Dear Dr. Pihlajoki,

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Academic Editor

PLOS ONE

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[This work was supported by Jane and Aatos Erkko Foundation (HR; https://jaes.fi), Sigrid Jusélius Foundation (HR, MH; https://www.sigridjuselius.fi/en/), Helsinki University Hospital Research Funds (MH; https://www.hus.fi/en), Academy of Finland (Project 2666621) (HR; https://www.aka.fi/en/), Finnish Foundation for Cardiovascular Research (HR; https://www.sydantutkimussaatio.fi/en/foundation). Sponsors or funders play no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.]

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[This work was supported by Jane and Aatos Erkko Foundation (HR; https://jaes.fi), Sigrid Jusélius Foundation (HR, MH; https://www.sigridjuselius.fi/en/), Helsinki University Hospital Research Funds (MH; https://www.hus.fi/en), Academy of Finland (Project 2666621) (HR; https://www.aka.fi/en/), Finnish Foundation for Cardiovascular Research (HR; https://www.sydantutkimussaatio.fi/en/foundation). Sponsors or funders play no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.]

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[I have read the journal's policy and the authors of this manuscript have the following competing interests: SMK, MJV and HR are inventors in a patent application “Pharmaceutical compound” (PCT/FI2017/050661) concerning the compound 3i-1000 and its derivatives. EI is currently employed by the company XenTech. SC has formerly been employed by the company XenTech and is currently employed by the company Champions Oncology. No other competing interests to disclose.].

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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

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

Reviewer #1: Yes

Reviewer #2: 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: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Very interesting in-depth experiment on a novel group of GATA4 inhibitors. Comparison of the effectiveness of several compounds reinforces the utility of the most potent variant.

The prognosis of the hepatoblastoma cell line used in the experiment [embryonal] represents ~20% of all hepatoblastomas, with ~60% survival at 24 months. It would be of therapeutic interest to study the effectiveness of these inhibitors on hepatoblastomas with some of the other histologic types, e.g. pure fetal [~30% of all hepatoblastomas with a 24-month survival of ~90%], or small cell undifferentiated [~3% of all hepatoblastomas with a 24-month survival of 0%].

Excellent graphs and pictures.

Some typos:

Line 47: ... effects of a novel ...;

Line 61: ... occur at any age of ...;

Line 85: 'CETSA", not "CESTA".

Line 134: ... tested a novel ...;

Line 139: ... compounds in the 3i-2010 ...;

Line 140: ... viability at the highest ...;

Line 141: ... already at a concentration ...;

Line 169: ... compounds' influence ...;

Line 179: ... at a concentration ...;

Line 179: ... spheroid viability by 85% ...;

Line 244: ... Consistent with the ...;

Line 289: ... survival may be mediated ...;

Line 296: ... to 3i-2012 in upcoming studies ...;

Line 315: ... are arrested at the G2/M phase.;

Line 319: ... at least part of the actions ...;

Line 322: ... have different histologic and genetic ...;

Line 330: Furthermore, a notable ...;

Line 331: ... response to 3i-2012 is regulated ... [proportion ... is ...];

Line 334: The synthesis of ...;

Line 452: ... were performed using IBM ...;

Line 462: ... by the Jane ...; ... the Sigfrid ...;

Line 463: ... the Helsinki ....

Reviewer #2: In the manuscript entitled "GATA4-targeted compounds induce apoptosis and diminish viability of hepatoblastoma cells," the authors screened compounds targeting GATA4 to provide potential new drug candidates for treating diseases such as hepatoblastoma. This work is valuable; however, the following issues should be addressed before the manuscript can be considered for further processing.

The authors performed initial screening and identified compounds exhibiting cytotoxicity. Potential related mechanisms were investigated via high-throughput screening. Nevertheless, it remains unclear whether the selected compounds are effective in vivo. Additionally, the direct target proteins of these compounds have not been explored. This study would be significantly strengthened if the pharmacological and efficacy investigations were conducted in greater depth and supported by more comprehensive evidence.

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Reviewer #1: No

Reviewer #2: No

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

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GATA4-targeted compounds induce apoptosis and diminish viability of hepatoblastoma cells

PONE-D-25-12058R1

Dear Dr. Pihlajoki,

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,

Consolato M. Sergi

Academic Editor

PLOS One

Additional Editor Comments (optional):

Please address the requests of the reviewers thoroughly.

Reviewers' comments: