{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:55:25Z","timestamp":1789678525385,"version":"4.0.1"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360543"],"award-info":[{"award-number":["82360543"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Currently, molecular targeted therapy remains a crucial approach to the treatment of NSCLC. However, the development of acquired drug resistance poses significant challenges for subsequent treatment. Identifying new therapeutic targets is of great significance for improving the prognosis of patients with NSCLC. Here, we verify synoviolin-1 (SYVN1) as a potential new therapeutic target for NSCLC. SYVN1 is highly expressed in NSCLC, and its upregulation is associated with poor prognosis. We show that the N-terminus (1\u2013290 aa) of SYVN1 directly interacts with the intracellular domain of the epidermal growth factor receptor (EGFR) and activates EGFR signaling, promoting NSCLC growth in vitro and in vivo. Specifically, SYVN1 facilitates Lys 63-linked ubiquitination of EGFR and inhibits proteasome-mediated EGFR degradation. Moreover, we found that SYVN1 inhibits EGFR endocytosis, thereby increasing the amount of EGFR on the cell membrane. Furthermore, we confirmed that LS-102, an enzyme activity inhibitor of SYVN1, inhibits cell proliferation induced by SYVN1. Significantly, LS-102 in combination with the EGFR-TKI AZD9291 exhibits strong inhibitory effects on NSCLC growth and reverses the resistance of NSCLC to AZD9291. Together, our study demonstrates that the SYVN1-EGFR axis plays a critical role in NSCLC development and suggests that targeting the SYVN1-EGFR axis to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.<\/jats:p>","DOI":"10.1038\/s41419-025-07978-2","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T19:20:08Z","timestamp":1756408808000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting the SYVN1-EGFR axis: a breakthrough strategy for TKI-resistant NSCLC"],"prefix":"10.1038","volume":"16","author":[{"given":"Xinsheng","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilai","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5835-2769","authenticated-orcid":false,"given":"Zhili","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5936-9259","authenticated-orcid":false,"given":"Jingjing","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"7978_CR1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1002\/cac2.12359","volume":"42","author":"P Chen","year":"2022","unstructured":"Chen P, Liu Y, Wen Y, Zhou C. Non-small cell lung cancer in China. Cancer Commun. 2022;42:937\u201370.","journal-title":"Cancer Commun"},{"key":"7978_CR2","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","volume":"398","author":"AA Thai","year":"2021","unstructured":"Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535\u201354.","journal-title":"Lancet"},{"key":"7978_CR3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1146\/annurev-pathol-011110-130206","volume":"6","author":"G da Cunha Santos","year":"2011","unstructured":"da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49\u201369.","journal-title":"Annu Rev Pathol"},{"key":"7978_CR4","doi-asserted-by":"publisher","first-page":"153","DOI":"10.7888\/juoeh.41.153","volume":"41","author":"K Yoneda","year":"2019","unstructured":"Yoneda K, Imanishi N, Ichiki Y, Tanaka F. Treatment of non-small cell lung cancer with EGFR-mutations. J UOEH. 2019;41:153\u201363.","journal-title":"J UOEH"},{"key":"7978_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2023.102664","volume":"122","author":"F Ciardiello","year":"2024","unstructured":"Ciardiello F, Hirsch FR, Pirker R, Felip E, Valencia C, Smit EF. The role of anti-EGFR therapies in EGFR-TKI-resistant advanced non-small cell lung cancer. Cancer Treat Rev. 2024;122:102664.","journal-title":"Cancer Treat Rev"},{"key":"7978_CR6","doi-asserted-by":"publisher","first-page":"i20","DOI":"10.1093\/annonc\/mdx704","volume":"29","author":"J Remon","year":"2018","unstructured":"Remon J, Steuer CE, Ramalingam SS, Felip E. Osimertinib and other third-generation EGFR TKI in EGFR-mutant NSCLC patients. Ann Oncol. 2018;29:i20\u2013i27.","journal-title":"Ann Oncol"},{"key":"7978_CR7","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S1470-2045(16)30033-X","volume":"17","author":"K Park","year":"2016","unstructured":"Park K, Tan EH, O\u2019Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577\u201389.","journal-title":"Lancet Oncol"},{"key":"7978_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0777-1","volume":"17","author":"SG Wu","year":"2018","unstructured":"Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17:38.","journal-title":"Mol Cancer"},{"key":"7978_CR9","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1073\/pnas.0709662105","volume":"105","author":"CH Yun","year":"2008","unstructured":"Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA. 2008;105:2070\u20135.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7978_CR10","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","volume":"121","author":"A Leonetti","year":"2019","unstructured":"Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725\u201337.","journal-title":"Br J Cancer"},{"key":"7978_CR11","doi-asserted-by":"publisher","first-page":"e121","DOI":"10.1016\/j.jtho.2016.05.019","volume":"11","author":"M Bersanelli","year":"2016","unstructured":"Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C, Squadrilli A, et al. L718Q Mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J Thorac Oncol. 2016;11:e121\u20133.","journal-title":"J Thorac Oncol"},{"key":"7978_CR12","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/nm.3854","volume":"21","author":"KS Thress","year":"2015","unstructured":"Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560\u20132.","journal-title":"Nat Med"},{"key":"7978_CR13","doi-asserted-by":"crossref","unstructured":"Amelia T, Kartasasmita RE, Ohwada T, Tjahjono DH. Structural insight and development of EGFR tyrosine kinase inhibitors. Molecules 2022;27:819.","DOI":"10.3390\/molecules27030819"},{"key":"7978_CR14","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1023\/A:1008209720526","volume":"8","author":"BR Voldborg","year":"1997","unstructured":"Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997;8:1197\u2013206.","journal-title":"Ann Oncol"},{"key":"7978_CR15","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.tcb.2013.11.002","volume":"24","author":"A Tomas","year":"2014","unstructured":"Tomas A, Futter CE, Eden ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 2014;24:26\u201334.","journal-title":"Trends Cell Biol"},{"key":"7978_CR16","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.molcel.2006.02.018","volume":"21","author":"F Huang","year":"2006","unstructured":"Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006;21:737\u201348.","journal-title":"Mol Cell"},{"key":"7978_CR17","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nrm3048","volume":"12","author":"R Avraham","year":"2011","unstructured":"Avraham R, Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol. 2011;12:104\u201317.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"7978_CR18","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1016\/j.molcel.2021.05.004","volume":"81","author":"MK Lemberg","year":"2021","unstructured":"Lemberg MK, Strisovsky K. Maintenance of organellar protein homeostasis by ER-associated degradation and related mechanisms. Mol Cell. 2021;81:2507\u201319.","journal-title":"Mol Cell"},{"key":"7978_CR19","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/nature23314","volume":"548","author":"S Schoebel","year":"2017","unstructured":"Schoebel S, Mi W, Stein A, Ovchinnikov S, Pavlovicz R, DiMaio F, et al. Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3. Nature. 2017;548:352\u20135.","journal-title":"Nature"},{"key":"7978_CR20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/ncprheum0699","volume":"4","author":"N Yagishita","year":"2008","unstructured":"Yagishita N, Yamasaki S, Nishioka K, Nakajima T. Synoviolin, protein folding and the maintenance of joint homeostasis. Nat Clin Pract Rheumatol. 2008;4:91\u20137.","journal-title":"Nat Clin Pract Rheumatol"},{"key":"7978_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102423","volume":"109","author":"Y Xu","year":"2020","unstructured":"Xu Y, Fang D. Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity. J Autoimmun. 2020;109:102423.","journal-title":"J Autoimmun"},{"key":"7978_CR22","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.tcb.2016.12.002","volume":"27","author":"L Qi","year":"2017","unstructured":"Qi L, Tsai B, Arvan P. New insights into the physiological role of endoplasmic reticulum-associated degradation. Trends Cell Biol. 2017;27:430\u201340.","journal-title":"Trends Cell Biol"},{"key":"7978_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-020-00679-7","volume":"19","author":"Y Fan","year":"2021","unstructured":"Fan Y, Wang J, Xu Y, Wang Y, Song T, Liang X, et al. Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression. Cell Commun Signal. 2021;19:18.","journal-title":"Cell Commun Signal"},{"key":"7978_CR24","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1002\/1878-0261.12856","volume":"15","author":"X Guo","year":"2021","unstructured":"Guo X, Wang A, Wang W, Wang Y, Chen H, Liu X, et al. HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple-negative breast cancer. Mol Oncol. 2021;15:642\u201356.","journal-title":"Mol Oncol"},{"key":"7978_CR25","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1080\/15384101.2023.2178102","volume":"22","author":"Y Wang","year":"2023","unstructured":"Wang Y, Wang S, Zhang W. HRD1 functions as a tumor suppressor in ovarian cancer by facilitating ubiquitination-dependent SLC7A11 degradation. Cell cycle. 2023;22:1116\u201326.","journal-title":"Cell cycle"},{"key":"7978_CR26","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.cellsig.2018.06.011","volume":"50","author":"L Liu","year":"2018","unstructured":"Liu L, Long H, Wu Y, Li H, Dong L, Zhong JL, et al. HRD1-mediated PTEN degradation promotes cell proliferation and hepatocellular carcinoma progression. Cell Signal. 2018;50:90\u20139.","journal-title":"Cell Signal"},{"key":"7978_CR27","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1007\/s13402-023-00811-y","volume":"46","author":"W Xie","year":"2023","unstructured":"Xie W, Shi L, Quan H, Xiao H, Chen J, Liu J, et al. SYVN1 ubiquitinates FoxO1 to induce \u03b2-catenin nuclear translocation, PD-L1-mediated metastasis, and immune evasion of hepatocellular carcinoma. Cell Oncol. 2023;46:1285\u201399.","journal-title":"Cell Oncol"},{"key":"7978_CR28","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1158\/1541-7786.MCR-23-0478","volume":"22","author":"H Sui","year":"2024","unstructured":"Sui H, Shi C, Yan Z, Chen J, Man L, Wang F. LRRC75A-AS1 drives the epithelial-mesenchymal transition in cervical cancer by binding IGF2BP1 and inhibiting SYVN1-mediated NLRP3 ubiquitination. Mol Cancer Res. 2024;22:1075\u201387.","journal-title":"Mol Cancer Res"},{"key":"7978_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11010-018-3447-0","volume":"454","author":"X Tan","year":"2019","unstructured":"Tan X, He X, Fan Z. Upregulation of HRD1 promotes cell migration and invasion in colon cancer. Mol Cell Biochem. 2019;454:1\u20139.","journal-title":"Mol Cell Biochem"},{"key":"7978_CR30","doi-asserted-by":"publisher","first-page":"3260","DOI":"10.1038\/s41388-023-02843-y","volume":"42","author":"B Che","year":"2023","unstructured":"Che B, Du Y, Yuan R, Xiao H, Zhang W, Shao J, et al. SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene. 2023;42:3260\u201373.","journal-title":"Oncogene"},{"key":"7978_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s13008-024-00121-1","volume":"19","author":"F Duan","year":"2024","unstructured":"Duan F, Kong F, Jiang T, Liu H. SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1. Cell Div. 2024;19:15.","journal-title":"Cell Div"},{"key":"7978_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.120620","volume":"301","author":"N Karamali","year":"2022","unstructured":"Karamali N, Ebrahimnezhad S, Khaleghi Moghadam R, Daneshfar N, Rezaiemanesh A. HRD1 in human malignant neoplasms: Molecular mechanisms and novel therapeutic strategy for cancer. Life Sci. 2022;301:120620.","journal-title":"Life Sci"},{"key":"7978_CR33","doi-asserted-by":"crossref","unstructured":"Liu L, Yu L, Zeng C, Long H, Duan G, Yin G, et al. E3 ubiquitin ligase hrd1 promotes lung tumorigenesis by promoting sirtuin 2 ubiquitination and degradation. Mol Cell Biol 2020; 40:e00257-19.","DOI":"10.1128\/MCB.00257-19"},{"key":"7978_CR34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104723","volume":"299","author":"C Zeng","year":"2023","unstructured":"Zeng C, Guo J, Wu J, Che T, Huang X, Liu H, et al. HRD1 promotes non-small cell lung carcinoma metastasis by blocking autophagy-mediated MIEN1 degradation. J Biol Chem. 2023;299:104723.","journal-title":"J Biol Chem"},{"key":"7978_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06208-x","volume":"14","author":"M Zhao","year":"2023","unstructured":"Zhao M, Huang C, Yang L, Pan B, Yang S, Chang J, et al. SYVN1-mediated ubiquitylation directs localization of MCT4 in the plasma membrane to promote the progression of lung adenocarcinoma. Cell Death Dis. 2023;14:666.","journal-title":"Cell Death Dis"},{"key":"7978_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2025.107603","volume":"212","author":"L Zhu","year":"2025","unstructured":"Zhu L, Liu YP, Yuan W, Sun BX, Huang YT, Zhao JK, et al. E3 ubiquitin ligase SYVN1 as a promising therapeutic target for diverse human diseases. Pharm Res. 2025;212:107603.","journal-title":"Pharm Res"},{"key":"7978_CR37","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.15252\/embj.201489897","volume":"34","author":"H Fujita","year":"2015","unstructured":"Fujita H, Yagishita N, Aratani S, Saito-Fujita T, Morota S, Yamano Y, et al. The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC-1\u03b2. Embo J. 2015;34:1042\u201355.","journal-title":"Embo J"},{"key":"7978_CR38","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.3892\/ijmm.2012.1129","volume":"30","author":"N Yagishita","year":"2012","unstructured":"Yagishita N, Aratani S, Leach C, Amano T, Yamano Y, Nakatani K, et al. RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis. Int J Mol Med. 2012;30:1281\u20136.","journal-title":"Int J Mol Med"},{"key":"7978_CR39","first-page":"5701","volume":"18","author":"H Fujita","year":"2018","unstructured":"Fujita H, Aratani S, Yagishita N, Nishioka K, Nakajima T. Identification of the inhibitory activity of walnut extract on the E3 ligase Syvn1. Mol Med Rep. 2018;18:5701\u20138.","journal-title":"Mol Med Rep"},{"key":"7978_CR40","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1111\/j.1600-0854.2008.00781.x","volume":"9","author":"DC Barral","year":"2008","unstructured":"Barral DC, Cavallari M, McCormick PJ, Garg S, Magee AI, Bonifacino JS, et al. CD1a and MHC class I follow a similar endocytic recycling pathway. Traffic. 2008;9:1446\u201357.","journal-title":"Traffic"},{"key":"7978_CR41","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1146\/annurev-biochem-032620-104421","volume":"91","author":"AD Cowan","year":"2022","unstructured":"Cowan AD, Ciulli A. Driving E3 ligase substrate specificity for targeted protein degradation: lessons from nature and the laboratory. Annu Rev Biochem. 2022;91:295\u2013319.","journal-title":"Annu Rev Biochem"},{"key":"7978_CR42","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.gene.2005.10.018","volume":"366","author":"N Normanno","year":"2006","unstructured":"Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366:2\u201316.","journal-title":"Gene"},{"key":"7978_CR43","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.cell.2007.11.013","volume":"131","author":"Y Yarden","year":"2007","unstructured":"Yarden Y, Shilo BZ. SnapShot: EGFR signaling pathway. Cell. 2007;131:1018.","journal-title":"Cell"},{"key":"7978_CR44","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1152\/physrev.00012.2016","volume":"97","author":"N Foot","year":"2017","unstructured":"Foot N, Henshall T, Kumar S. Ubiquitination and the regulation of membrane proteins. Physiol Rev. 2017;97:253\u201381.","journal-title":"Physiol Rev"},{"key":"7978_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2017.72","volume":"6","author":"T Avril","year":"2017","unstructured":"Avril T, Vaul\u00e9on E, Chevet E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis. 2017;6:e373.","journal-title":"Oncogenesis"},{"key":"7978_CR46","doi-asserted-by":"crossref","unstructured":"Khaled J, Kopsida M, Lennern\u00e4s H, Heindryckx F. Drug resistance and endoplasmic reticulum stress in hepatocellular carcinoma. Cells 2022;11:632.","DOI":"10.3390\/cells11040632"},{"key":"7978_CR47","doi-asserted-by":"publisher","first-page":"2413","DOI":"10.1093\/bioinformatics\/btx162","volume":"33","author":"A Ianevski","year":"2017","unstructured":"Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics. 2017;33:2413\u20135.","journal-title":"Bioinformatics"},{"key":"7978_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26222-x","volume":"12","author":"M Niu","year":"2021","unstructured":"Niu M, Xu J, Liu Y, Li Y, He T, Ding L, et al. FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth. Nat Commun. 2021;12:5919.","journal-title":"Nat Commun"},{"key":"7978_CR49","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1038\/nm.3739","volume":"20","author":"D Popovic","year":"2014","unstructured":"Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242\u201353.","journal-title":"Nat Med"},{"key":"7978_CR50","doi-asserted-by":"publisher","first-page":"9166","DOI":"10.1093\/nar\/gkad631","volume":"51","author":"L Qiu","year":"2023","unstructured":"Qiu L, Xu W, Lu X, Chen F, Chen Y, Tian Y, et al. The HDAC6-RNF168 axis regulates H2A\/H2A.X ubiquitination to enable double-strand break repair. Nucleic Acids Res. 2023;51:9166\u201382.","journal-title":"Nucleic Acids Res"},{"key":"7978_CR51","doi-asserted-by":"publisher","first-page":"781","DOI":"10.21873\/cgp.20232","volume":"17","author":"N Losuwannarak","year":"2020","unstructured":"Losuwannarak N, Roytrakul S, Chanvorachote P. Gigantol targets MYC for ubiquitin-proteasomal degradation and suppresses lung cancer cell growth. Cancer Genom Proteom. 2020;17:781\u201393.","journal-title":"Cancer Genom Proteom"},{"key":"7978_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27609-6","volume":"13","author":"L Wang","year":"2022","unstructured":"Wang L, Chen C, Song Z, Wang H, Ye M, Wang D, et al. EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nat Commun. 2022;13:12.","journal-title":"Nat Commun"},{"key":"7978_CR53","doi-asserted-by":"crossref","unstructured":"Farrell AS, Sears RC. MYC degradation. Cold Spring Harb Perspect Med. 2014;4:a014365 (2014).","DOI":"10.1101\/cshperspect.a014365"},{"key":"7978_CR54","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.canlet.2022.01.029","volume":"531","author":"TK Rimkus","year":"2022","unstructured":"Rimkus TK, Arrigo AB, Zhu D, Carpenter RL, Sirkisoon S, Doheny D, et al. NEDD4 degrades TUSC2 to promote glioblastoma progression. Cancer Lett. 2022;531:124\u201335.","journal-title":"Cancer Lett"},{"key":"7978_CR55","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s00432-017-2537-9","volume":"144","author":"Y Xiong","year":"2018","unstructured":"Xiong Y, Wang L, Wang S, Wang M, Zhao J, Zhang Z, et al. SIRT3 deacetylates and promotes degradation of P53 in PTEN-defective non-small cell lung cancer. J Cancer Res Clin Oncol. 2018;144:189\u201398.","journal-title":"J Cancer Res Clin Oncol"},{"key":"7978_CR56","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/1878-0261.12844","volume":"15","author":"R Deng","year":"2021","unstructured":"Deng R, Guo Y, Li L, He J, Qiang Z, Zhang H, et al. BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN. Mol Oncol. 2021;15:279\u201398.","journal-title":"Mol Oncol"},{"key":"7978_CR57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114533","volume":"239","author":"D Hong","year":"2022","unstructured":"Hong D, Zhou B, Zhang B, Ren H, Zhu L, Zheng G, et al. Recent advances in the development of EGFR degraders: PROTACs and LYTACs. Eur J Med Chem. 2022;239:114533.","journal-title":"Eur J Med Chem"},{"key":"7978_CR58","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1016\/j.yexcr.2008.07.029","volume":"315","author":"A Sorkin","year":"2009","unstructured":"Sorkin A, Goh LK. Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res. 2009;315:683\u201396.","journal-title":"Exp Cell Res"},{"key":"7978_CR59","doi-asserted-by":"crossref","unstructured":"De Nisco NJ, Casey AK, Kanchwala M, Lafrance AE, Coskun FS, Kinch LN, et al. Manipulation of IRE1-dependent MAPK signaling by a vibrio agonist-antagonist effector pair. mSystems 2021;6:e00872\u221220.","DOI":"10.1128\/mSystems.00872-20"},{"key":"7978_CR60","first-page":"715","volume":"45","author":"H Cai","year":"2020","unstructured":"Cai H, Han B, Hu Y, Zhao X, He Z, Chen X, et al. Metformin attenuates the D\u2011galactose\u2011induced aging process via the UPR through the AMPK\/ERK1\/2 signaling pathways. Int J Mol Med. 2020;45:715\u201330.","journal-title":"Int J Mol Med"},{"key":"7978_CR61","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/s42003-020-01378-2","volume":"3","author":"W Huang","year":"2020","unstructured":"Huang W, Liao CC, Han Y, Lv J, Lei M, Li Y, et al. Co-activation of Akt, Nrf2, and NF-\u03baB signals under UPR(ER) in torpid Myotis ricketti bats for survival. Commun Biol. 2020;3:658.","journal-title":"Commun Biol"},{"key":"7978_CR62","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.1962591","volume":"10","author":"C Fang","year":"2021","unstructured":"Fang C, Weng T, Hu S, Yuan Z, Xiong H, Huang B, et al. IFN-\u03b3-induced ER stress impairs autophagy and triggers apoptosis in lung cancer cells. Oncoimmunology. 2021;10:1962591.","journal-title":"Oncoimmunology"},{"key":"7978_CR63","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.mce.2015.11.005","volume":"422","author":"L Yu","year":"2016","unstructured":"Yu L, Andruska N, Zheng X, Shapiro DJ. Anticipatory activation of the unfolded protein response by epidermal growth factor is required for immediate early gene expression and cell proliferation. Mol Cell Endocrinol. 2016;422:31\u201341.","journal-title":"Mol Cell Endocrinol"},{"key":"7978_CR64","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1038\/s41388-020-1260-1","volume":"39","author":"F Ricciardiello","year":"2020","unstructured":"Ricciardiello F, Gang Y, Palorini R, Li Q, Giamp\u00e0 M, Zhao F, et al. Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation. Oncogene. 2020;39:4103\u201317.","journal-title":"Oncogene"},{"key":"7978_CR65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2303448120","volume":"120","author":"Z Liu","year":"2023","unstructured":"Liu Z, Liu G, Ha DP, Wang J, Xiong M, Lee AS. ER chaperone GRP78\/BiP translocates to the nucleus under stress and acts as a transcriptional regulator. Proc Natl Acad Sci USA. 2023;120:e2303448120.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7978_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09734-5","volume":"10","author":"J Bertran-Alamillo","year":"2019","unstructured":"Bertran-Alamillo J, Cattan V, Schoumacher M, Codony-Servat J, Gimenez-Capitan A, Cantero F, et al. AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy. Nat Commun. 2019;10:1812.","journal-title":"Nat Commun"},{"key":"7978_CR67","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/j.ccell.2021.07.006","volume":"39","author":"K Tanaka","year":"2021","unstructured":"Tanaka K, Yu HA, Yang S, Han S, Selcuklu SD, Kim K, et al. Targeting aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell. 2021;39:1245\u20131261.e1246.","journal-title":"Cancer Cell"},{"key":"7978_CR68","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.987882","volume":"13","author":"YJ Wu","year":"2022","unstructured":"Wu YJ, Li ZH, Li JY, Zhou Y, Wang RY, Chen XY, et al. Elucidation of the binding mechanism of astragaloside IV derivative with human serum albumin and its cardiotoxicity in zebrafish embryos. Front Pharm. 2022;13:987882.","journal-title":"Front Pharm"},{"key":"7978_CR69","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s13318-018-0515-5","volume":"44","author":"LS Qing","year":"2019","unstructured":"Qing LS, Chen TB, Sun WX, Chen L, Luo P, Zhang ZF, et al. Pharmacokinetics comparison, intestinal absorption and acute toxicity assessment of a novel water-soluble astragaloside IV derivative (astragalosidic acid, LS-102). Eur J Drug Metab Pharmacokinet. 2019;44:251\u20139.","journal-title":"Eur J Drug Metab Pharmacokinet"},{"key":"7978_CR70","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6577","volume":"5","author":"BK Garvalov","year":"2014","unstructured":"Garvalov BK, Foss F, Henze AT, Bethani I, Gr\u00e4f-H\u00f6chst S, Singh D, et al. PHD3 regulates EGFR internalization and signalling in tumours. Nat Commun. 2014;5:5577.","journal-title":"Nat Commun"},{"key":"7978_CR71","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/416451a","volume":"416","author":"S Polo","year":"2002","unstructured":"Polo S, Sigismund S, Faretta M, Guidi M, Capua MR, Bossi G, et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature. 2002;416:451\u20135.","journal-title":"Nature"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07978-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07978-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07978-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T21:55:37Z","timestamp":1757454937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07978-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7978"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07978-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]},"assertion":[{"value":"25 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and approved by the ethics committee of the First Affiliated Hospital of Nanchang University. The protocol for lung pathological tissue was also approved by the Institutional Review Board of the First Affiliated Hospital of Nanchang University [Approval No. (2023)CDYFYYLK(01-068) and (2024)CDYFYYLK(08-042)], and informed consent was obtained from the patients. The tissue microarray staining assay was approved by the Ethics Committee of Shanghai Outdo Biotech Company (Approval No. SHYJS-CP-2206002).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"655"}}