{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T03:42:27Z","timestamp":1769312547987,"version":"3.49.0"},"reference-count":64,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T00:00:00Z","timestamp":1745625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL131745"],"award-info":[{"award-number":["R01HL131745"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Merit Review I01 CX002350"],"award-info":[{"award-number":["Merit Review I01 CX002350"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Veterans Affairs","award":["R01HL131745"],"award-info":[{"award-number":["R01HL131745"]}]},{"name":"Department of Veterans Affairs","award":["Merit Review I01 CX002350"],"award-info":[{"award-number":["Merit Review I01 CX002350"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypercapnia, the elevation of CO2 in blood and tissue, is a risk factor for mortality in patients with severe lung disease and pulmonary infections. We previously showed that hypercapnia increases viral replication and mortality in mice infected with influenza A virus (IAV). Elevated CO2 also augmented cholesterol content and pseudo-SARS-CoV-2 entry in bronchial epithelial cells. Interestingly, cellular cholesterol facilitates IAV uptake, replication, assembly, and egress from cells. Here, we report that hypercapnia increases viral protein expression in airway epithelium of mice infected with IAV. Elevated CO2 also enhanced IAV adhesion and internalization, viral protein expression, and viral replication in bronchial epithelial cells. Hypercapnia increased the expression and activation of the transcription factor sterol-regulatory element binding protein 2 (SREBP2), resulting in elevated expression of cholesterol synthesis enzymes, decreased expression of a cholesterol efflux transporter, and augmented cellular cholesterol. Moreover, reducing cellular cholesterol with an SREBP2 inhibitor or statins blocked hypercapnia-induced increases in viral adhesion and internalization, viral protein expression, and IAV replication. Inhibitors of mTOR and Akt also blocked the effect of hypercapnia on viral growth. Our findings suggest that targeting cholesterol synthesis and\/or mTOR\/Akt signaling may hold promise for reducing susceptibility to influenza infection in patients with advanced lung disease and hypercapnia.<\/jats:p>","DOI":"10.3390\/ijms26094133","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:48:33Z","timestamp":1745840913000},"page":"4133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hypercapnia Increases Influenza A Virus Infection of Bronchial Epithelial Cells by Augmenting Cellular Cholesterol via mTOR and Akt"],"prefix":"10.3390","volume":"26","author":[{"given":"Fei","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiko","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter H. S.","family":"Sporn","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"},{"name":"Research Service, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-4560","authenticated-orcid":false,"given":"S. Marina","family":"Casalino-Matsuda","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1046\/j.1525-1497.2003.20615.x","article-title":"APACHE II predicts long-term survival in COPD patients admitted to a general medical ward","volume":"18","author":"Goel","year":"2003","journal-title":"J. Gen. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1378\/chest.124.2.459","article-title":"Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD","volume":"124","author":"Groenewegen","year":"2003","journal-title":"Chest"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1378\/chest.82.3.310","article-title":"The prognosis of patients with chronic obstructive pulmonary disease after hospitalization for acute respiratory failure","volume":"82","author":"Martin","year":"1982","journal-title":"Chest"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mohan, A., Premanand, R., Reddy, L.N., Rao, M.H., Sharma, S.K., Kamity, R., and Bollineni, S. (2006). Clinical presentation and predictors of outcome in patients with severe acute exacerbation of chronic obstructive pulmonary disease requiring admission to intensive care unit. BMC Pulm. Med., 6.","DOI":"10.1186\/1471-2466-6-27"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1001\/jama.1973.03220340019004","article-title":"Acute respiratory failure in obstructive lung disease. Long-term survival after treatment in an intensive care unit","volume":"225","author":"Moser","year":"1973","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.amjmed.2004.10.014","article-title":"Arterial carbon dioxide tension on admission as a marker of in-hospital mortality in community-acquired pneumonia","volume":"118","author":"Sin","year":"2005","journal-title":"Am. J. Med."},{"key":"ref_7","first-page":"55","article-title":"Influenza infection and COPD","volume":"2","author":"Mallia","year":"2007","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jcv.2009.07.010","article-title":"Importance of viral and bacterial infections in chronic obstructive pulmonary disease exacerbations","volume":"46","author":"Lampron","year":"2009","journal-title":"J. Clin. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3109\/15412555.2013.777400","article-title":"Predicting chronic obstructive pulmonary disease hospitalizations based on concurrent influenza activity","volume":"10","author":"Gerke","year":"2013","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1056\/NEJMra0800353","article-title":"Infection in the pathogenesis and course of chronic obstructive pulmonary disease","volume":"359","author":"Sethi","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_11","unstructured":"Global-Initiative-for-Chronic-Obstructive-Lung-Disease (2025, April 22). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Updated 2025. Available online: https:\/\/goldcopd.org\/."