NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate

Round 1

Reviewer 1 Report

Dear Authors, 

Your manuscript ijms-2213678 'NFIXing cancer: the role of NFIX in oxidative stress response and cell fate' is definitely a high-quality review, which is in line with the field of the journal. It is well-structured and generally well-written, with the exception of minor stylistic/punctuational issues. Also, I recommend making figure legends more concise by moving any discussion to the main text.  Please see the text with my corrections/comments attached. I recommend acceptance of you manuscript with minor revisions. 

Comments for author File: Comments.pdf

Author Response

We thank the reviewer for the positive feedback on our manuscript. We have corrected the minor spelling mistakes as suggested and reduced the text of the legends to Figures 1 and 3, and part of the text has been incorporated into the manuscript.

Reviewer 2 Report

Unraveling the molecular enigma of different pathologies is an important steppingstone for the development of novel strategies of prevention, treatment or management of diseases. This manuscript serves to provide a comprehensive review summarizing currently available knowledge on the nuclear factor I (NFI) family of transcription factors, particularly on NFIX as a key player in the onset and progression of malignant diseases. Furthermore, the role of oxidative stress as an important regulator of NFIX.  In this sense, the paper is highly up-to-date and of potential interest to the readers. The review is very detail-oriented and supported by an array of figures.

I would recommend the authors to check the linguistic aspect, since a number of typos is present in the current version of the manuscript.  For an easier orientation, I would also suggest to add a List of Abbreviations that may help the reader to navigate faster through the review.

Since the roles of NFIX are well described based on the body of evidence collected by the authors, I am wondering about its potential to serve as a diagnostic marker for selected diseases. Also, are there any treatment options for diseases caused by an altered NFIX expression? This could be discussed briefly.

The paper could benefit from a Conclusion section that would summarize the most relevant information collected by the authors, and provide a take home message for the reader.

Finally, the manuscript should be formatted according to the template provided by the Editorial office of the Journal and unify the Reference list as per the Instructions for authors.

Author Response

We thank the reviewer for the positive feedback on our manuscript. We have corrected the minor spelling mistakes and added a list of abbreviations at the end of the manuscript. We also added a section where we briefly discuss NFIX as a potential prognostic marker and a possible approach to use NFIX silencing as a therapeutic approach.

The work being reviewed highlights the role of NFIX in cancer, particularly by showing its strict association with increased oxidative stress.  NFIX . Previous studies suggest that NFIX may be a promising prognostic marker [80,94,135] and even though Mmore research is needed to fully understand the relationship between NFIX and ROS in the context of cancer, and to determine the potential ofis possible that targeting NFIX asoffers a means ofway to modulateing ROS levels in cancer.

When designing new therapeutic strategies, it is crucial to consider that targeting NFIX can impact vital cell mechanisms in various cell types, such as hematopoietic, neuronal, or germ cells. Strategies such as using adeno‐associated virus (AAV)-based gene therapy for efficient and tissue/cell-specific delivery of NFIX silencing molecules (including miRNA or lncRNA) could provide a successful approach. Additionally, a growing number of therapeutic approaches are currently being established to increase ROS levels in cancer cells to a point that surpasses the cells' redox tolerance, triggering an overt oxidative stress response that ultimately may lead to cancer cell death [136]. A better understanding of how NFIX crosstalks with the oxidative stress response may provide yet another application for the modulation of NFIX levels in cancer treatment.

 

In addition we also added a brief conclusion paragraph to highlight the main points of the manuscript.

Over the past few decades, NFIX has primarily been studied in the context of skeletal muscle development and muscle dystrophies, as well as in relation to neuronal and hematopoietic cell differentiation and fate. In this review, we explored the role of NFIX in cancer and its crosstalk with oxidative stress pathways. Given the crucial function of NFIX in cell differentiation during embryonic development, it is possible that a potential link between NFIX, oxidative stress and cancer cell dedifferentiation might be a pivotal factor in tumor progression. Collectively, this review increases our understanding of the involvement of NFIX in both development and cancer, which is essential for the establishment of targeted cancer therapies.