Review for 10.1186/s12876-024-03345-1 (2024)

Title: Autophagy-mediated ferroptosis is involved in development of severe acute pancreatitis
Version: 4 Date: 05 May 2024
Reviewer:  Mudasir Rashid
Reviewer's report:
The manuscript titled “Autophagy-mediated ferroptosis is involved in development of severe
acute pancreatitis”. This study unveils key markers of ferroptosis in pancreatic tissues during
SAP, including heightened lipid peroxidation, reduced levels of GPX4 and GSH, increased
MDA levels, and notable mitochondrial damage. The identification of decreased levels of
ferroptosis-related proteins further underscores its involvement. The inhibition of ferroptosis by
Fer-1 offers a promising therapeutic avenue, potentially mitigating SAP severity. Moreover, the
revelation of autophagy's dual role, both promoting ferroptosis and exacerbating iron overload
in SAP, adds complexity to our understanding of disease mechanisms.
I carefully and thoroughly assessed the content of the manuscript and identified several key
points that I believe are important to highlight. The following comments are:
#The line has not been mentioned and was difficult to pinpoint. However, the has mentioned
AP in the introduction of the first paragraph which is this I don’t understand.
# Author needs to “pathway.[6]” change the full stop/factor position [6].”
# Author needs to add that the full forms are somewhere, but need to be at first place rather at
the last of “Fer-1 and Lip-1”, # need to check the supports or support word…
# Author needs to add what is NCOA4 and why it is not uniform (Ncoa4) in the manuscript.
# Why only male adult male Sprague–Dawley rats were included in the study and the specific
reason not mentioned in the manuscript?
# Author needs to add uniformity, such as spacing in “0.1ml” or “1 ml” or “h or “hour” various
placeless needs to check and correct them.
#Figure 2e is not clearly aligned and looks like different exposed blots and why FTH1 in Sahm
showed two bands and other have one band, Figure “h” has not been added what magnification
and it is not clear what is what, why not SLC7A11/GPX4 has not done Immunofluorescence.
# All the figures are not clear (captions) in any of the figures, what graph and so on and fig3e
is some bold and not uniform.
# Similarly, Fig4f is not clear, and k is missing what magnification is and why blue/ DAPI is
not visible.
# Author has reliance on a single ferroptosis inhibitor, Fer-1, which may not fully represent
the diversity of potential therapeutic interventions.  Furthermore, the reliance on a single
inhibitor on 3-MA as an autophagy inhibitor may oversimplify autophagy's role, the study
focuses on elucidating the association between ferroptosis and SAP Autophagy is a multifaceted
phenomenon regulated by numerous factors and pathways beyond PI3K, and employing
additional autophagy inhibitors or genetic approaches could provide a more comprehensive
understanding of its involvement in ferroptosis. pathogenesis, potentially overlooking other
contributing factors. Additionally, while Fer-1 demonstrates efficacy in attenuating ferroptosis,
its long-term effects and clinical applicability require further exploration and has not been
mentioned in the manuscript.
#Despite these limitations, this study represents a significant step towards understanding the
pathophysiology of SAP and offers a foundation for future investigations in this field.