Aldehyde Detoxification in Cancer: Metabolic Guardians of the Genome
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsAldehyde detoxification in cancer: metabolic guardians of the genome; by Brandon T. James, Emma P. Kosmeder and Meng Wang.
This is a well written and well structured review with appropriate citation of relevant references, focussing on aldehydes, particularly from endogenous sources, as an important source of genotoxic damage. There is a good description of how mammals have evolved a diverse family of aldehyde detoxification enzymes, including aldehyde dehydrogenases (ALDHs) that directly catabolize free aldehydes, alcohol dehydrogenase 5 (ADH5) that detoxifies formaldehyde and glyoxalases (GLO1 and HAGH) that can process aldehyde-glutathione conjugates to detoxify the dicarbonyl aldehydes methylglyoxal and glyoxal, with many of these enzymes showing overlapping substrate specificities. The authors emphasise the recognition that reactive aldehydes are not merely passive metabolic by-products, but are active endogenous genotoxins, and that the enzymes clearing them constitute a tier 1 first line of genome defence, accompanied a tier 2 second line of DNA repair by several relevant DNA repair pathways, with the combination being highly relevant to protection against cancer-associated genome instability.
The review manuscript could be strengthened in three areas in particular.
1. An improved and more detailed description of how the Fanconi Anaemia DNA repair pathway functions to remove interstrand DNA crosslinks caused by aldehydes. In particular, the important roles of the FA anchor complex, FA core complex, FANCD2/I complex and the scaffold complex formed by SLX4 or FANCP that serves as a central docking platform for structure-specific endonuclease that act to resolve DNA interstrand crosslinks. It plays a crucial, non-redundant role in the Fanconi Anaemia pathway by coordinating the enzymes required to unhook the crosslink. A key paper to cite is: Fang, C., Zhu, Z., Cao, J. et al. Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors. Orphanet J Rare Dis 20, 389 (2025). https://doi.org/10.1186/s13023-025-03896-w
2. There should be an improved and more detailed description of how the Mismatch Repair DNA repair pathway functions, with description of a key study using a Lynch Syndrome (LS) mouse model (conditional Msh2 knockout), in which researchers demonstrated that long-term ethanol consumption leading to acetaldehyde generation markedly accelerated colorectal tumourigenesis. A key paper to cite is: Ethanol-induced formation of colorectal tumours and precursors in a mouse model of Lynch Syndrome. Cerretelli et al. Journal of Pathology 2021 Dec;255(4):464-474. doi: 10.1002/path.5796. Epub 2021 Oct 13. PMID: 34543445.
3. A different mouse model (with Aldh1b1 knockout) with long-term ethanol consumption leading to acetaldehyde generation showed that loss of Aldh1b1 can also contribute to hepatocellular tumour formation as well as to colorectal tumourigenesis. A key paper to cite is: The murine hepatic sequelae of long-term ethanol consumption are sex-specific and exacerbated by Aldh1b1 loss. Muller et al Experimental and Molecular Pathology 2018.
Any papers recommended in the report are for reference only. They are not mandatory. You may cite and reference other papers related to this topic.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis work represents complex analysis from multiple literature data and affords better understanding of complex problem of aldehyde genotoxicity in respect to DNA repair and carcinogenesis.
In the first part of the work clue enzymes participating in cell protection and metabolic conversion of aldehydes from different biochemical sources were discussed. The corresponding data are successfully supplemented by the observations on knock-down animals. A scaled analysis of clinical data and association of basic aldehyde detoxification genes and their association with human cancers was further described. At the end of the manuscript a prognosis for exploitation of aldehyde detoxification system for clinical treatment of cancer has been given. I suggest this paper to be a candidate for publication in Biomolecules after some corrections.
1. First of all, a list of abbreviations would be worth given as the presented materials are sometimes difficult to read.
2. It must be indicated if the data from Figures 1-2 are novel or have been published/supplemented elsewhere.
3. Are aldehyde-mediated genome protection associated with DNA repair based on PARPs and/or caspase mediated pathways?
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors replied to the queries. I'd like to thank the authors for interesting research. The manuscript can now be accepted for publication in Biomolecules.