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1378\/chest.12-0576","article-title":"Hypocapnia and hypercapnia are predictors for ICU admission and mortality in hospitalized patients with community-acquired pneumonia","volume":"142","author":"Laserna","year":"2012","journal-title":"Chest"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/ppul.20984","article-title":"Lower respiratory infections by adenovirus in children. Clinical features and risk factors for bronchiolitis obliterans and mortality","volume":"44","author":"Murtagh","year":"2009","journal-title":"Pediatr. Pulmonol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1164\/rccm.200410-1369OC","article-title":"Risk factors for death of patients with cystic fibrosis awaiting lung transplantation","volume":"173","author":"Belkin","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"154022","DOI":"10.1016\/j.jcrc.2022.154022","article-title":"Clinical characteristics, physiological features, and outcomes associated with hypercapnia in patients with acute hypoxemic respiratory failure due to COVID-19\u2014insights from the PRoVENT-COVID study","volume":"69","author":"Tsonas","year":"2022","journal-title":"J. Crit. Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"489","DOI":"10.4049\/jimmunol.2000085","article-title":"Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1","volume":"205","author":"Chen","year":"2020","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e170316","DOI":"10.1172\/jci.insight.170316","article-title":"Myeloid Zfhx3 deficiency protects against hypercapnia-induced suppression of host defense against influenza A virus","volume":"9","author":"Chen","year":"2024","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Casalino-Matsuda, S.M., Wang, N., Ruhoff, P.T., Matsuda, H., Nlend, M.C., Nair, A., Szleifer, I., Beitel, G.J., Sznajder, J.I., and Sporn, P.H.S. (2018). Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-32008-x"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Investig"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chen, F., Matsuda, A., Budinger, G.R.S., Sporn, P.H.S., and Casalino-Matsuda, S.M. (2023). Hypercapnia increases ACE2 expression and pseudo-SARS-CoV-2 entry in bronchial epithelial cells by augmenting cellular cholesterol. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1251120"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1039\/C7SC03236F","article-title":"Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering","volume":"9","author":"Goronzy","year":"2018","journal-title":"Chem. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.1093\/emboj\/16.18.5501","article-title":"Interaction of influenza virus haemagglutinin with sphingolipid-cholesterol membrane domains via its transmembrane domain","volume":"16","author":"Scheiffele","year":"1997","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, Y.J., Chen, C.Y., Yang, J.H., and Chiu, Y.F. (2022). Modulating cholesterol-rich lipid rafts to disrupt influenza A virus infection. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.982264"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.virol.2017.07.024","article-title":"Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses","volume":"510","author":"Bajimaya","year":"2017","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15201","DOI":"10.1073\/pnas.1103746108","article-title":"The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1042\/BST0370217","article-title":"A complex interplay between Akt, TSC2 and the two mTOR complexes","volume":"3","author":"Huang","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1165\/rcmb.2012-0487OC","article-title":"Hypercapnia impairs lung neutrophil function and increases mortality in murine pseudomonas pneumonia","volume":"49","author":"Gates","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1099\/vir.0.2008\/004606-0","article-title":"The multifunctional NS1 protein of influenza A viruses","volume":"89","author":"Hale","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nature06531","article-title":"Structure and mechanism of the M2 proton channel of influenza A virus","volume":"451","author":"Schnell","year":"2008","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1016\/j.bpj.2020.03.021","article-title":"Target Membrane Cholesterol Modulates Single Influenza Virus Membrane Fusion Efficiency but Not Rate","volume":"118","author":"Liu","year":"2020","journal-title":"Biophys. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/nrmicro3367","article-title":"At the centre: Influenza A virus ribonucleoproteins","volume":"13","author":"Eisfeld","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.7164\/antibiotics.29.1346","article-title":"ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium","volume":"29","author":"Endo","year":"1976","journal-title":"J. Antibiot."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1059344","article-title":"Structural mechanism for statin inhibition of HMG-CoA reductase","volume":"292","author":"Istvan","year":"2001","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","article-title":"Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease","volume":"8","author":"Panwar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","article-title":"Activation of a metabolic gene regulatory network downstream of mTOR complex 1","volume":"39","author":"Yecies","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.bbamcr.2011.09.017","article-title":"Akt acutely activates the cholesterogenic transcription factor SREBP-2","volume":"1823","author":"Luu","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7999","DOI":"10.1073\/pnas.1705304114","article-title":"mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells","volume":"114","author":"Eid","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nchembio.117","article-title":"Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases","volume":"4","author":"Apsel","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Vadlakonda, L., Dash, A., Pasupuleti, M., Anil Kumar, K., and Reddanna, P. (2013). The Paradox of Akt-mTOR Interactions. Front. Oncol., 3.","DOI":"10.3389\/fonc.2013.00165"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1128\/AAC.02798-13","article-title":"Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro","volume":"58","author":"Denisova","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bj.2018.08.004","article-title":"The role of respiratory epithelium in host defence against influenza virus infection","volume":"41","author":"Denney","year":"2018","journal-title":"Biomed. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1161\/ATVBAHA.111.226688","article-title":"MicroRNA modulation of cholesterol homeostasis","volume":"31","author":"Moore","year":"2011","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41467-018-08015-x","article-title":"SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target","volume":"10","author":"Yuan","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1038\/s41467-022-33041-1","article-title":"SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus","volume":"13","author":"Branche","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110424","DOI":"10.1016\/j.isci.2024.110424","article-title":"Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication","volume":"27","author":"Zhang","year":"2024","journal-title":"iScience"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.1128\/JVI.74.10.4634-4644.2000","article-title":"Influenza virus assembly and lipid raft microdomains: A role for the cytoplasmic tails of the spike glycoproteins","volume":"74","author":"Zhang","year":"2000","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1085\/jgp.200709932","article-title":"Cholesterol promotes hemifusion and pore widening in membrane fusion induced by influenza hemagglutinin","volume":"131","author":"Biswas","year":"2008","journal-title":"J. Gen. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Verma, D.K., Gupta, D., and Lal, S.K. (2018). Host Lipid Rafts Play a Major Role in Binding and Endocytosis of Influenza A Virus. Viruses, 10.","DOI":"10.3390\/v10110650"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Yang, Q., Elz, A.E., Panis, M., Liu, T., Nilsson-Payant, B.E., and Blanco-Melo, D. (2023). Modulation of Influenza A virus NS1 expression reveals prioritization of host response antagonism at single-cell resolution. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1267078"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0367-326X(03)00123-0","article-title":"Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses","volume":"74","author":"Pavlova","year":"2003","journal-title":"Fitoterapia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345","DOI":"10.4062\/biomolther.2015.019","article-title":"Anti-Influenza Activity of Betulinic Acid from Zizyphus jujuba on Influenza A\/PR\/8 Virus","volume":"23","author":"Hong","year":"2015","journal-title":"Biomol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3892\/ijmm.2014.1761","article-title":"Simvastatin modulates cellular components in influenza A virus-infected cells","volume":"34","author":"Mehrbod","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Radigan, K.A., Urich, D., Misharin, A.V., Chiarella, S.E., Soberanes, S., Gonzalez, A., Perlman, H., Wunderink, R.G., Budinger, G.R., and Mutlu, G.M. (2012). The effect of rosuvastatin in a murine model of influenza A infection. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035788"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mehrbod, P., Omar, A.R., Hair-Bejo, M., Haghani, A., and Ideris, A. (2014). Mechanisms of action and efficacy of statins against influenza. Biomed Res. Int., 2014.","DOI":"10.1155\/2014\/872370"},{"key":"ref_55","first-page":"1513","article-title":"The effect of statins on the prevalence and mortality of influenza virus infection: A systematic review and meta-analysis","volume":"18","author":"Mannarino","year":"2022","journal-title":"Arch. Med. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1093\/cvr\/cvt203","article-title":"Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation","volume":"100","author":"Ma","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.3724\/abbs.2023122","article-title":"SREBP2 inhibitor betulin sensitizes hepatocellular carcinoma to lenvatinib by inhibiting the mTOR\/IL-1\u03b2 pathway","volume":"55","author":"Fan","year":"2023","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1091\/mbc.e05-11-1094","article-title":"Involvement of Akt in ER-to-Golgi transport of SCAP\/SREBP: A link between a key cell proliferative pathway and membrane synthesis","volume":"17","author":"Du","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Kuss-Duerkop, S.K., Wang, J., Mena, I., White, K., Metreveli, G., Sakthivel, R., Mata, M.A., Mu\u00f1oz-Moreno, R., Chen, X., and Krammer, F. (2017). Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006635"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"eabe4509","DOI":"10.1126\/scisignal.abe4509","article-title":"mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif","volume":"14","author":"Baffi","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.1158\/1078-0432.CCR-07-5232","article-title":"Statin-dependent suppression of the Akt\/mammalian target of rapamycin signaling cascade and programmed cell death 4 up-regulation in renal cell carcinoma","volume":"14","author":"Woodard","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1165\/rcmb.2005-0386OC","article-title":"Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium","volume":"34","author":"Forteza","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Stirling, D.R., Swain-Bowden, M.J., Lucas, A.M., Carpenter, A.E., Cimini, B.A., and Goodman, A. (2021). CellProfiler 4: Improvements in speed, utility and usability. BMC Bioinform., 22.","DOI":"10.1186\/s12859-021-04344-9"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"12543","DOI":"10.1128\/JVI.77.23.12543-12551.2003","article-title":"Role for influenza virus envelope cholesterol in virus entry and infection","volume":"77","author":"Sun","year":"2003","journal-title":"J. Virol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4133\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:22Z","timestamp":1760030542000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/9\/4133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,26]]},"references-count":64,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26094133"],"URL":"https:\/\/doi.org\/10.3390\/ijms26094133","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,26]]}}}