Review for 10.1186/s12876-025-04126-0 (2025)

Title: Interferon therapy for chronic hepatitis B virus infection affects nucleoside metabolism:
A metabolomics study
Version: 1 Date: 12 Mar 2025
Reviewer's report:
Article Title: Interferon therapy for chronic hepatitis B virus infection affected the methylated
modifications of nucleoside: a metabolomics study
Interferon therapy represents a potent approach for achieving clinical cure of chronic HBV
infection. In this investigation, a blood metabolomics analysis was conducted on patients
with chronic HBV infection who underwent varying durations of interferon treatment. The
findings indicated that interferon influenced ABC transporters, caffeine metabolism, and protein
digestion and absorption. Notably, three of the identified differential metabolites were associated
with pyrimidine nucleoside metabolites, which may modulate HBV through alterations in
methylation processes. Correlation analyses were performed in conjunction with clinical
parameters. While the study exhibits a degree of innovation, significant conceptual issues exist,
rendering it unsuitable for publication in this journal.
Major questions#
1. The absence of line numbers and the prevalence of grammatical inaccuracies in the manuscript
hinder its readability. Certain references were inaccurately cited, for instance, [11], which was
designated as guidelines for chronic hepatitis B; however, the actual reference indicates that [11]
is a review published in 2023. It is advisable to verify the original sources referenced.
2. The title refers to the impact of interferon on nucleoside methylation modifications in the
context of chronic hepatitis B virus infection; however, this manuscript did not include any
relevant assessments of methylation modifications. The study identified several metabolites,
potentially related to pyrimidine metabolism, and posited their influence on hepatitis B virus
replication via methylation modifications, which is not substantiated. It is recommended that
the title be amended to accurately represent the article's content or that relevant methylation
experiments, such as whole genome methylation phosphite sequencing, be incorporated to
evaluate the methylation status of CpG islands within the HBV DNA genome, thereby
facilitating a more comprehensive analysis of the role of methylation modifications in HBV
infection.
3. This investigation categorized the enrolled participants into four cohorts based on the duration
of PEG IFN # treatment (0, 1, 3, and 6 months). As indicated in the article, this is a cross-
sectional study that selected patients undergoing varying lengths of interferon therapy and
gathered their clinical data. However, it remains unclear whether the baseline characteristics
of the patients before interferon administration were balanced. Additionally, the inclusion and
exclusion criteria did not specify the presence of liver cirrhosis or liver fibrosis among the
patients. If any participants had liver cirrhosis, it could potentially skew the results regarding
white blood cell counts, platelet levels, ALT, and AST, leading to misleading conclusions.
4. Given that a comparison of various durations of interferon therapy is planned, why not conduct
a longitudinal study? Analyzing the composition and concentration of metabolites in the same
patient at 0, 1, 3, and 6 months of treatment would provide a more accurate representation of
metabolite fluctuations.
5. In the final section of the results, a correlation was identified among WBC, PLT, ALT,
AST, and various metabolites; however, this observation was not explored in the discussion,
particularly regarding the underlying mechanisms linking the metabolites to the aforementioned
biomarkers.