{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:40:36Z","timestamp":1787582436526,"version":"build-2736575974"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":69,"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":["82472708"],"award-info":[{"award-number":["82472708"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302981"],"award-info":[{"award-number":["82302981"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372649"],"award-info":[{"award-number":["82372649"]}],"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>\n                    Aberrant phosphatidylinositol 3-kinase (PI3K) activation drives many cancers, but PI3K inhibitors like Pictilisib often induce cytostasis rather than cytotoxicity, limiting their therapeutic potential. Here we demonstrate that PI3K inhibition combined with nutrient stress triggers methuosis, a non-apoptotic form of programmed cell death characterized by dysregulated macropinosomes. This response occurs selectively in PI3K-aberrant cancer cells that maintain macropinocytic uptake despite PI3K inhibition. Methuosis-associated vacuoles originate from macropinosomes that retain endosomal markers but fail to undergo lysosomal fusion. Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the AKT inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than AKT signaling, is required. Mechanistically, PI3K blockade prevents conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P\n                    <jats:sub>2<\/jats:sub>\n                    ) to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P\n                    <jats:sub>3<\/jats:sub>\n                    ) causing PI(4,5)P\n                    <jats:sub>2<\/jats:sub>\n                    to accumulate on internalizing macropinosomal membranes. This aberrant PI(4,5)P\n                    <jats:sub>2<\/jats:sub>\n                    enrichment impairs ion channel function across multiple channel families, disrupting intracellular osmotic balance. Ion dysregulation triggers aquaporin-1-mediated water influx, driving catastrophic vacuolar expansion and cell death. Although Pictilisib activates pro-survival autophagy, this fails to prevent methuosis-mediated cytotoxicity. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P\n                    <jats:sub>2<\/jats:sub>\n                    -dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted cancer efficacy.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08994-6","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T05:04:52Z","timestamp":1781586292000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pictilisib and nutrient stress synergize to induce methuosis via PI(4,5)P2-dependent macropinocytic dysregulation in cancer cells"],"prefix":"10.1038","volume":"17","author":[{"given":"Xuefei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8154-2853","authenticated-orcid":false,"given":"Xiaolin","family":"Sang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuemei","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingming","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiezheng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xining","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6016-9516","authenticated-orcid":false,"given":"Xiuling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4394-4274","authenticated-orcid":false,"given":"Xinmiao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4094-8245","authenticated-orcid":false,"given":"Pixu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5618-8709","authenticated-orcid":false,"given":"Hailing","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"8994_CR1","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","volume":"170","author":"DA Fruman","year":"2017","unstructured":"Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605\u201335.","journal-title":"Cell"},{"key":"8994_CR2","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nrd2926","volume":"8","author":"P Liu","year":"2009","unstructured":"Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627\u201344.","journal-title":"Nat Rev Drug Discov"},{"key":"8994_CR3","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/s43018-021-00218-4","volume":"2","author":"P Castel","year":"2021","unstructured":"Castel P, Toska E, Engelman JA, Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer. 2021;2:587\u201397.","journal-title":"Nat Cancer"},{"key":"8994_CR4","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1158\/2159-8290.CD-18-1175","volume":"9","author":"AB Hanker","year":"2019","unstructured":"Hanker AB, Kaklamani V, Arteaga CL. Challenges for the clinical development of pi3k inhibitors: strategies to improve their impact in solid tumors. Cancer Discov. 