Association of Statin Use with Reduced Primary Liver Cancer Risk, Independent of Age and Cirrhosis Protection in MASLD
, Timothy Arnold 6,7, Mustafa R. Bashir 8,9, Jimmy T. Efird 10,11, Manal F. Abdelmalek 12, Anna Mae Diehl 1 and Ayako Suzuki 1,13,*Round 1
Reviewer 1 Report
Comments and Suggestions for Authors1. The large VA-based retrospective cohort and long follow-up are major strengths, providing strong statistical power and temporal assessment. Despite multivariable adjustment, residual confounding (e.g., health-seeking behavior, metabolic control, fibrosis stage, alcohol use misclassification) may partially explain the observed association. The manuscript would benefit from additional sensitivity analyses (e.g., propensity score methods, inverse probability weighting, or marginal structural models).
2. Time-varying statin exposure is appropriately considered, but the manuscript should more explicitly address potential **immortal time bias** and how it was handled.
3. Patients prescribed statins may differ systematically from non-users (e.g., better healthcare access, cardiovascular comorbidity management). More importantly, fibrosis stage is the strongest predictor of HCC in MASLD. If advanced fibrosis was incompletely captured or misclassified, confounding may persist. Stratified analyses by validated fibrosis scores (e.g., FIB-4 categories) or cirrhosis status would improve robustness.
4. A competing-risk regression (e.g., Fine–Gray model) would provide a more accurate estimate of cumulative PLC incidence.
5.The data support chemopreventive potential, but randomized evidence is still lacking. The discussion should more clearly distinguish association from recommendation.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsGeneral Recommendation: Major Revision Required.
1. The iThenticate report shows a 45% similarity index, which is unacceptable. Please reduce it to approximately 20% and provide a revised report; otherwise, publication is not recommended.
2. The abstract states the cohort is 92% male, indicating significant gender bias. However, the conclusion claims benefits regardless of sex. Please address this limitation and revise the conclusion as it is not yet applicable to female populations.
3. FIB-4 was used, but how many patients underwent liver biopsy? This information is missing.
4. The abstract mentions a median follow-up of 9.7 years. How many participants actually reached the 10-year mark?
5. Baseline statin use was analyzed, but can adherence be assumed over a decade? Does baseline use accurately reflect long-term exposure?
6. In Table 1, the cirrhosis group comprises only 0.5%. Isn't this sample too small to draw reliable conclusions?
7. Smoking is a known risk factor for PLC. Was this controlled for in the analysis?
8. Line 312 states atorvastatin and rosuvastatin were most effective. Were dosages controlled? Could this reflect higher-intensity prescribing rather than a specific drug effect?
9. Regarding Model 5 (Line 217), FIB-4 is derived from a statistical model and may introduce endogeneity. Please discuss this limitation.
10. The Statistical Methods section mentions MICE but does not report missingness mechanisms or sensitivity analyses.
11. The Study Exposures section defines exposure as cumulative dose. Was the potential impact of statin discontinuation or switching considered?
12. The manuscript frequently mentions a dose-dependent effect. Was a formal trend test performed?
13. For Study Outcome, the switch from ICD-9 to ICD-10 coding is noted. Could this coding change introduce bias? Consider sensitivity analyses, such as interrupted time series.
14. The conclusion states the effect is "regardless of disease stage." Given the limited number of advanced-stage patients, this claim may be overstated.
15. Figure 2 is too small and the font is illegible.
The English could be improved to more clearly express the research.
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsAuthors addressed raised issues appropriately.
Author Response
Thank you for your constructive comments and prompt review; we greatly appreciate your insights, which have improved our manuscript.
Reviewer 2 Report
Comments and Suggestions for AuthorsOverall Recommendation: Accept with minor revisions.
The authors have shown great respect for my comments. They addressed each point and made corresponding revisions to the manuscript. I find their approach professional and commendable. However, I noticed that the original references were crossed out, suggesting some issues with the references. I recommend the authors cite the following papers:
I suggest citing this paper (DOI: 10.1016/j.jpet.2026.103836) in the Discussion section. Since the authors discuss potential mechanisms by which statins may exert anti-hepatocellular carcinoma (HCC) effects, this article would usefully supplement the discussion by illustrating how different drugs might influence HCC development through distinct but interconnected pathways. This would provide broader mechanistic context for the observed protective effects of statins.
