Dear Dr. Lee,

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Anna Di Sessa, PhD, MD

Academic Editor

PLOS ONE

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Additional Editor Comments:

Although the paper has potential, it would benefit from major revisions before it can be considered for publication. All the issues raised by the reviewers need to be carefully addressed.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1:  The article represents a pioneering effort in applying the MASLD criteria to a large-scale cohort, thereby addressing a gap identified in prior research, such as the NAFLD study by Lee et al. (2021). While the core data presented in the paper are reliable, several aspects require standardization to enhance the academic rigor of the presentation.

1. The article does not sufficiently establish the origins of the term "metabolic dysfunction-associated steatohepatopathy" (MASLD) in the Introduction and Methods sections. It is crucial to reference Rinella et al. (2023), which is the inaugural international Delphi Consensus that established the terminology and diagnostic criteria for MASLD, replacing the former NAFLD classification. Properly tracing the terminology to its origin is recommended to prevent subjective definitions of diagnostic criteria.

2.The article's mechanism partially relies on previous studies without introducing novel pathways. It is advised to underscore the clinical significance of the MASLD classification in the Discussion section.

3.The paper lacks a prospective efficacy analysis, and it is recommended to supplement this with a detailed basis for calculation. The Cox model was validated but lacked multiple comparison corrections; a Bonferroni correction is advised.

3.The flowchart should label the temporal distribution of excluded cases to check for selection bias. Table headings were misplaced (P5 Table1 should be above the table); reference 17 (Ryu et al. 2015) was not cited in the text; and the abbreviation MASLD was not initially defined. A thorough review is recommended for the next manuscript to prevent these errors.

Reviewer #2:  Dear authors, Thank you for this interesting manuscript. here are my comments for more clarity:

1. Introduction and Background

The introduction effectively sets the context with global and Korean-specific data on working hours. However, it could briefly elaborate on why MASLD is a priority outcome (e.g., its rising prevalence and links to cardiometabolic disease beyond NAFLD). Please add 1–2 sentences in lines 58–66 referencing the global burden of MASLD (e.g., cite a recent review on its epidemiology) to strengthen the rationale.

2. Methods

o In lines 118–128, please specify if overtime was explicitly included in the self-reported question or if it relies on participant interpretation.

o For subgroup analyses (lines 174–177), it is better to justify the age cutoff (≤47 vs. ≥48 years) more explicitly—e.g., if it is based on the 90th percentile to capture younger vs. older workers.

o Please add a sentence on power calculations or sample size justification, given the low number of long-hour workers (n=2,243 vs. 115,111 in the reference group).

3. Results

o Please ensure consistency in reporting: The abstract says "higher risk of developing MASLD" (HR 1.17), but specify it's for ≥60 vs. 35–59 hours.

4. Discussion

o It is better to discuss policy implications more explicitly: Given Korea's work-hour reforms (Ref. 4), how might these findings inform thresholds like 52 or 60 hours/week?

o Please add a brief note on why the association persisted in MASLD alone vs. MASLD+MetALD, perhaps tying it to alcohol's role in long-hour workers (higher heavy drinking at baseline).

• Clarity and Writing: The manuscript is well-written overall

5. Generally

• Clarity and Writing: The manuscript is well-written overall, but some sentences are lengthy (e.g., lines 80–88). Break them for readability.

• Dates: IRB approval and data access are dated 2025 (lines 93–97), while data collection ends in 2023. If this is a projection or typo, clarify; otherwise, there is no issue given the query date (Sep 2025).

Reviewer #3:  I believe that the authors have exposed enormous and highly appreciated efforts in conducting this longitudinal cohort study to examine the association between long work hours and steatotic liver disease. However, some remarks should be considered:

THE TITLE:

the cohort study was conducted on patients being diagnosed with MASLD (with no alcohol or light alcohol intake), or MetALD (metabolic and alcohol-157 associated liver disease). both terms must be emphasized in the title and using “metabolic dysfunction-associated steatotic liver disease” alone will be misleading, since it means MASLD only. I suggest the following title “Effects of long working hours on Steatotic Liver Disease (MASLD and MetALD) in healthy workers: A 10-year cohort study”

ABSTRACT:

Since MetALD was being examined in this decade cohort study, the abstract did not reveal any information regarding those examined patients, regarding the objectives, results and conclusion sentences. I believe the authors should re-evaluate their manuscript in each details to be comprehensively summarized in the abstract.

