{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:42:41Z","timestamp":1785436961226,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"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":["32090034"],"award-info":[{"award-number":["32090034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32090034"],"award-info":[{"award-number":["32090034"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hangzhou City Leading Innovation and Entrepreneurship Team","award":["TD2020004"],"award-info":[{"award-number":["TD2020004"]}]},{"name":"\u201cPioneer\u201d and \u201cLeading Goose\u201d R&D Program of Zhejiang","award":["2024SSYS0033"],"award-info":[{"award-number":["2024SSYS0033"]}]},{"DOI":"10.13039\/100032572","name":"Westlake Education Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100032572","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Westlake Laboratory of Life Sciences and Biomedicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While altered lipid metabolism is a hallmark of cancer, specific phospholipid dependencies remain poorly defined. Here, we identify phosphatidylserine synthase 1 (PTDSS1) as a targetable metabolic vulnerability in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Pharmacological inhibition of PTDSS1 selectively and potently suppresses tumor growth both in vitro and in vivo. Mechanistically, PTDSS1 blockade triggers a rapid collapse of cellular phosphatidylserine (PS) and phosphatidylethanolamine (PE) pools, fundamentally disrupting endoplasmic reticulum (ER) homeostasis. This targeted lipid depletion activates a PERK-mediated autophagic response that ultimately yields to apoptosis. Clinically, pan-cancer transcriptomic analysis links elevated PTDSS1 expression to reduced overall survival across diverse malignancies. Collectively, we establish PTDSS1 as an essential maintainer of ER integrity and highlight PS biosynthesis as a viable therapeutic target for exploiting tumor-specific metabolic dependencies.<\/jats:p>","DOI":"10.3390\/ijms27146226","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:53:58Z","timestamp":1783932838000},"page":"6226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Phosphatidylserine Synthesis for Tumor Cell Suppression in Esophageal Squamous Cell Carcinoma and Glioblastoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1303-9353","authenticated-orcid":false,"given":"Yixuan","family":"Hu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqi","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeqiong","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duo","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Gene Expression, School of Life Sciences, Westlake University, Hangzhou 310030, China"},{"name":"Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.devcel.2021.04.013","article-title":"Lipid metabolism in cancer: New perspectives and emerging mechanisms","volume":"56","author":"Broadfield","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41416-019-0650-z","article-title":"Reprogramming of fatty acid metabolism in cancer","volume":"122","author":"Koundouros","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.cmet.2019.08.013","article-title":"Mechanisms and Implications of Metabolic Heterogeneity in Cancer","volume":"30","author":"Kim","year":"2019","journal-title":"Cell Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/s12276-023-01020-1","article-title":"Metabolic reprogramming and epigenetic modifications in cancer: From the impacts and mechanisms to the treatment potential","volume":"55","author":"Xu","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Stoica, C., Ferreira, A.K., Hannan, K., and Bakovic, M. (2022). Bilayer Forming Phospholipids as Targets for Cancer Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095266"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1158\/0008-5472.CAN-23-2491","article-title":"ACSL4-Mediated Membrane Phospholipid Remodeling Induces Integrin \u03b21 Activation to Facilitate Triple-Negative Breast Cancer Metastasis","volume":"84","author":"Qiu","year":"2024","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"118095","DOI":"10.1016\/j.biopha.2025.118095","article-title":"Lipid metabolism in cancer: Exploring phospholipids as potential biomarkers","volume":"187","author":"Delmas","year":"2025","journal-title":"BioMed Pharmacother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cmet.2019.11.010","article-title":"Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer","volume":"31","author":"Snaebjornsson","year":"2020","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s43018-023-00702-z","article-title":"Lipids as mediators of cancer progression and metastasis","volume":"5","author":"Vogel","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.biophys.093008.131234","article-title":"The distribution and function of phosphatidylserine in cellular membranes","volume":"39","author":"Leventis","year":"2010","journal-title":"Annu Rev. Biophys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng.2829","article-title":"Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome","volume":"46","author":"Sousa","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e009468","DOI":"10.1136\/jitc-2024-009468","article-title":"Phosphatidylserine as a tumor target for CAR-T cell therapy","volume":"13","author":"Castro","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s12964-025-02090-6","article-title":"Dys-regulated phosphatidylserine externalization as a cell intrinsic immune escape mechanism in cancer","volume":"23","author":"Pulica","year":"2025","journal-title":"Cell