I recommend citing this paper (DOI: 10.2147/DDDT.S511372) in either the Introduction or Discussion. As the authors address key stages in the progression from MASLD to HCC, this reference could help illustrate that drugs targeting fibrotic and metabolic regulatory pathways may have multiple mechanisms of action in the chemoprevention of MASLD-related HCC.
I suggest citing this paper (DOI: 10.3748/wjg.v31.i25.107893) in the Discussion. Beyond metabolic regulation, statins may directly inhibit tumorigenesis by influencing key cell cycle molecules or immune cell infiltration. This would provide mechanistic support for the cirrhosis-independent protective effects observed by the authors.
I recommend citing this paper (DOI: 10.3390/ph18060900) in the Discussion. The combination of natural products with classic statin drugs may yield stronger anti-HCC effects through synergistic regulation of different targets. This could provide a theoretical basis and future direction for the authors to explore combination chemoprevention strategies.
Author Response
Reviewer 2
The authors have shown great respect for my comments. They addressed each point and made corresponding revisions to the manuscript. I find their approach professional and commendable. However, I noticed that the original references were crossed out, suggesting some issues with the references. I recommend the authors cite the following papers:
Response: Thank you for your insightful comments and suggestions, which have improved the quality of our manuscript. Regarding the reference list, no original citations were intentionally removed; the list was replaced with an updated version to incorporate three new methodological references.
I suggest citing this paper (DOI: 10.1016/j.jpet.2026.103836) in the Discussion section. Since the authors discuss potential mechanisms by which statins may exert anti-hepatocellular carcinoma (HCC) effects, this article would usefully supplement the discussion by illustrating how different drugs might influence HCC development through distinct but interconnected pathways. This would provide broader mechanistic context for the observed protective effects of statins.
Response: Thank you for your suggestion. The reference was added along with other mechanistic papers as follows.
Page 12, line 454-457: Finally, the potential hepatoprotective effects of statins on PLC risk may be modified by pharmacogenomic variation or concomitant medications (e.g., fenofibrates, ezetimibe, theophylline),[55-58] which were not evaluated in this study.
I recommend citing this paper (DOI: 10.2147/DDDT.S511372) in either the Introduction or Discussion. As the authors address key stages in the progression from MASLD to HCC, this reference could help illustrate that drugs targeting fibrotic and metabolic regulatory pathways may have multiple mechanisms of action in the chemoprevention of MASLD-related HCC.
Response: Thank you for sharing this interesting and relevant reference. In light of our recent publication examining the role of statins in cirrhosis prevention, the primary focus of the present manuscript is on cancer prevention (PLC risk). For this reason, we did not include an in-depth discussion of cirrhosis or fibrosis prevention.
We agree with the reviewer that the mechanisms underlying statin-associated chemoprevention in MASLD-related HCC are multifaceted and important. However, a comprehensive discussion of these pathways may be beyond the scope of the current manuscript and may be better suited to a dedicated review. Therefore, we have opted not to incorporate this reference in the present revision.
Suggested paper: Curcumin Analog J7 Attenuates Liver Fibrosis and Metabolic Dysregulation in a Rat Model of Type 2 Diabetes via Modulation of TGF-β/Smad and NFκB/BCL-2/BAX Pathways
I suggest citing this paper (DOI: 10.3748/wjg.v31.i25.107893) in the Discussion. Beyond metabolic regulation, statins may directly inhibit tumorigenesis by influencing key cell cycle molecules or immune cell infiltration. This would provide mechanistic support for the cirrhosis-independent protective effects observed by the authors.
Response: The suggested paper was added along with another paper linking statins and kinase signaling (PMID: 40832614).
Page 10, line 374-377: Including both baseline cirrhosis and incident cirrhosis in the model resulted in minimal effect attenuation, suggesting statins may exert hepatoprotection through multiple mechanisms, (e.g., kinase signaling [44, 45]).
I recommend citing this paper (DOI: 10.3390/ph18060900) in the Discussion. The combination of natural products with classic statin drugs may yield stronger anti-HCC effects through synergistic regulation of different targets. This could provide a theoretical basis and future direction for the authors to explore combination chemoprevention strategies.
Response: The suggested paper was added in the following sentence, along with “dietary supplements”.
Page 12, line 455-458: Finally, the potential hepatoprotective effects of statins on PLC risk may be modified by pharmacogenomic variation or concomitant medications/dietary supplements (e.g., fenofibrates, ezetimibe, theophylline),[57-61] which were not evaluated in this study.