INTRODUCTION:

MetALD disease should not be mentioned as part of MASLD system, and must be extensively differentiated in between, through providing etiologic manifestations of each disease (cause, criteria, alcohol intake), and main levels of their pathophysiologic progression. As well, recently published articles correlating the MetALD with workload or long working hours will be highly recommended to cite.

However, the objectives of the study must reflect the conducted work in this cohort study, and NOT depending on correlation of MASLD with work load only.

MATERIALS AND METHODS:

The study analyzed data from 117,354 participants, enhancing statistical power and generalizability within the Korean working population, and through applying rigorous exclusion criteria (i.e., excluding participants with confounding conditions (e.g., viral hepatitis, steatogenic medications)) has improved the internal validity. As well, depending on MASLD diagnosis via abdominal ultrasonography is more accurate than indirect indices like the Hepatic Steatosis Index.

• Sensitivity Analysis was performed in the study, through including models that account for time-varying exposure to test robustness. However, the authors should clarify if any of multi-pronged strategies being applied to enhance data accuracy and validity, such as workplace records (to obtain actual working hours from employer records), digital tools (e.g., swipe cards, login/logout systems to track work duration more accurately), Cross-Validation, or Repeated Measures (Collect working hours data at multiple time points to identify inconsistencies or trends).

• Moreover, limited occupational detail (e.g., white-collar vs. blue-collar), which could influence exposure and outcomes, exclusion of changing work hours during follow-up in the main analysis, potentially omitting relevant variability. In addition, behavioral factors like sleep and diet were discussed but not measured, limiting mechanistic insights.

RESULTS:

Using Cox proportional hazards models with multiple adjustments (age, sex, lifestyle, socioeconomic factors) have strengthened the findings, and subgroup analyses, through stratification by age and sex have provided nuanced insights into vulnerable populations in the detailed tables

• The authors should further discussed any possible residual confounding lead to the modest association of MASLD with long work hours (adjusted HR for MASLD was 1.17), and the argument regarding the bias being developed from the exclusion of participants with missing data was inadequate and need in-depth justification.

• While the sensitivity analysis used three categories of working hours, the main analysis used only two, limiting granularity. Besides, the models did not test for interaction effects (e.g., between sex and working hours), which could reveal synergistic risks.

DISCUSSION:

The authors provide a comprehensive explanation of physiological pathways linking long working hours to MASLD, and findings are contextualized with previous studies, including cross-sectional and meta-analytic evidence.

• Efforts must be paid to justify the absence of deep analysis of female-specific factors (e.g., unpaid labor, hormonal changes), while male vulnerability is well-discussed. Some proposed biological mechanisms (e.g., gut-liver axis disruption) are hypothetical and not directly measured, and further details regarding any unpublished analysis should be explained. In addition, the discussion lacks concrete suggestions for workplace or policy interventions.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Effects of long working hours on metabolic dysfunction-associated steatotic liver disease, with and without increased alcohol intake, in healthy workers: A 10-year cohort study

PONE-D-25-36457R1

Dear Dr. Lee,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Anna Di Sessa, PhD, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: The authors have addressed all my comments. I have no other questions. The paper may be accepted in Plos One.

Thank you for your invitation.

Reviewer #3: I appreciate the authors’ detailed responses and the revisions made to address the reviewers’ concerns.

The authors have satisfactorily clarified the inquires regarding undetailed remarks in the abstract, introduction, methodology, results, discussion and conclusion sections through providing additional data, which strengthens the manuscript.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: Yes:  Zhigang Ren

Reviewer #3: No

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