Commun. Signal"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/ITT.S134834","article-title":"Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer","volume":"7","author":"Belzile","year":"2018","journal-title":"Immunotargets Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.semcancer.2017.08.012","article-title":"Phosphatidylserine: A cancer cell targeting biomarker","volume":"52","author":"Sharma","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/s41586-026-10266-4","article-title":"Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion","volume":"653","author":"Medina","year":"2026","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1126\/science.1411571","article-title":"Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C","volume":"258","author":"Nishizuka","year":"1992","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.bbalip.2006.03.006","article-title":"Phosphatidic acid- and phosphatidylserine-binding proteins","volume":"1761","author":"Stace","year":"2006","journal-title":"Biochim Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2501177122","DOI":"10.1073\/pnas.2501177122","article-title":"Molecular insights into human phosphatidylserine synthase 2 and its regulation of SREBP pathways","volume":"122","author":"Li","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5665","DOI":"10.1016\/j.cell.2024.08.004","article-title":"Molecular insights into human phosphatidylserine synthase 1 reveal its inhibition promotes LDL uptake","volume":"187","author":"Long","year":"2024","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1042\/BJ20081597","article-title":"Purification and characterization of human phosphatidylserine synthases 1 and 2","volume":"418","author":"Tomohiro","year":"2009","journal-title":"Biochem J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19133","DOI":"10.1074\/jbc.272.31.19133","article-title":"Cloning of a Chinese hamster ovary (CHO) cDNA encoding phosphatidylserine synthase (PSS) II, overexpression of which suppresses the phosphatidylserine biosynthetic defect of a PSS I-lacking mutant of CHO-K1 cells","volume":"272","author":"Kuge","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12888","DOI":"10.1074\/jbc.M800714200","article-title":"Defining the importance of phosphatidylserine synthase-1 (PSS1): Unexpected viability of PSS1-deficient mice","volume":"283","author":"Arikketh","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4031","DOI":"10.1158\/0008-5472.CAN-22-1006","article-title":"Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion","volume":"82","author":"Yoshihama","year":"2022","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e202212074","DOI":"10.1083\/jcb.202212074","article-title":"Phosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma","volume":"223","author":"Omi","year":"2024","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12967-022-03311-z","article-title":"Untargeted metabolomics analysis of esophageal squamous cell cancer progression","volume":"20","author":"Yang","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.nut.2014.10.014","article-title":"Phosphatidylserine and the human brain","volume":"31","author":"Glade","year":"2015","journal-title":"Nutrition"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded protein response: Controlling cell fate decisions under ER stress and beyond","volume":"13","author":"Hetz","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"Ron","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5851","DOI":"10.1073\/pnas.0911617107","article-title":"Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control","volume":"107","author":"Han","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1091\/mbc.e11-12-0995","article-title":"Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells","volume":"23","author":"Lajoie","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/j.1600-0854.2009.00903.x","article-title":"Lipid-induced ER stress: Synergistic effects of sterols and saturated fatty acids","volume":"10","author":"Pineau","year":"2009","journal-title":"Traffic"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbamem.2017.04.006","article-title":"The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease","volume":"1859","author":"Kennelly","year":"2017","journal-title":"Biochim Biophys. Acta Biomembr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.molcel.2012.08.016","article-title":"The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network","volume":"48","author":"Thibault","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1073\/pnas.95.8.4199","article-title":"Control of phosphatidylserine biosynthesis through phosphatidylserine-mediated inhibition of phosphatidylserine synthase I in Chinese hamster ovary cells","volume":"95","author":"Kuge","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"(2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455, 1061\u20131068.","DOI":"10.1038\/nature07385"},{"key":"ref_38","unstructured":"(2013). The Genotype-Tissue Expression (GTEx) project. Nat. Genet., 45, 580\u2013585."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1158\/1078-0432.CCR-10-2724","article-title":"Global gene expression profiling and validation in esophageal squamous cell carcinoma and its association with clinical phenotypes","volume":"17","author":"Su","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1016\/j.cell.2025.03.026","article-title":"Precision proteogenomics reveals pan-cancer impact of germline variants","volume":"188","author":"Terekhanova","year":"2025","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6226\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:16:45Z","timestamp":1784089005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146226"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146226","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}