-->PONE-D-25-43608-->-->LAMP2A-dependent chaperone-mediated autophagy enhances oxidative stress resistance in gastric cancer cells through selective degradation of accumulated oxidized DJ-1-->-->PLOS ONE

Dear Dr. pang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please find attached the detailed comments from the reviewers. We kindly ask you to carefully address each point raised in your revision. When submitting the revised manuscript, please also provide a point-by-point response to the reviewers’ comments, outlining the changes made or explaining your reasoning if any suggestions were not incorporated.

==============================

Please submit your revised manuscript by Nov 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Zu Ye, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that your Data Availability Statement is currently as follows: [All relevant data are within the manuscript and its Supporting Information files.]

Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition)

For example, authors should submit the following data:

- The values behind the means, standard deviations and other measures reported;

- The values used to build graphs;

- The points extracted from images for analysis.

Authors do not need to submit their entire data set if only a portion of the data was used in the reported study.

If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories.

If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access.

3. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels.

In your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. Email us at plosone@plos.org if you have any questions.

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Partly

Reviewer #4: Partly

**********

-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

Reviewer #4: Yes

**********

-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The manuscript examines the role of chaperone-mediated autophagy (CMA) in gastric cancer under conditions of oxidative stress. The authors demonstrate that LAMP2A, the rate-limiting component of CMA, is upregulated in gastric cancer tissues and further induced upon exposure to H₂O₂. Knockdown of LAMP2A sensitises gastric cancer cells to apoptosis triggered by oxidative stress, whereas its overexpression promotes cell survival. They propose that CMA selectively degrades hyperoxidised DJ-1, thereby maintaining redox homeostasis and protecting tumour cells. The study concludes that the interaction between LAMP2A and DJ-1 represents a key mechanism conferring resistance to oxidative stress in gastric cancer cells.

Major comments:

1. The central claim that hyperoxidised DJ-1 is a CMA substrate is not fully substantiated; the oxidation status of DJ-1 was inferred indirectly and not directly measured (for example, using specific antibodies, redox-sensitive mutants, or mass spectrometry).

2. Rescue experiments are lacking. Demonstrating that shRNA-resistant LAMP2A can reverse the observed phenotypes would considerably strengthen the conclusions.

3. Controls using antioxidants (e.g., NAC, GSH donors) are not included, making it unclear whether the observed effects are truly ROS-dependent.

4. The authors equate LAMP2A knockdown with CMA inhibition, but more direct assessment of CMA activity is necessary (for example, KFERQ reporter assays or lysosomal uptake assays).

Minor comments:

1. The manuscript would benefit from language editing to reduce repetition and improve clarity.

2. Figure legends lack methodological details such as number of replicates and statistical tests. Quantification of western blot bands should also be included.

3. Justification for selecting 150 µM and 300 µM H₂O₂ concentrations is required, as toxicity may vary across cell lines.

4. Negative controls in co-IP and immunofluorescence experiments should be clearly described (for example, IgG controls, secondary-only staining).

5. Some references are outdated; inclusion of recent studies on CMA and DJ-1 in cancer would strengthen the background.

6. The data availability statement (“not publicly available due to privacy of laboratory content”) is inconsistent with PLOS ONE’s open data policy and must be corrected.

Reviewer #2: The manuscript by Shuangshuang Le and co-workers describes the role of LAMP2A in gastric cancer under oxidative stress condition. The topic is interesting; however, some points should be clarified.

1) The overexpression of LAMP2A in gastric cancer has been demonstrated in the reference 14 (Zhou J et al., 2016). Authors should clarify the novelty of their results shown in Figure 1 compared to the previous published data.

2) Authors declare that LAMP2A knockdown inhibit CMA activity in their experimental model. To support this conclusion, authors should analyse additional CMA markers such as the expression of Hsc70 on lysosomes.

3) Authors should better describe the results of Figure 4C and D. Dot plots show that in both downregulated and overexpressed LAMP conditions, the number of double-positive cells increase compared to the control suggesting that both conditions enhance the percentage of dying cells under oxidative stress. How can these data be explained?

