{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:10Z","timestamp":1787029210003,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82271085"],"award-info":[{"award-number":["82271085"]}]},{"name":"National Natural Science Foundation of China","award":["82171055"],"award-info":[{"award-number":["82171055"]}]},{"name":"National Natural Science Foundation of China","award":["24J12800200"],"award-info":[{"award-number":["24J12800200"]}]},{"name":"National Natural Science Foundation of China","award":["23XHYD-28"],"award-info":[{"award-number":["23XHYD-28"]}]},{"name":"National Natural Science Foundation of China","award":["32230047"],"award-info":[{"award-number":["32230047"]}]},{"name":"National Natural Science Foundation of China","award":["2023YFA1801100"],"award-info":[{"award-number":["2023YFA1801100"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["82271085"],"award-info":[{"award-number":["82271085"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["82171055"],"award-info":[{"award-number":["82171055"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["24J12800200"],"award-info":[{"award-number":["24J12800200"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["23XHYD-28"],"award-info":[{"award-number":["23XHYD-28"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["32230047"],"award-info":[{"award-number":["32230047"]}]},{"name":"Program of Shanghai Municipal Commission of Science and Technology","award":["2023YFA1801100"],"award-info":[{"award-number":["2023YFA1801100"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["82271085"],"award-info":[{"award-number":["82271085"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["82171055"],"award-info":[{"award-number":["82171055"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["24J12800200"],"award-info":[{"award-number":["24J12800200"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["23XHYD-28"],"award-info":[{"award-number":["23XHYD-28"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["32230047"],"award-info":[{"award-number":["32230047"]}]},{"name":"Xuhui Hospital and regional cooperation project","award":["2023YFA1801100"],"award-info":[{"award-number":["2023YFA1801100"]}]},{"name":"National Natural Science Foundation of China","award":["82271085"],"award-info":[{"award-number":["82271085"]}]},{"name":"National Natural Science Foundation of China","award":["82171055"],"award-info":[{"award-number":["82171055"]}]},{"name":"National Natural Science Foundation of China","award":["24J12800200"],"award-info":[{"award-number":["24J12800200"]}]},{"name":"National Natural Science Foundation of China","award":["23XHYD-28"],"award-info":[{"award-number":["23XHYD-28"]}]},{"name":"National Natural Science Foundation of China","award":["32230047"],"award-info":[{"award-number":["32230047"]}]},{"name":"National Natural Science Foundation of China","award":["2023YFA1801100"],"award-info":[{"award-number":["2023YFA1801100"]}]},{"name":"National Key Research and Development Program of China","award":["82271085"],"award-info":[{"award-number":["82271085"]}]},{"name":"National Key Research and Development Program of China","award":["82171055"],"award-info":[{"award-number":["82171055"]}]},{"name":"National Key Research and Development Program of China","award":["24J12800200"],"award-info":[{"award-number":["24J12800200"]}]},{"name":"National Key Research and Development Program of China","award":["23XHYD-28"],"award-info":[{"award-number":["23XHYD-28"]}]},{"name":"National Key Research and Development Program of China","award":["32230047"],"award-info":[{"award-number":["32230047"]}]},{"name":"National Key Research and Development Program of China","award":["2023YFA1801100"],"award-info":[{"award-number":["2023YFA1801100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Metabolic stress from amino acid (AA) insufficiency is increasingly linked to pathological angiogenesis, but specific essential AA (EAA) roles remain undefined. Neovascular age-related macular degeneration (AMD), a major cause of blindness driven by aberrant ocular neovascularization, has limited efficacy with current VEGFA-targeting therapies. We sought to identify specific EAAs that regulate pathological angiogenesis and dissect their mechanisms to propose new therapeutic strategies. Methods: Human retinal microvascular endothelial cells (HRMVECs) were used to identify angiogenesis-regulating amino acids through systematic EAA screening. The molecular mechanism was investigated using shRNA-mediated knockdown of key stress response regulators (HRI, PKR, PERK, GCN2) and ATF4. Angiogenesis was assessed via tubule formation and migration assays. Therapeutic potential was examined in a laser-induced choroidal neovascularization (CNV) mouse model, evaluated by fluorescein angiography and histomorphometry. Results: Deprivation of methionine, lysine, and threonine potently induced capillary-like tube formation (p &lt; 0.01). Mechanistically, restriction of these three EAAs activated HRI and GCN2 kinases, converging on eIF2\u03b1 phosphorylation to induce ATF4 and its target VEGFA. Dual, but not single, knockdown of HRI and GCN2 abolished eIF2\u03b1-ATF4 signaling and angiogenic responses. Restricting these EAAs exacerbated CNV area in mice. Conclusions: Our findings reveal a coordinated HRI\/GCN2-ATF4-VEGFA axis linking EAA scarcity to vascular remodeling, establishing proof-of-concept for targeting this pathway in CNV. This work highlights the therapeutic potential of modulating specific AA availability or targeting the HRI\/GCN2-ATF4 axis to treat CNV.<\/jats:p>","DOI":"10.3390\/nu17183006","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T16:53:42Z","timestamp":1758300822000},"page":"3006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Amino Acids That Regulate Angiogenesis and Alter Pathogenesis of a Mouse Model of Choroidal Neovascularization"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5627-7752","authenticated-orcid":false,"given":"Chenchen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Opthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Opthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingke","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Opthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0075-8616","authenticated-orcid":false,"given":"Jing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-0693","authenticated-orcid":false,"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-5757","authenticated-orcid":false,"given":"Jihong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Opthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai 200031, China"},{"name":"Key Laboratory of Myopia and Related Eye Diseases, NHC, Shanghai 200031, China"},{"name":"Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e27774","DOI":"10.1097\/MD.0000000000027774","article-title":"Ranibizumab and conbercept for treating wet age-related macular degeneration in China: A systematic review and meta-analysis","volume":"100","author":"Jiang","year":"2021","journal-title":"Medicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1001\/jama.2023.26074","article-title":"Age-Related Macular Degeneration: A Review","volume":"331","author":"Fleckenstein","year":"2024","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zych, M., Wojnar, W., Dudek, S., and Kaczmarczyk-Sedlak, I. (2019). Rosmarinic and Sinapic Acids May Increase the Content of Reduced Glutathione in the Lenses of Estrogen-Deficient Rats. Nutrients, 11.","DOI":"10.3390\/nu11040803"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ascunce, K., Dhodapkar, R.M., Huang, D., and Hafler, B.P. (2023). Innate immune biology in age-related macular degeneration. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1118524"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41586-020-2078-2","article-title":"Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway","volume":"579","author":"Guo","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41421-021-00332-8","article-title":"Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis","volume":"7","author":"Zhang","year":"2021","journal-title":"Cell Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cell.2018.03.001","article-title":"Amino Acid Restriction Triggers Angiogenesis via GCN2\/ATF4 Regulation of VEGF and H(2)S Production","volume":"173","author":"Longchamp","year":"2018","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1158\/1538-7445.AM2020-688","article-title":"Abstract 688: Targeting tumor associated host cells by modifiers of integrated endoplasmic reticulum stress response","volume":"80","author":"Upcin","year":"2020","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4413","DOI":"10.1038\/s41388-018-0227-y","article-title":"HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells","volume":"37","author":"White","year":"2018","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1177\/1120672119840245","article-title":"Complement factor B gene polymorphisms and risk of age-related macular degeneration: A meta-analysis","volume":"30","author":"Su","year":"2020","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.celrep.2016.06.044","article-title":"Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2","volume":"16","author":"Laeger","year":"2016","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1038\/s41467-024-48134-2","article-title":"FOXC1 regulates endothelial CD98 (LAT1\/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation","volume":"15","author":"Bhakuni","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41586-020-2076-4","article-title":"A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol","volume":"579","author":"Fessler","year":"2020","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: From mechanism to disease","volume":"368","author":"Walter","year":"2020","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.ophtha.2019.11.010","article-title":"Anti-Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration: Systematic Literature Review and Expert Opinion","volume":"127","author":"Sadda","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2314095","DOI":"10.1002\/adma.202314095","article-title":"Emerging Co-Assembled and Sustained Released Natural Medicinal Nanoparticles for Multitarget Therapy of Choroidal Neovascularization","volume":"36","author":"Shen","year":"2024","journal-title":"Adv. Mater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e70378","DOI":"10.1096\/fj.202402041R","article-title":"Dietary intake of whale oil-containing omega-3 long-chain polyunsaturated fatty acids attenuates choroidal neovascularization in mice","volume":"39","author":"Yanai","year":"2025","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sahye-Pudaruth, S., and Ma, D.W.L. (2023). Assessing the Highest Level of Evidence from Randomized Controlled Trials in Omega-3 Research. Nutrients, 15.","DOI":"10.3390\/nu15041001"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45506","DOI":"10.18632\/oncotarget.17221","article-title":"Anti-complement component 5 antibody targeting MG4 domain inhibits choroidal neovascularization","volume":"8","author":"Jo","year":"2017","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1167\/iovs.61.8.30","article-title":"The Binding of CD93 to Multimerin-2 Promotes Choroidal Neovascularization","volume":"61","author":"Tosi","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.15252\/embj.201695518","article-title":"Role of glutamine and interlinked asparagine metabolism in vessel formation","volume":"36","author":"Huang","year":"2017","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.15252\/embj.201796436","article-title":"Glutamine fuels proliferation but not migration of endothelial cells","volume":"36","author":"Kim","year":"2017","journal-title":"EMBO J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s12276-020-0375-3","article-title":"Amino acids in cancer","volume":"52","author":"Lieu","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sarf, E.A., Dyachenko, E.I., and Bel\u2019skaya, L.V. (2024). The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer. Biomedicines, 12.","DOI":"10.3390\/biomedicines12061329"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Guo, D., Murdoch, C.E., Xu, H., Shi, H., Duan, D.D., Ahmed, A., and Gu, Y. (2017). Vascular endothelial growth factor signaling requires glycine to promote angiogenesis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-15246-3"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s42255-022-00584-y","article-title":"A