Review Reports

Round 1

Reviewer 1 Report

The review manuscript by Y Setayeshpour et al. discusses the cell death known as ferroptosis. This is an iron-dependent form of cell elimination in cancer cells, due to the accumulation of oxidative stress. The authors highlighted many crucial aspects of ferroptosis that impact intracellular and extracellular factors.  Here, emphasized recent advances in understanding the role of ferroptosis within the context of cancer.  The manuscript is well written and it can be considered for publication after addressing the following comments:

1.     The elucidation of GPX4-dependent and -independent antioxidant defense pathways in the context of ferroptosis provides valuable insights into the cellular mechanisms involved in protecting against this form of cell death. The discussion on the role of GPX4 as a major intracellular protector and its co-factor GSH, regulated by the transcription factor NRF2, demonstrates the significance of antioxidant proteins in preventing ferroptosis. Furthermore, the mention of the ferroptosis suppressor protein 1 (FSP1) and its GPX4-independent mechanism of protection, along with the involvement of dihydroorotate dehydrogenase (DHODH), expands the understanding of diverse pathways contributing to ferroptosis regulation.

2.     Sec.3.4:  The authors should further emphasize the context-dependent nature of p53's role in regulating ferroptosis. While the section briefly mentions this, it is important to highlight the specific conditions or cellular contexts in which p53 acts as a promoter or inhibitor of ferroptosis. Providing more detailed examples and discussing the factors that determine p53's role in different settings would enhance the understanding of the complexity of p53-mediated regulation of ferroptosis.

3.     Sec.4.3: While the influence of mono- and polyunsaturated fatty acids on ferroptosis susceptibility is discussed, further exploration is necessary to understand the precise mechanisms by which these fatty acids regulate ferroptosis in cancer cells. The involvement of specific enzymes, transporters, and signaling pathways in the metabolism and uptake of fatty acids should be elucidated to gain insights into the interplay between lipid metabolism and ferroptosis. Moreover, a more extensive examination of the impact of different types of fatty acids on ferroptosis sensitivity in various cancer types would enhance the discussion.

4.      Sec. 4.8: The section provides a concise overview of the interaction between ferroptosis and the innate immune system, highlighting the release of danger-associated molecular patterns (DAMPs) by ferroptotic cancer cells. The role of DAMPs, such as ATP and HMGB1, in promoting inflammation and activating the innate immune system is appropriately discussed. The potential influence of varying DAMP expression levels on the frequency of immunogenic ferroptosis and immune response is also mentioned.

However, the authors should further elaborate on the specific mechanisms by which DAMPs regulate ferroptosis and its implications for cancer therapy. While the section briefly mentions that HMGB1-deficient cells show decreased levels of ferroptotic cell death, more details on the underlying molecular pathways and signaling cascades involved would enhance the understanding of this relationship.

Moreover, the authors should highlight the potential therapeutic implications of manipulating DAMP levels to enhance the benefits of ferroptosis in anticancer strategies. Discussing specific approaches or studies that target DAMPs to modulate ferroptosis and improve treatment outcomes would provide valuable insights and direction for future research in this field.

 

5.      Sec.Future perspectives: Given the expected spatial heterogeneity within solid tumors, it would be insightful to discuss the challenges associated with targeting different regions of the tumor with ferroptosis-based treatments. Addressing the variations in response to ferroptosis among different tumor regions and exploring potential strategies to overcome these challenges would be valuable for tailoring therapies to individual patients.

Minor editing of English language required

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Reviewer 2 Report

The manuscript titled "Environmental Determinants of Ferroptosis in Cancer ' by Yasaman Setayeshpour et al. is a critical work highlighting interesting facts but I would like to add a couple of missing features. The authors need to shed light on the contribution and significance of CAFs as an important component of TME to regulate iron signaling in PDAC as recently shown by PMID: 37075122 . Again the relevance of ferroptosis regulation as shown by PMID: 32241947 should be stressed upon while detailing the mechanisms.

The authors should also lay more stress on the developments that have translational impact and the findings in this context from clinical setting.

Author Response

Please see the attachment.

Author Response File: Author Response.docx