Reviewer #3: DJ-1 (PARK7) is known to protect cells against oxidative stress and is a target for degradation by chaperone-mediated autophagy (CMA). In the present manuscript, the authors examined the involvement of DJ-1 (PARK7) in LAMP2A-mediated oxidative stress resistance in gastric cancer cells. The authors demonstrated that both LAMP2A and DJ-1 were upregulated in gastric cancer cells and H2O2-induced oxidative stress further increased their levels. LAMP2A and DJ-1 interacted with each other, and DJ-1 contains a conserved KFERQ-like motif, suggesting DJ-1 is a substrate for CMA. However, inhibition of CMA by LAMP2A knockdown caused an increase in DJ-1 which was associated with a decrease in the antiapoptotic protein Bcl2 and an increase in the pro-apoptotic protein BAX. The authors proposed that oxidative-stressed induced clearance of hyperoxidized DJ-1 is responsible for gastric cancer cell survival.

The results are straightforward but requires additional study to substantiate their conclusion.

Comments:

1. While the results show that an increase in DJ-1 by LAMP2A alters the ratio of pro- and anti-apoptotic proteins, no evidence has been provided to support that there are two forms of DJ-1 and the hyperoxidized form of DJ-1 promotes apoptosis. Does the extent of LAMP2A knockdown affects the outcome?

2. At least 2 different LAMP2A shRNA should be used in all experiments.

3. In Fig. 1, the protein level of MKN28 is more than AGS but in Fig. 2, H2O2 had no effect on LAMP2A expression in MKN28 cells but caused a substantial increase in AGS cells. In Fig 1C and 1D, NKM28 should be MKN28.

4. Fig. 4D: LAMP2A KD increased apoptosis and decreased cell proliferation in MKN45 cells in response to H2O2. While LAMP2A overexpression in AGS cells attenuated early apoptotic cells following H2O2 treatment, the late apoptotic and/or necrotic cells were increased with little change in the healthy cells (B3). What is the effect of LAMP2A overexpression on cell proliferation?

5. Fig. 5A: DJ-1 is increased to a similar extent in AGS, MKN45 and MKN28 cells.

6. Fig. 6: What is the effect of LAMP2A overexpression on DJ-1 level and apoptosis?

7. Discussion, Pg. 15, 2nd para: The sentence “Tumor microenvironment….CMA activity” should be corrected.

8. Pg. 16, 2nd para: DJ-1 is not a new antioxidant molecule, and it is also not a recently discovered molecule. In fact, Ref. 33 published in 2004 is focused on DJ-1. Is the antioxidant function of DJ-1 recently discovered?

9. Pg. 17, 1st para: The sentence “Given DJ-1's established cytoprotective properties through redox homeostasis maintenance and apoptosis inhibition” is incomplete.

10. Pg. 18: It was mentioned that “CMA may regulate neuronal mitochondrial homeostasis by degrading oxidatively damaged DJ-1 protein, as demonstrated in a recent study [34].” Is an alteration in mitochondrial homeostasis caused by the degradation of oxidatively damaged DJ-1 responsible for its effects on pro- and anti-apoptotic proteins? Ref 34 was published almost 10 years ago and not recently.

Reviewer #4: In the current manuscript the authors have examined the role of DJ-1 and LMAP2 mediated autophagy in gastric cancer cells. Authors have reported the significance of DJ-1 and LAMP2 interaction in promotion of gastric carcinoma. The overall manuscript is well written. However, authors need to address the following concerns:

1. LAMP2-DJ1 interaction is not convincing. The arrangement of IP blot is confusing. The IF image is of very poor quality. More over LAMP2 protein is localized in the lysosomal or late endosomal membrane not in the nucleus where most of the DJ1 is localized after H2O2 treatment.

2. To further confirm the LAMp2 and DJ1 localization authors need to perform PLA or other similar kind of assay.

3. Since the protein expression level varies among different cell types, it is not ideal to compare the only LAMP2 expression in Fig 1D. To establish the higher expression, authors need to include other autophagy related proteins too.

4. H2O2 at higher dose can activate various signaling pathways, therefore authors need to repeat the main experiments in presence of another inducer and perform the rescue experiment with NAC.

5. After LAMP2 over expression, the DJ1 protein level needs to be examined.

6. The Fig 1A, the histology of the cancer samples are completely different than the control. the authors need to provide more information about the patient sample collection procedure.

7. There is no text in under section 3.7.

8. 150 uM of H2O2 is quite high and after 5 days of treatment there is not much significant difference in cell proliferation in figure 4A &B which is confusing.