YAP\/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth","volume":"4","author":"Ong","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Li, M., Wu, Y., and Ye, L. (2022). The Role of Amino Acids in Endothelial Biology and Function. Cells, 11.","DOI":"10.3390\/cells11081372"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e21612","DOI":"10.1096\/fj.202100233R","article-title":"Activating transcription factor 4 regulates angiogenesis under lipid overload via methionine adenosyltransferase 2A-mediated endothelial epigenetic alteration","volume":"35","author":"Chen","year":"2021","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wunderle, C., Haller, L., Laager, R., Bernasconi, L., Neyer, P., Stumpf, F., Tribolet, P., Stanga, Z., Mueller, B., and Schuetz, P. (2024). The Association of the Essential Amino Acids Lysine, Methionine, and Threonine with Clinical Outcomes in Patients at Nutritional Risk: Secondary Analysis of a Randomized Clinical Trial. Nutrients, 16.","DOI":"10.3390\/nu16162608"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1007\/s12672-024-01467-2","article-title":"Mechanism of CXCL8 regulation of methionine metabolism to promote angiogenesis in gliomas","volume":"15","author":"Chang","year":"2024","journal-title":"Discov. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1093\/jn\/nxaa396","article-title":"Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex","volume":"151","author":"Jonsson","year":"2021","journal-title":"J. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/s41467-022-28599-9","article-title":"ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1","volume":"13","author":"Statzer","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, R.H., Chu, Y.H., and Lin, K.T. (2021). The Hidden Role of Hydrogen Sulfide Metabolism in Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126562"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/febs.14359","article-title":"Regulation of tumor-stroma interactions by the unfolded protein response","volume":"286","author":"Obacz","year":"2019","journal-title":"FEBS J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cherubini, A., and Zito, E. (2022). ER stress as a trigger of UPR and ER-phagy in cancer growth and spread. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.997235"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1038\/s41388-021-01659-y","article-title":"The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions","volume":"40","author":"Varone","year":"2021","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"256","DOI":"10.4049\/immunohorizons.2200064","article-title":"How the Unfolded Protein Response Is a Boon for Tumors and a Bane for the Immune System","volume":"7","author":"Raines","year":"2023","journal-title":"Immunohorizons"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"200184","DOI":"10.1183\/16000617.0184-2020","article-title":"The integrated stress response in pulmonary disease","volume":"29","author":"Emanuelli","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20230796","DOI":"10.1515\/med-2023-0796","article-title":"Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1\/XBP1 and PERK\/eIF2alpha\/ATF4 signaling pathways","volume":"18","author":"Wang","year":"2023","journal-title":"Open Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrc.2017.51","article-title":"Microenvironmental regulation of tumour angiogenesis","volume":"17","author":"Biziato","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1158\/1078-0432.CCR-19-1985","article-title":"Impact of Prior Bevacizumab Treatment on VEGF-A and PlGF Levels and Outcome Following Second-Line Aflibercept Treatment: Biomarker Post Hoc Analysis of the VELOUR Trial","volume":"26","author":"Paccard","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/s41392-023-01570-w","article-title":"Endoplasmic reticulum stress: Molecular mechanism and therapeutic targets","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.celrep.2017.04.042","article-title":"mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4","volume":"19","author":"Park","year":"2017","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8053","DOI":"10.1039\/D4FO01613K","article-title":"High methionine intake alters gut microbiota and lipid profile and leads to liver steatosis in mice","volume":"15","author":"Zhou","year":"2024","journal-title":"Food Funct."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7832","DOI":"10.1038\/s41467-023-43550-2","article-title":"Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila","volume":"14","author":"Kosakamoto","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"loaf009","DOI":"10.1093\/lifemeta\/loaf009","article-title":"Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass","volume":"4","author":"Xin","year":"2025","journal-title":"Life Metab."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Darawshi, O., Yassin, O., Shmuel, M., Wek, R.C., Mahdizadeh, S.J., Eriksson, L.A., Hatzoglou, M., and Tirosh, B. (2024). Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107575"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1042\/BCJ20220531","article-title":"Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2\u03b1 phosphorylation","volume":"481","author":"Shanmugam","year":"2024","journal-title":"Biochem. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1016\/j.molcel.2023.08.004","article-title":"Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response","volume":"83","author":"Swanda","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sekine, Y., Houston, R., Fessler, E., Jae, L.T., Narendra, D.P., and Sekine, S. (2022). A mitochondrial iron-sensing pathway regulated by DELE1. bioRxiv.","DOI":"10.1101\/2022.04.14.488327"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/18\/3006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:15Z","timestamp":1760035575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/18\/3006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":52,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["nu17183006"],"URL":"https:\/\/doi.org\/10.3390\/nu17183006","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]}}}