLP-1) receptor agonists, a class that includes semaglutide, are associated with a 42% reduction in HCC risk in patients with type 2 diabetes^[29]. The proposed “chemopreventive” effect is thought to be indirect, stemming from significant weight loss, improved insulin sensitivity, and reduced systemic inflammation rather than direct antitumor activity^[51].

Based on available research as of mid-2026, lanifibranor is an investigational antifibrotic MASH therapy with theoretical chemopreventive relevance but is not used or approved for HCC chemoprevention. However, it is a leading investigational drug for MASH. The Phase 2b NATIVE trial showed that lanifibranor improved liver histology in MASH patients, a population at potential risk for developing HCC^[31,54]. Because MASH-related fibrosis and cirrhosis are major drivers of HCC, lanifibranor’s ability to reverse fibrosis suggests it may reduce HCC risk, but it is not currently classified as a chemopreventive agent.

Resmetirom is a MASH-directed agent with preclinical antitumor signals requiring long-term human validation. A recent study offers the first detailed preclinical assessment of resmetirom as a potential modifier of MASLD-associated hepatocarcinogenesis^[55]. Using hydrodynamic tail-vein injection models driven by NRas^V12/Myr-AKT, ΔN90-β-catenin/c-Myc, or c-Myc/TP53 knockout, combined with a Western diet and low-dose CCl₄, Zhang et al. showed that resmetirom significantly reduced hepatic steatosis and HCC burden across oncogenic settings. To link these effects to disease progression, they developed a multistage Western diet/CCl₄ model recapitulating MASLD, MASH, advanced fibrosis, and overt MASLD/MASH-HCC, and performed single-cell RNA sequencing on 134,760 liver and tumor cells^[55]. This integrative approach showed expansion of myeloid populations, particularly M2-like and MASH-associated macrophages (TREM2⁺GPNMB⁺), together with hepatic stellate cell activation and the emergence of dysplastic hepatocytes with copy-number alterations, closely recapitulating the cellular landscape of human MASLD/MASH-HCC. The limitations of this study include differences between animal models and humans, and the timing of drug administration, implying that these findings do not firmly establish resmetirom as an HCC therapy. However, these authors provide a detailed Midkine/Low-density lipoprotein receptor-related protein 1 (MDK/LRP1)-centered framework to guide rational combination strategies and future clinical trial design^[56]. Additionally, resmetirom should be tested as a potential chemopreventive agent given its ability to improve MASH histology while displaying antitumor effects by reversing steatosis, improving liver metabolism, and reducing immunosuppressive MDK/LRP1 interactions.

Barone et al. conducted a systematic review to clarify the role of angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors in HCC^[57]. Their meta-analytic evaluation indicated that, in humans, renin-angiotensin system inhibitors, whether administered alone or in combination, were associated with a significantly reduced cumulative incidence of HCC recurrence, although no improvement in overall survival was observed.

Crouchet et al. established a simplified human cell-based model incorporating a prognostic liver signature (PLS) predictive of liver disease progression and HCC risk. In their initial study, this platform was applied to screen more than 20,000 compounds, followed by experimental validation in a cell-based system, leading to the identification of captopril, an ACE inhibitor primarily used to treat hypertension, as a promising candidate for HCC chemoprevention^[58]. In their subsequent study, these researchers further investigated ACE as a therapeutic target for HCC chemoprevention and demonstrated that captopril could attenuate liver fibrosis and delay progression toward HCC in both a diethylnitrosamine (DEN)-induced rat cirrhosis model and a diet-induced rat model of MASH-associated hepatocarcinogenesis^[59]. RNA sequencing analysis of cirrhotic rat liver tissue demonstrated that captopril suppressed molecular pathways implicated in fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Complementary mechanistic studies in liver disease models further indicated angiotensin-mediated transactivation of the EGFR pathway.

Further supporting the translational relevance of this strategy, captopril significantly reversed the high-risk HCC status defined by the PLS in liver tissue obtained from patients with advanced fibrosis. Collectively, these findings suggest that captopril may represent a safe and cost-effective candidate for HCC chemoprevention and may delay progression of fibrotic liver disease toward HCC in preclinical settings.

Based on available evidence, it remains premature to recommend ACE inhibitors (ACEIs) as primary chemopreventive agents in MASLD/nonalcoholic steatohepatitis (NASH)^[60,61]. However, a strong rationale supports further basic and translational research to clarify the pathogenic mechanisms underlying the effects of ACEIs and, more importantly, randomized controlled trials evaluating their impact on HCC chemoprevention.

SGLT2 inhibitors (SGLT-2i) are gaining attention as metabolic partners in MASLD, with potential implications for lowering HCC risk through indirect pathways rather than proven antitumor effects. By improving glycemic control, promoting modest weight loss, reducing visceral adiposity, and ameliorating hepatic steatosis, these agents may attenuate insulin resistance, lipotoxicity, oxidative stress, and inflammatory signaling that contribute to fibrogenesis and hepatocarcinogenesis^[62]. Emerging clinical data also suggest favorable effects on aminotransferases, liver fat, fibrosis markers, and broader cardiometabolic outcomes. In their nationwide cohort study, Bea et al. found that SGLT-2i were associated with a reduced risk of hepatic decompensation events in patients with MASLD compared with TZDs and showed similar effectiveness to GLP-1RA^[63]. The hepatic effectiveness of SGLT-2i was greater in female patients and patients younger than 65 years. However, whether these metabolic improvements translate into clinically meaningful HCC chemoprevention remains uncertain; direct protective effects against HCC have not yet been demonstrated in prospective trials.

Recent investigations have identified aripiprazole, an oral atypical antipsychotic, as a potential candidate for HCC chemoprevention^[64]. Clinical analysis of liver tissue has shown that aripiprazole targets are expressed in various liver cell compartments, including fibroblasts, macrophages, and epithelial cancer cells, and are linked to fibrotic liver disease and HCC. In a rat model of MASH-driven HCC induced by a choline-deficient L-amino acid-defined high-fat diet, aripiprazole slowed the progression of liver disease and the development of HCC by altering fibrogenic and inflammatory pathways. Mechanistically, it exerted antifibrotic and anti-inflammatory effects by changing fibroblast and macrophage phenotypes. Cancer cell studies demonstrated reduced tumor initiation and proliferation through the inhibition of c-Met encoding the hepatocyte growth factor receptor (HGFR)’ and extracellular sginal-regulated kinase (ERK) signaling and disruption of mitochondrial function. In patient-derived tumor spheroids, aripiprazole also affected immune responses in the tumor microenvironment^[64]. These findings collectively support aripiprazole as a potentially promising candidate for HCC chemoprevention, although clinical experience is limited, and further observational studies and trials in high-risk populations are necessary.

A robust body of published evidence, summarized elsewhere^[65], pinpoints sex disparities in HCC, with men having a higher risk approximately 2.5 times that of women. Sex, reproductive status, and gender also modify several other aspects of HCC pathobiology, ranging from disease stage at presentation to treatment outcomes^[65]. Reproductive and hormonal factors appear to modify HCC risk in women: higher parity, later natural menopause, and hormone replacement therapy (HRT) were associated with lower risk, whereas premenopausal oophorectomy before age 50 was associated with increased risk^[66]. Hormone replacement therapy is associated with reduced HCC risk and improved survival among postmenopausal women with hepatitis B^[67]. However, menopausal HRT is not indicated for the chemoprevention of HCC^[68,69].