When Rosuvastatin Meets Curcumin: Preclinical Insight into Novel Synergistic Combination

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this study, the authors seek to synthesize and assess existing preclinical data pertaining to the concomitant administration of curcumin and rosuvastatin, with a specific focus on their potential synergistic mechanisms. The research methodology is sound, and the introduction provides ample contextual background information. I would like to propose the following suggestions:

1. See the journal format; whether Figure 1 was produced by the Authors or reproduced from another reference.
2. In section 1.1, discuss Rosuvastatin’s (also a statin) 3 pleiotropic, antioxidant, and anti-inflammatory effects, sometimes mentioned as “Statins, on the other hand” (line 72), which suggests all of them, including Rosuvastatin. Please correct the statement. Need to confirm the statement.
3. In line 78, better to compare Rosuvastatin as well with Lovastatin.
4. Please add the MoA of Curcumin in Figure 2, as suggested in the figure legend. Also, Figure 2 could be separated into Figure 2 and Figure 3, and placed in each subsection 1.1 (MoA, Structure, and clinical use of Rosuvastatin) and 1.2 (MoA, Structure, and clinical use of curcumin).
5. Table 2 mentions chronological order, while reference 38 (2016) falls behind reference 37. Please correct the sequence.
6. It would be further recommended to separate the three in vitro and four in vivo studies in two separate tables for readers’ convenience.
7. As a review article, readers will be most benificial with Reprinted/adapted figures from the original report. For example, lines 318-323, PK profile figure reproduced from Zhou et al. [37] could be added here with the publisher's permission. A couple of other comparative observations are similar.
8. Since the manuscript does not contain any abbreviation list, it would be better to full ellaborate of each at its first appearance.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The topic is potentially interesting; however, the central premise of the manuscript is not adequately supported. Most included studies do not formally evaluate pharmacological synergy, and one of the seven studies is an analytical method-development paper rather than biological evidence. The available studies are few, heterogeneous, and largely derived from overlapping research groups, with no formal risk-of-bias assessment or robust interaction analysis. In addition, the reported pharmacokinetic interaction may represent a safety concern rather than a therapeutic advantage. Because these issues affect the core rationale, evidence synthesis, and conclusions of the review, they cannot be resolved through routine revision. I therefore recommend rejection.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript provides a comprehensive summary of the preclinical data on the combination of the discussed substances for potential use in the treatment of hyperlipidemia. In this sense, it is an interesting and useful overview and summary of the available information.

I am not convinced that this represents real “future pharmacology”; rather, it is an improvement on current pharmacology in the field of hyperlipidemia therapy. The future of pharmacotherapy for hyperlipidemia is more likely to lie in the field of biologics and therapies derived from them. In this regard, in my opinion, the article lacks at least a brief summary of emerging therapies, some of which are already clinically available (mAbs such as evolocumab and alicorumab, and SiRNA such as inclisiran), as well as an explanation of the position of a potential combination of rosuvastatin and curcumin in future pharmacotherapy for hyperlipidemia, preferably in the introduction.

In Fig. 2, it would be appropriate to depict the 4-fluorophenyl substituent in the same manner as the other aromatic rings.

Lines 131 through 136 discuss the antioxidant mechanism of curcumin; it would be appropriate to accompany this with a relevant structural scheme.

Furthermore, I would recommend being more cautious in the conclusions drawn from the literature review. Most of the cited studies use very high doses of curcumin (100–300 mg/kg) in animal experiments. This corresponds to doses of 7–21 g for a 70-kg human. Such doses are very difficult to imagine in clinical use, although, of course, the human body’s response may differ. Nevertheless, it would be appropriate to mention this in the conclusion as well.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf