{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T18:12:16Z","timestamp":1778868736224,"version":"3.51.4"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016308","name":"Wuxi Health and Family Planning Commission","doi-asserted-by":"publisher","award":["Q202559"],"award-info":[{"award-number":["Q202559"]}],"id":[{"id":"10.13039\/501100016308","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008109","name":"Wuxi Municipal Bureau on Science and Technology","doi-asserted-by":"publisher","award":["K20252010"],"award-info":[{"award-number":["K20252010"]}],"id":[{"id":"10.13039\/501100008109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Chaperone-mediated autophagy (CMA) promotes cancer cell survival by selectively removing oxidatively damaged proteins, yet its precise molecular mechanisms and role in redox adaptation remain incompletely understood. This study aimed to elucidate the function of CMA in regulating oxidative stress resistance in gastric cancer (GC) cells, focusing on the LAMP2A\u2013DJ-1 regulatory axis. LAMP2A expression was assessed in GC tissues and cell lines via immunohistochemistry, qPCR, and western blot. Oxidative stress models were established using hydrogen peroxide (H\u2082O\u2082). Genetic manipulation of LAMP2A was performed to evaluate its impact on cell proliferation, apoptosis, and CMA substrate recognition. Protein interactions were examined by co-immunoprecipitation and immunofluorescence. We found that LAMP2A was upregulated in GC and further induced by oxidative stress. Knockdown of LAMP2A impaired CMA activity, sensitizing GC cells to H\u2082O\u2082-induced apoptosis. DJ-1, an antioxidant protein, was identified as a CMA substrate containing a conserved KFERQ-like motif. Oxidative stress enhanced DJ-1\u2013LAMP2A interaction and promoted their lysosomal colocalization. LAMP2A deficiency led to accumulation of hyperoxidized DJ-1, concomitant with upregulation of pro-apoptotic BAX and downregulation of anti-apoptotic Bcl-2. We identify hyperoxidized DJ-1 as a novel CMA substrate and demonstrate that LAMP2A-dependent clearance of oxidized DJ-1 constitutes a key adaptive mechanism that maintains redox homeostasis and promotes survival in gastric cancer cells under oxidative stress.<\/jats:p>","DOI":"10.1371\/journal.pone.0331823","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:36:19Z","timestamp":1778866579000},"page":"e0331823","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["LAMP2A-dependent chaperone-mediated autophagy enhances oxidative stress resistance in gastric cancer cells through selective degradation of accumulated oxidized DJ-1"],"prefix":"10.1371","volume":"21","author":[{"given":"Shuangshuang","family":"Le","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongtong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianjuan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1192-2655","authenticated-orcid":true,"given":"Maogui","family":"Pang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"issue":"6","key":"pone.0331823.ref001","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"F Bray","year":"2018","journal-title":"CA: A Cancer Journal for Clinicians"},{"issue":"1","key":"pone.0331823.ref002","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13045-023-01451-3","article-title":"Gastric cancer treatment: recent progress and future perspectives","volume":"16","author":"W-L Guan","year":"2023","journal-title":"J Hematol Oncol"},{"issue":"130","key":"pone.0331823.ref003","first-page":"1","article-title":"Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis","volume":"22","author":"Y Ren","year":"2023","journal-title":"Molecular Cancer"},{"issue":"11","key":"pone.0331823.ref004","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1039\/D2CS00172A","article-title":"Recent progress in the development of fluorescent probes for imaging pathological oxidative stress","volume":"52","author":"Y Geng","year":"2023","journal-title":"Chem Soc Rev"},{"key":"pone.0331823.ref005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.20892\/j.issn.2095-3941.2024.0182","article-title":"The role of reactive oxygen species in gastric cancer","author":"Y Wang","year":"2024","journal-title":"Cancer Biol Med"},{"issue":"8","key":"pone.0331823.ref006","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41580-023-00585-z","article-title":"Autophagy and autophagy-related pathways in cancer","volume":"24","author":"J Debnath","year":"2023","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pone.0331823.ref007","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abm1140","article-title":"LAMP2A regulates the loading of proteins into exosomes","volume":"8","author":"JV Ferreira","year":"2022","journal-title":"Science Advances"},{"issue":"6","key":"pone.0331823.ref008","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.4103\/1673-5374.385848","article-title":"Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases","volume":"19","author":"Q Jia","year":"2024","journal-title":"Neural Regen Res"},{"issue":"5","key":"pone.0331823.ref009","article-title":"Chaperone-mediated autophagy: Molecular mechanisms, biological functions, and diseases","volume":"4","author":"R Yao","year":"2023","journal-title":"MedComm (2020)"},{"issue":"1","key":"pone.0331823.ref010","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1080\/15548627.2022.2063004","article-title":"Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells","volume":"19","author":"E Desideri","year":"2023","journal-title":"Autophagy"},{"issue":"6","key":"pone.0331823.ref011","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1007\/s12264-022-00818-9","article-title":"Chaperone-mediated Autophagy Regulates Cell Growth by Targeting SMAD3 in Glioma","volume":"38","author":"H Liu","year":"2022","journal-title":"Neurosci Bull"},{"issue":"10","key":"pone.0331823.ref012","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1111\/bph.16165","article-title":"Discovery of a potent inhibitor of chaperone-mediated autophagy that targets the HSC70-LAMP2A interaction in non-small cell lung cancer cells","volume":"182","author":"R-F Dong","year":"2025","journal-title":"Br J Pharmacol"},{"issue":"11","key":"pone.0331823.ref013","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.4161\/auto.21654","article-title":"LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy","volume":"8","author":"T Saha","year":"2012","journal-title":"Autophagy"},{"issue":"3","key":"pone.0331823.ref014","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1080\/15548627.2015.1136770","article-title":"Chaperone-mediated autophagy regulates proliferation by targeting RND3 in gastric cancer","volume":"12","author":"J Zhou","year":"2016","journal-title":"Autophagy"},{"issue":"12","key":"pone.0331823.ref015","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1080\/15548627.2022.2069450","article-title":"Intrinsic role of chaperone-mediated autophagy in cancer stem cell maintenance","volume":"18","author":"J Auzmendi-Iriarte","year":"2022","journal-title":"Autophagy"},{"issue":"7","key":"pone.0331823.ref016","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents","volume":"21","author":"H Sies","year":"2020","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"11","key":"pone.0331823.ref017","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.3390\/cells8111315","article-title":"Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma","volume":"8","author":"A Lo Dico","year":"2019","journal-title":"Cells"},{"issue":"19","key":"pone.0331823.ref018","article-title":"Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex","volume":"122","author":"BK Dash","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0331823.ref019","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.3390\/biomedicines11072050","article-title":"The Complex Role of Chaperone-Mediated Autophagy in Cancer Diseases","volume":"11","author":"J Liu","year":"2023","journal-title":"Biomedicines"},{"issue":"7","key":"pone.0331823.ref020","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.tcb.2023.11.005","article-title":"Lysosomal microautophagy: an emerging dimension in mammalian autophagy","volume":"34","author":"Y Kuchitsu","year":"2024","journal-title":"Trends Cell Biol"},{"issue":"8","key":"pone.0331823.ref021","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1080\/15548627.2021.1935007","article-title":"Chaperone-mediated autophagy: a gatekeeper of neuronal proteostasis","volume":"17","author":"M Bourdenx","year":"2021","journal-title":"Autophagy"},{"key":"pone.0331823.ref022","doi-asserted-by":"crossref","first-page":"15330338221114178","DOI":"10.1177\/15330338221114178","article-title":"The Antioxidative Role of Chaperone-Mediated Autophagy as a Downstream Regulator of Oxidative Stress in Human Diseases","volume":"21","author":"S Le","year":"2022","journal-title":"Technol Cancer Res Treat"},{"issue":"11","key":"pone.0331823.ref023","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1080\/15548627.2023.2235196","article-title":"LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles","volume":"19","author":"L Qiao","year":"2023","journal-title":"Autophagy"},{"issue":"5604","key":"pone.0331823.ref024","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1077209","article-title":"Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism","volume":"299","author":"V Bonifati","year":"2003","journal-title":"Science"},{"key":"pone.0331823.ref025","doi-asserted-by":"crossref","first-page":"296","DOI":"10.3390\/cells13040296","article-title":"Pathogenesis of DJ-1\/PARK7-Mediated Parkinson\u2019s Disease","volume":"13","author":"LD Skou","year":"2024","journal-title":"Cells"},{"key":"pone.0331823.ref026","doi-asserted-by":"crossref","first-page":"116944","DOI":"10.1016\/j.jep.2023.116944","article-title":"Celastrus orbiculatus Thunb. extract targeting DJ-1 inhibits non-small cell lung cancer invasion and metastasis through mitochondrial-induced ROS accumulation","volume":"318","author":"X Ni","year":"2024","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pone.0331823.ref027","first-page":"113","article-title":"Ciclopirox Olamine Induces Proliferation Inhibition and Protective Autophagy in Hepatocellular Carcinoma","volume":"12","author":"X Wan","year":"2023","journal-title":"Pharm"},{"issue":"6","key":"pone.0331823.ref028","first-page":"2046","article-title":"Silencing of DJ-1 reduces proliferation, invasion, and migration of papillary thyroid cancer cells in vitro, probably by increase of PTEN expression","volume":"12","author":"K Qiu","year":"2019","journal-title":"Int J Clin Exp Pathol"},{"key":"pone.0331823.ref029","doi-asserted-by":"crossref","first-page":"153186","DOI":"10.1016\/j.phymed.2020.153186","article-title":"Rosmarinic acid exerts an anticancer effect on osteosarcoma cells by inhibiting DJ-1 via regulation of the PTEN-PI3K-Akt signaling pathway","volume":"68","author":"Z Ma","year":"2020","journal-title":"Phytomedicine"},{"issue":"11","key":"pone.0331823.ref030","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/abbs\/gmaa110","article-title":"DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN\/PI3K\/Akt\/Nrf2 pathway","volume":"52","author":"L Qiu","year":"2020","journal-title":"Acta Biochim Biophys Sin"},{"issue":"4","key":"pone.0331823.ref031","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3892\/or.2024.8797","article-title":"DJ\u20111 is involved in the peritoneal metastasis of gastric cancer through activation of the Akt signaling pathway","volume":"52","author":"Z-M Zhu","year":"2024","journal-title":"Oncology Reports"},{"issue":"4","key":"pone.0331823.ref032","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jmb.2005.12.030","article-title":"The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein","volume":"356","author":"W Zhou","year":"2006","journal-title":"J Mol Biol"},{"issue":"16","key":"pone.0331823.ref033","doi-asserted-by":"crossref","first-page":"10816","DOI":"10.1074\/jbc.M509079200","article-title":"Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases","volume":"281","author":"J Choi","year":"2006","journal-title":"J Biol Chem"},{"issue":"10","key":"pone.0331823.ref034","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1089\/ars.2013.5446","article-title":"The Oxidation States of DJ-1 Dictate the Cell Fate in Response to Oxidative Stress Triggered by 4-HPR: Autophagy or Apoptosis?","volume":"21","author":"J Cao","year":"2014","journal-title":"Antioxidants & Redox Signaling"},{"issue":"8","key":"pone.0331823.ref035","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1080\/15548627.2016.1179401","article-title":"Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7","volume":"12","author":"B Wang","year":"2016","journal-title":"Autophagy"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331823","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:36:26Z","timestamp":1778866586000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331823"}},"subtitle":[],"editor":[{"given":"Zu","family":"Ye","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0331823","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}