Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review, authors vividly describe the heme and PPIX as queen and the dark twin, which impressive. Authors illustrate the biosynthesis of heme and its degradation, and summarized the metabolic characteristic of heme and PPIX and related enzymes or transporters in liver cancers and inflammation.  This review is so informative and important that it should be published in Molecules. Author may consider the following comments to improve the manuscript. 

1) Regarding the figure legend, it is better to put the "left", "middle" "right" part directly after the figure title, make them have same stye with the figure title. 

2) In the figures, Cancer_1, cancer_2, ... are kind of misleading. Apprently,  they represent the data from 4 different cancer patients. But they actually mean cancer stage-1, -2, -3, -4. It is better to use cancer stage-1, -2,... in the figures.

3)Authors mentioned the degradation of erythrocyte-driven heme. It is better to tell readers the synthesis pathway of heme and hemoglobin in erythrocyte.

Author Response

please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review summarizes the relationship between heme metabolism and pathological conditions, such as inflammation and hepatic cancer. In healthy tissues, heme metabolism is severely regulated, and no intermediates are accumulated, whereas in cancer tissues, some intermediates, especially protoporphyrin IX, are accumulated because of the inactivation of ferrochelatase and the activation of hydroxymethylbilane synthase. Also, heme metabolism is also regulated spatially because hepatocytes and Kupffer cells have different functions in heme metabolism, for example, Kupffer cells are specialized in heme degradation and iron recycling. The review is worth the publication in molecules, whereas I have some concerns as shown in the comments below.

Comments

1. Cytochrome-mediate metabolism in line 226 and cytochrome genes in line 530 may be better to revise as CYP-mediated metabolism and CYP genes because cytochrome P450s (CYPs) and other cytochromes such as ETC related genes have completely different functions.
2. In Figure 2, authors displayed the increase of expression of CYC1 in cancer tissues as a representative of ETC-related genes. However, it is well known that glycolysis is enhanced, and aerobic respiration is inhibited in cancer cells as Warburg effect. It is also well known that cytochrome c is essential for proper development of the apoptotic process. If you have data that the expression of the other ETC-related gene is increased in cancer, it may be better to display it instead of CYC1.

Author Response

please see the attachment

Author Response File: Author Response.pdf