2019;9:482\u201391.","journal-title":"Cancer Discov"},{"key":"8994_CR5","doi-asserted-by":"publisher","first-page":"406","DOI":"10.2478\/jtim-2024-0025","volume":"12","author":"M Ke","year":"2024","unstructured":"Ke M, Zhu H, Lin Y, Zhang Y, Tang T, Xie Y, et al. Actin-related protein 2\/3 complex subunit 1B promotes ovarian cancer progression by regulating the AKT\/PI3K\/mTOR signaling pathway. J Transl Intern Med. 2024;12:406\u201323.","journal-title":"J Transl Intern Med"},{"key":"8994_CR6","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/s41573-021-00209-1","volume":"20","author":"B Vanhaesebroeck","year":"2021","unstructured":"Vanhaesebroeck B, Perry MWD, Brown JR, Andre F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20:741\u201369.","journal-title":"Nat Rev Drug Discov"},{"key":"8994_CR7","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1093\/annonc\/mdw320","volume":"27","author":"P Vuylsteke","year":"2016","unstructured":"Vuylsteke P, Huizing M, Petrakova K, Roylance R, Laing R, Chan S, et al. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann Oncol. 2016;27:2059\u201366.","journal-title":"Ann Oncol"},{"key":"8994_CR8","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1200\/JCO.2015.63.9179","volume":"34","author":"P Schmid","year":"2016","unstructured":"Schmid P, Pinder SE, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II randomized preoperative window-of-opportunity study of the pi3k inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2016;34:1987\u201394.","journal-title":"J Clin Oncol"},{"key":"8994_CR9","doi-asserted-by":"crossref","unstructured":"Zwang Y, Jonas O, Chen C, Rinne ML, Doench JG, Piccioni F, et al. Synergistic interactions with PI3K inhibition that induce apoptosis. Elife. 2017;6:e24523.","DOI":"10.7554\/eLife.24523"},{"key":"8994_CR10","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1038\/s41573-023-00749-8","volume":"22","author":"K Hadian","year":"2023","unstructured":"Hadian K, Stockwell BR. The therapeutic potential of targeting regulated non-apoptotic cell death. Nat Rev Drug Discov. 2023;22:723\u201342.","journal-title":"Nat Rev Drug Discov"},{"key":"8994_CR11","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","volume":"29","author":"D Tang","year":"2019","unstructured":"Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29:347\u201364.","journal-title":"Cell Res"},{"key":"8994_CR12","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1158\/2159-8290.CD-20-0789","volume":"11","author":"E Koren","year":"2021","unstructured":"Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11:245\u201365.","journal-title":"Cancer Discov"},{"key":"8994_CR13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1515\/jtim-2025-0004","volume":"13","author":"Z Guo","year":"2025","unstructured":"Guo Z, Liu Y, Chen D, Sun Y, Li D, Meng Y, et al. Targeting regulated cell death: apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis in anticancer immunity. J Transl Intern Med. 2025;13:10\u201332.","journal-title":"J Transl Intern Med"},{"key":"8994_CR14","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.trecan.2021.09.004","volume":"8","author":"J Puccini","year":"2022","unstructured":"Puccini J, Badgley MA, Bar-Sagi D. Exploiting cancer\u2019s drinking problem: regulation and therapeutic potential of macropinocytosis. Trends Cancer. 2022;8:54\u201364.","journal-title":"Trends Cancer"},{"key":"8994_CR15","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1158\/1541-7786.MCR-07-2036","volume":"6","author":"JH Overmeyer","year":"2008","unstructured":"Overmeyer JH, Kaul A, Johnson EE, Maltese WA. Active ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Mol Cancer Res. 2008;6:965\u201377.","journal-title":"Mol Cancer Res"},{"key":"8994_CR16","doi-asserted-by":"crossref","unstructured":"Tang D, Wang J, Kroemer G, Kang R. Targeting macropinocytosis for cancer therapy. Nat Rev Cancer. 2025;26:167\u2013184.","DOI":"10.1038\/s41568-025-00892-x"},{"key":"8994_CR17","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/icb.2011.20","volume":"89","author":"JP Lim","year":"2011","unstructured":"Lim JP, Gleeson PA. Macropinocytosis: an endocytic pathway for internalising large gulps. Immunol Cell Biol. 2011;89:836\u201343.","journal-title":"Immunol Cell Biol"},{"key":"8994_CR18","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrm2447","volume":"9","author":"JA Swanson","year":"2008","unstructured":"Swanson JA. Shaping cups into phagosomes and macropinosomes. Nat Rev Mol Cell Biol. 2008;9:639\u201349.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8994_CR19","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41568-018-0048-x","volume":"18","author":"BT Finicle","year":"2018","unstructured":"Finicle BT, Jayashankar V, Edinger AL. Nutrient scavenging in cancer. Nat Rev Cancer. 2018;18:619\u201333.","journal-title":"Nat Rev Cancer"},{"key":"8994_CR20","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adq7305","volume":"10","author":"G Cognet","year":"2024","unstructured":"Cognet G, Muir A. Identifying metabolic limitations in the tumor microenvironment. Sci Adv. 2024;10:eadq7305.","journal-title":"Sci Adv"},{"key":"8994_CR21","doi-asserted-by":"crossref","unstructured":"Chen L, Huang M. Oncometabolites in cancer: from cancer cells to the tumor microenvironment. Holist Integr Oncol. 2024;3:26.","DOI":"10.1007\/s44178-024-00096-7"},{"key":"8994_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-54788-9","volume":"15","author":"G Lambies","year":"2024","unstructured":"Lambies G, Lee SW, Duong-Polk K, Aza-Blanc P, Maganti S, Galapate CM, et al. Cell polarity proteins promote macropinocytosis in response to metabolic stress. Nat Commun. 2024;15:10541.","journal-title":"Nat Commun"},{"key":"8994_CR23","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1016\/j.ccell.2025.06.021","volume":"43","author":"Y Zhang","year":"2025","unstructured":"Zhang Y, Ling L, Murad R, Maganti S, Manceau A, Hetrick HA, et al. Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer. Cancer Cell. 2025;43:1677\u201396.e1615.","journal-title":"Cancer Cell"},{"key":"8994_CR24","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.ccell.2021.02.016","volume":"39","author":"H Su","year":"2021","unstructured":"Su H, Yang F, Fu R, Li X, French R, Mose E, et al. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell. 2021;39:678\u201393.e611.","journal-title":"Cancer Cell"},{"key":"8994_CR25","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/nprot.2014.004","volume":"9","author":"C Commisso","year":"2014","unstructured":"Commisso C, Flinn RJ, Bar-Sagi D. Determining the macropinocytic index of cells through a quantitative image-based assay. Nat Protoc. 2014;9:182\u201392.","journal-title":"Nat Protoc"},{"key":"8994_CR26","first-page":"100141","volume":"2","author":"T Wu","year":"2021","unstructured":"Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation. 2021;2:100141.","journal-title":"Innovation"},{"key":"8994_CR27","doi-asserted-by":"publisher","first-page":"3335","DOI":"10.1038\/s41388-024-03173-3","volume":"43","author":"X Sang","year":"2024","unstructured":"Sang X, Han J, Wang Z, Cai W, Liao X, Kong Z, et al. SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways. Oncogene. 2024;43:3335\u201347.","journal-title":"Oncogene"},{"key":"8994_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1366\/10-06095","volume":"65","author":"A Chaurra","year":"2011","unstructured":"Chaurra A, Gutzman BM, Taylor E, Ackroyd PC, Christensen KA. Lucifer Yellow as a live cell fluorescent probe for imaging water transport in subcellular organelles. Appl Spectrosc. 2011;65:20\u201325.","journal-title":"Appl Spectrosc"},{"key":"8994_CR29","doi-asserted-by":"publisher","first-page":"17707","DOI":"10.1016\/S0021-9258(19)47429-2","volume":"266","author":"T Yoshimori","year":"1991","unstructured":"Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem. 1991;266:17707\u201312.","journal-title":"J Biol Chem"},{"key":"8994_CR30","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-019-1831-x","volume":"576","author":"C Ramirez","year":"2019","unstructured":"Ramirez C, Hauser AD, Vucic EA, Bar-Sagi D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. Nature. 2019;576:477\u201381.","journal-title":"Nature"},{"key":"8994_CR31","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-1-59745-178-9_2","volume":"440","author":"AI Ivanov","year":"2008","unstructured":"Ivanov AI. Pharmacological inhibition of endocytic pathways: is it specific enough to be useful? Methods Mol Biol. 2008;440:15\u201333.","journal-title":"Methods Mol Biol"},{"key":"8994_CR32","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/nrc1692","volume":"5","author":"Y Kondo","year":"2005","unstructured":"Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5:726\u201334.","journal-title":"Nat Rev Cancer"},{"key":"8994_CR33","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","volume":"140","author":"N Mizushima","year":"2010","unstructured":"Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313\u201326.","journal-title":"Cell"},{"key":"8994_CR34","doi-asserted-by":"publisher","first-page":"28726","DOI":"10.1074\/jbc.A114.627778","volume":"290","author":"KJ Petherick","year":"2015","unstructured":"Petherick KJ, Conway OJ, Mpamhanga C, Osborne SA, Kamal A, Saxty B, et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J Biol Chem. 2015;290:28726.","journal-title":"J Biol Chem"},{"key":"8994_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51400-y","volume":"15","author":"W Ko","year":"2024","unstructured":"Ko W, Lee E, Kim JE, Lim HH, Suh BC. The plasma membrane inner leaflet PI(4,5)P(2) is essential for the activation of proton-activated chloride channels. Nat Commun. 2024;15:7008.","journal-title":"Nat Commun"},{"key":"8994_CR36","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1146\/annurev.biophys.37.032807.125859","volume":"37","author":"BC Suh","year":"2008","unstructured":"Suh BC, Hille B. PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys. 2008;37:175\u201395.","journal-title":"Annu Rev Biophys"},{"key":"8994_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102035","volume":"298","author":"KD Gada","year":"2022","unstructured":"Gada KD, Logothetis DE. PKC regulation of ion channels: the involvement of PIP(2). J Biol Chem. 2022;298:102035.","journal-title":"J Biol Chem"},{"key":"8994_CR38","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1083\/jcb.200103107","volume":"154","author":"FD Brown","year":"2001","unstructured":"Brown FD, Rozelle AL, Yin HL, Balla T, Donaldson JG. Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic. J Cell Biol. 2001;154:1007\u201317.","journal-title":"J Cell Biol"},{"key":"8994_CR39","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1124\/mol.63.5.1043","volume":"63","author":"YS Bae","year":"2003","unstructured":"Bae YS, Lee TG, Park JC, Hur JH, Kim Y, Heo K, et al. Identification of a compound that directly stimulates phospholipase C activity. Mol Pharm. 2003;63:1043\u201350.","journal-title":"Mol Pharm"},{"key":"8994_CR40","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.651982","volume":"9","author":"M Ritter","year":"2021","unstructured":"Ritter M, Bresgen N, Kerschbaum HH. From pinocytosis to methuosis-fluid consumption as a risk factor for cell death. Front Cell Dev Biol. 2021;9:651982.","journal-title":"Front Cell Dev Biol"},{"key":"8994_CR41","doi-asserted-by":"publisher","first-page":"4408","DOI":"10.1021\/acsnano.8b00196","volume":"12","author":"C Zhang","year":"2018","unstructured":"Zhang C, Zhang A, Hou W, Li T, Wang K, Zhang Q, et al. Mimicking pathogenic invasion with the complexes of Au(22)(SG)(18)-engineered assemblies and folic acid. ACS Nano. 2018;12:4408\u201318.","journal-title":"ACS Nano"},{"key":"8994_CR42","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.trecan.2019.04.002","volume":"5","author":"Y Zhang","year":"2019","unstructured":"Zhang Y, Commisso C. Macropinocytosis in cancer: a complex signaling network. Trends Cancer. 2019;5:332\u20134.","journal-title":"Trends Cancer"},{"key":"8994_CR43","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1158\/1541-7786.MCR-10-0090","volume":"8","author":"H Bhanot","year":"2010","unstructured":"Bhanot H, Young AM, Overmeyer JH, Maltese WA. Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Mol Cancer Res. 2010;8:1358\u201374.","journal-title":"Mol Cancer Res"},{"key":"8994_CR44","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.216049","volume":"555","author":"L Wang","year":"2023","unstructured":"Wang L, Mi D, Hu J, Liu W, Zhang Y, Wang C, et al. A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer. Cancer Lett. 2023;555:216049.","journal-title":"Cancer Lett"},{"key":"8994_CR45","doi-asserted-by":"publisher","first-page":"24583","DOI":"10.1073\/pnas.1911393116","volume":"116","author":"RK Srivastava","year":"2019","unstructured":"Srivastava RK, Li C, Khan J, Banerjee NS, Chow LT, Athar M. Combined mTORC1\/mTORC2 inhibition blocks growth and induces catastrophic macropinocytosis in cancer cells. Proc Natl Acad Sci USA. 2019;116:24583\u201392.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8994_CR46","doi-asserted-by":"publisher","first-page":"7618","DOI":"10.1073\/pnas.0307512101","volume":"101","author":"Y Gao","year":"2004","unstructured":"Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA. 2004;101:7618\u201323.","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08994-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08994-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08994-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:02:56Z","timestamp":1787580176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08994-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8994"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08994-6","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"assertion":[{"value":"10 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2026","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","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The animal study was approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Wenzhou Medical University (WYYY-IACUC-AEC-2025-029). All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"752"}}