**********

-->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: Dipankar Ash

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

-->PONE-D-25-43608R1-->-->LAMP2A-dependent chaperone-mediated autophagy enhances oxidative stress resistance in gastric cancer cells through selective degradation of accumulated oxidized DJ-1-->-->PLOS One

Dear Dr. pang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Feb 13 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Zu Ye, Ph.D.

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

Reviewer #5: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #5: Partly

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #5: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #3: (No Response)

Reviewer #5: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #5: No

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: (No Response)

Reviewer #3: The authors addressed the reviewer’s comment. However, they should clarify which shRNAs against LAMP2A were used. Based on Figure 3B, LV-shL2A-2 caused maximum knockdown. While the authors did not indicate which LV-sh-L2A was used in Fig. 4 and Fig. 6, it is likely that LV-shL2A-2 was used since other clones did not cause complete knockdown. While the authors indicated that they used a second independent shRNA in supplementary Fig.2A, B and C to rule out off-target effects but according to Fig.S2 A, B and C, they repeated the experiment with the same clone and that’s why the results are very similar. They should clearly specify which shRNA was used and how the levels of shRNA affected the results. In addition, they should perform the experiments with 2 distinct shRNAs.

Reviewer #5: In this study, the authors investigated the role of chaperone-mediated autophagy (CMA) in regulating oxidative stress responses in gastric cancer. The authors showed that LAMP2A, a key mediator of CMA, is upregulated in gastric cancer cell lines and clinical samples and is further induced under oxidative stress conditions. Functional experiments demonstrated that LAMP2A downregulation impaired CMA activity, increased sensitivity to oxidative stress, and promoted apoptosis, whereas LAMP2A overexpression conferred cytoprotective effects. The authors identified DJ-1 as a novel CMA substrate and showed that oxidative stress enhances LAMP2A–DJ-1 colocalization. Mechanistically, CMA inhibition led to the accumulation of hyperoxidized DJ-1, accompanied by increased pro-apoptotic BAX and decreased anti-apoptotic BCL-2 expression. Overall, the authors propose that the LAMP2A–DJ-1 axis constitutes a key adaptive mechanism that maintains redox homeostasis and supports gastric cancer cell survival under oxidative stress.

Comments:

- The abstract would benefit from improved narrative flow. Currently, it reads as a list of experimental steps rather than a cohesive summary. Methodological details (e.g., specific assays used) can be reduced in favor of emphasizing key findings and conclusions.

- Revise the introduction to improve grammar and flow. Redundant or closely related sentences should be merged for clarity (e.g., the definition of oxidative stress and ROS accumulation).

- Improve sentence flow and use clearer transitions when introducing CMA and the role of LAMP2A (e.g., “CMA requires lysosomal-associated membrane protein 2A (LAMP2A) for substrate translocation”).

- Revise awkward or overly long sentences for clarity. For example, the sentence describing LAMP2A downregulation in HCC should be restructured to improve readability and logical flow.

- Correct grammatical errors such as the missing verb in the sentence:

“Consistent with previous reports [14], we confirmed that LAMP2A shows consistently higher expression across gastric adenocarcinoma tissues and cell lines.”

- The statement implying that elevated LAMP2A levels directly indicate enhanced CMA activity is not sufficiently supported by the data. Please revise to a more cautious interpretation (e.g., “may indicate increased CMA activity”).

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #3: No

Reviewer #5: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

-->PONE-D-25-43608R2-->-->LAMP2A-dependent chaperone-mediated autophagy enhances oxidative stress resistance in gastric cancer cells through selective degradation of accumulated oxidized DJ-1-->-->PLOS One

Dear Dr. pang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I am writing to bring to your attention a discrepancy between several of the blot images in Figure 6 and the raw images you provided. Specifically, the molecular sizes shown in Figure 6A do not appear to align with the ladders in the original blot images for Bcl-2 and DJ-1.

To proceed with the editorial process, it is essential that the raw data are consistent with the data presented in the manuscript. I would like to request that you review and check the figure accordingly.

Please submit your revised manuscript by May 20 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Zu Ye, Ph.D.

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #5: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #5: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #5: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #5: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: (No Response)

Reviewer #5: All comments were addressed, the readability was improved and additional experiments were performed.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #5: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

LAMP2A-dependent chaperone-mediated autophagy enhances oxidative stress resistance in gastric cancer cells through selective degradation of accumulated oxidized DJ-1

PONE-D-25-43608R3

Dear Dr. Pang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Zu Ye, Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: