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Dear authors,
Thank you for your submission and revisions. I believe this work now offers a well-structured, accurate review.
Note a few minor considerations to address during proofreading:
- English clarity is improved, but may benefit from one more light editorial polish.
- Some figures (fig 3) quality might require final formatting and resolution check
[# PeerJ Staff Note - this decision was reviewed and approved by Gwyn Gould, a PeerJ Section Editor covering this Section #]
**PeerJ Staff Note:** Although the Academic and Section Editors are happy to accept your article as being scientifically sound, a final check of the manuscript shows that it would benefit from further editing. Therefore, please identify necessary edits and address these while in proof stage.
Dear authors, thank you for your submission and patience.
Although I considered some of the revisions pointed out as minor, several aspects require substantive but straightforward improvements:
- Expanding the abstract and USP inhibitor discussion
- Correcting a mechanistic figure
- potentially adding references and clarifying statements
- Improving grammar and consistency of references
& also, small clarifications and typo corrections.
But importantly, there are important factual and conceptual deficiencies in the manuscript (notably the sparse and partially incorrect "development of USP inhibitors" section, mislabeling of several inhibitors/compounds, conceptual misconceptions about what the inhibitors target, and an incorrect catalytic mechanism figure!?!
I'd say there are a few very worrisome issues identified:
- The manuscript states (line ~257–266) that “P5091, HBX19818, and GNE-6776” are USP7 inhibitors but later calls P5091 a USP14 inhibitor (line 258). P5091 is a USP7 inhibitor, not USP14
- IU1 is a USP14 inhibitor (first specific USP14 inhibitor series). The manuscript mixes up targets in that passage.
- The manuscript refers to “gentianin” as a USP22 inhibitor; recent literature reports gentiopicroside (a secoiridoid glycoside) as a USP22 inhibitor — check whether the authors meant gentiopicroside or some other compound and correct the name and citation. (https://pubmed.ncbi.nlm.nih.gov/38968798/)
- The manuscript repeatedly implies (lines ~267–276) that inhibitors target K48/K63 chains directly (“K48 and K63-linked ubiquitin chains are the most likely targets for inhibitors”). This phrasing is misleading: small-molecule inhibitors target DUB enzymes (or E3s, ligases, etc.), not ubiquitin chain linkages per se. A DUB can have chain preference, but the inhibitors are directed at enzymes. Rephrase and clarify mechanism: what is being inhibited is the enzyme activity (DUB), which in turn affects proteins carrying certain chain types?
- “Development of USP inhibitors” section is underdeveloped and contains inaccuracies: substantially expand this section with mechanism (covalent/noncovalent), selectivity profiles, stage (in vitro / in vivo / preclinical / clinical if any), and structures/SMILES or a panel figure with structures.
- Reviewer 4 correctly points out that the depiction of the catalytic step is wrong. Mechanism for cysteine protease DUBs: the catalytic cysteine performs a nucleophilic attack on the isopeptide bond between the ubiquitin C-terminus and the lysine of the substrate (i.e., attack on the carbonyl of the isopeptide linkage), forming a thioester intermediate, then hydrolysis releases ubiquitin. The figure and the text must be corrected and expanded briefly to mention the catalytic triad and the thioester intermediate. So, please, correct Figure 2B and add a short explanatory paragraph describing the nucleophilic attack, thioester intermediate, and role of His/Asp in proton transfer.
- Multiple reviewers flagged many lines where assertions lack specific citations.
- Table 1 items must be fully referenced in the reference list and tied back to main text. Some Table 1 references appear in the end but verify that every statement in the table has a clear citation and/or evidence type (cell line / animal / human cohort).
- Survey methodology needs clarification and reproducibility. Provide explicit details: databases searched (PubMed, Web of Science, EMBASE?), search strings and date range (e.g., “PubMed search conducted up to June 30, 2025 using terms: 'USP OR ubiquitin-specific protease' AND 'lung cancer'”), inclusion/exclusion criteria, and whether non-English articles were included. This improves transparency and addresses R4. Or is it a narrative review?
- Reviewer 3 and R4 asked the abstract to be expanded (≥150 words), including more specifics on which USPs are discussed, what pathways and therapeutic angles are covered, and one sentence about methodology (search). Add clearer take-home messages and limitations.
- And, tone down or qualify any broad statements that are not fully supported by citations (e.g., “K48 and K63 are most likely targets for inhibitors” — rephrase to be mechanistic and cite evidence).
Please, provide at your convenience (1) a revised manuscript, (2) a point-by-point response to reviewers, (3) a marked-up manuscript and figures/tables showing changes, and (4) confirmation that English has been professionally edited.
**Language Note:** The Academic Editor has identified that the English language must be improved. PeerJ can provide language editing services - please contact us at [email protected] for pricing (be sure to provide your manuscript number and title). Alternatively, you should make your own arrangements to improve the language quality and provide details in your response letter. – PeerJ Staff
This is a useful review of UPS in lung cancer. Although quite descriptive in the first sections that describe the functions of the different USPs in lung cancer. The introduction could perhaps make a reference to other diseases where USP has a preeminent role.
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The development of USP inhibitors should be further developed. For example, the authors only mentioned the names of the USP7 inhibitors and not their functions. Additionally, the 1st two paragraphs only describe mechanisms of action/degradation of USPs, not the development of the USP inhibitors. I believe I reference to when and what was the first USP inhibitor developed is warranted, even if that was not for cancer.
Figure 3 should have the names of some of the compounds added to the USP number, to complete the narrative on the section about USP inhibitors.
Minor notes:
Line 20 ‘excellent treatment resistance' is not a commonly used expression; line 164: not clear whether the referred aptamer-siRNA nano-zinc carriers are USP14 inhibitors.
Line 183: in vitro or in vivo studies
Line 196: The authors are referring to the progression of cancer cells. Is this referring to invasion assays or migration assays done? This is not clear.
Line 200: typo
In this manuscript, the author Xiao Yun Shen et al. outline the molecular mechanisms and targeted options for USPs in lung cancer, as well as their prospective implications in precision medicine. The manuscript is well written and organized, and rich in content. Therefore, I would like to recommend its publication in PeerJ.
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This review covers an important area of protein biochemistry, enzymology, and human disease by focusing on a subset of the deubiquitinase (DUB) family (~100-120 members) members which are linked to roles in lung cancer development and progression. By focusing on this specific DUB subset, the authors make a compelling case for these enzymes as valid drug targets in this major disease condition.
However, the article suffers from a number of issues that have to be rectified - see detailed list below.
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The various issues that need to be addressed are listed as they arise in the manuscript rather than in order of importance.
1) The abstract is OK, but it needs more detail on exactly what is being discussed in the topic under review. Currently, this feels thin, needs to be at least 150 words in length.
2) Check Harvard format of references in text and endnotes carefully - many errors in referencing format are apparent. Use EndNote, Zotero, Mendeley, or Reference Manager.
3) Numerous grammatical errors, needs careful proofing of the English language and writing.
4) line 44. E2 ubiquitin-conjugating enzyme or UBC.
5) Work referenced in text should have this format.
He et al. OR He and colleagues indicated that.......
(He et al., 2021)
6) Figure legends lack clarity as to the exact figure titles and legends.
7) References for the table must be in the reference list at the end and referred to briefly in the main text.
This manuscript needs careful English language editing for grammar and structure to make this work better to read.
no comment
no comment
no comment
The authors discuss a group of important enzymes and their relation with lung cancer. The topic is of high interest. The review is relatively short and according to the comments below, it should be expanded. The language is acceptable.
Major comments:
1_ The manuscript section ‘development of USP inhibitors’ is very poor and does not cover a substantial spectrum of the reported USP inhibitors. In this sense, the review is highly deficient. The authors need to check with the scientific literature and apply substantial updating of their review on small molecules targeting the USP proteins.
2_ In figure 2 B the mechanism of cleavage shown is incorrect. The cysteine attacks the isopeptide bond of ubiquitin. The authors need to correct the figure and discuss the mechanism of catalysis in more detail at a relevant paragraph in the text.
3_ In several cases, a multitude of information is conveyed to the reader, but the respective references to external studies are very limited. I bring as an example the targets of USP10 (lines 132-135) where at least one reference for each discussed target is needed. Similar issues may be found at other parts of the manuscript, where there are important statements which are not supported by any related references, essentially compromising the main aim of a regular review article (i.e. lines 81-86, 99-101, 119-122, 221-229.
Minor comments:
1_ The abstract is poor and needs extension and conceptual enhancement. The parentheses are not needed. The term ‘targeted options’ needs clarification. The authors need to explain how ‘precision medicine’ is involved in the specific context.
2_ The section 'Survey methodology' needs rephrasing and reconsideration of the text in lines 74-78.
3_ The abbreviations need be explained throughout the text. Is K48 in line 245 a Lysine 48 residue?
4_ Chemical structures are needed for every small molecule inhibitor discussed in section ‘Development of USP inhibitors’.
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