{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:33:27Z","timestamp":1787027607977,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institutes of Health grants","doi-asserted-by":"publisher","award":["R01AR068279"],"award-info":[{"award-number":["R01AR068279"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Harrington Cancer and Health Foundation"},{"name":"Brain Drug Discovery Center, Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Foam cell formation, a hallmark of early atherosclerotic lesion development, is closely associated with mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. Disruption in mitochondrial activity leads to electron leakage, elevated ROS generation, and collapse of mitochondrial membrane potential, contributing to vascular pathogenesis. In this study, we investigated the role of Kr\u00fcppel-like factor 2 (KLF2), a transcription factor known for its vasculoprotective effects, in regulating mitochondrial function during foam cell (FC) formation in RAW264.7 cells. This study demonstrates that KLF2 is decreased during FC formation of RAW264.7 cells. In contrast, lipids are highly uptaken, and both intracellular and mitochondrial ROS are increased, with enhanced mitochondrial membrane potential and mitochondrial functions during FC formation of RAW264.7 cells. To investigate the role of KLF2 in this FC formation process, we utilized both loss-of-function and gain-of-function approaches of KLF2 in RAW264.7 cells. This study demonstrates that KLF2 plays a multifaceted and protective role in preventing FC formation by regulating the uptake of lipids, reducing both intracellular and mitochondrial ROS, mitochondrial membrane potential, and mitochondrial activities, as loss-of-function of KLF2 promoted FC formation with overactivity, and gain-of-function reduced FC formation by limiting activities of all the parameters mentioned above. These findings provide mechanistic insights into the protective role of KLF2 and propose it as a potential therapeutic target for the future management of cardiovascular diseases.<\/jats:p>","DOI":"10.3390\/biology15020111","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T09:40:29Z","timestamp":1767692429000},"page":"111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Kr\u00fcppel-like Factor 2 (KLF2) in the Regulation of Lipid Accumulation, ROS, and Mitochondrial Functions During Foam Cell Formation in RAW264.7 Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5354-5827","authenticated-orcid":false,"given":"Md Sariful Islam","family":"Howlader","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106-1712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjusri","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106-1712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4773-3629","authenticated-orcid":false,"given":"Surajit","family":"Hansda","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106-1712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prathyusha","family":"Naidu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106-1712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3343-0096","authenticated-orcid":false,"given":"Hiranmoy","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106-1712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.freeradbiomed.2016.04.001","article-title":"Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling","volume":"100","author":"Brand","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How mitochondria produce reactive oxygen species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.freeradbiomed.2005.02.014","article-title":"Mitochondrial dysfunction in cardiovascular disease","volume":"38","author":"Ballinger","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/cvr\/cvn280","article-title":"Mitochondrial oxidative stress and dysfunction in myocardial remodelling","volume":"81","author":"Tsutsui","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature17399","article-title":"Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1","volume":"532","author":"Chouchani","year":"2016","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17767","DOI":"10.1002\/jcb.29042","article-title":"Inhibition of mitochondrial activity ameliorates atherosclerosis in ApoE\u2212\/\u2212 mice via suppressing vascular smooth cell activation and macrophage foam cell formation","volume":"120","author":"Xia","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/jcp.27110","article-title":"Heat shock protein 70: A promising therapeutic target for myocardial ischemia\u2013reperfusion injury","volume":"234","author":"Song","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1113\/jphysiol.2003.049478","article-title":"Mitochondrial formation of reactive oxygen species","volume":"552","author":"Turrens","year":"2003","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6653","DOI":"10.1073\/pnas.0508235103","article-title":"Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes","volume":"103","author":"Das","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1161\/CIRCULATIONAHA.104.525774","article-title":"Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells","volume":"112","author":"Mir","year":"2005","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"115971","DOI":"10.1016\/j.biopha.2023.115971","article-title":"Secretory products of DPSC mitigate inflammatory effects in microglial cells by targeting MAPK pathway","volume":"170","author":"Howlader","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Das, M., Deb, M., Laha, D., Joseph, M., Kanji, S., Aggarwal, R., Iwenofu, O.H., Pompili, V.J., Jarjour, W., and Das, H. (2019). Myeloid kr\u00fcppel-like factor 2 critically regulates K\/BxN serum-induced arthritis. Cells, 8.","DOI":"10.3390\/cells8080908"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Laha, D., Sarkar, J., Maity, J., Pramanik, A., Howlader, M.S.I., Barthels, D., and Das, H. (2022). Polyphenolic compounds inhibit osteoclast differentiation while reducing autophagy through limiting ROS and the mitochondrial membrane potential. Biomolecules, 12.","DOI":"10.3390\/biom12091220"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Greene, C.J., Anderson, S., Barthels, D., Howlader, M.S.I., Kanji, S., Sarkar, J., and Das, H. (2022). DPSC products accelerate wound healing in diabetic mice through induction of SMAD molecules. Cells, 11.","DOI":"10.3390\/cells11152409"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1007\/s11033-025-10613-0","article-title":"Pharmacological and toxicological roles of Kruppel-like factors (KLFs) in the cardiovascular system: A review","volume":"52","author":"Zhao","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101622","DOI":"10.1016\/j.redox.2020.101622","article-title":"KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism","volume":"36","author":"Maity","year":"2020","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sebti, S.M., and Hamilton, A.D. (2001). Farnesyltransferase and geranylgeranyltransferase I inhibitors as novel agents for cancer and cardiovascular diseases. Farnesyltransferase Inhibitors in Cancer Therapy, Springer.","DOI":"10.1007\/978-1-59259-013-1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0022-1759(86)90368-6","article-title":"Rapid colorimetric assay for cell growth and survival: Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability","volume":"89","author":"Denizot","year":"1986","journal-title":"J. Immunol. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1161\/01.RES.0000258450.44413.96","article-title":"Mitochondrial dysfunction in atherosclerosis","volume":"100","author":"Madamanchi","year":"2007","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1113\/JP271301","article-title":"Mitochondrial dynamics, mitophagy and cardiovascular disease","volume":"594","author":"Pennanen","year":"2016","journal-title":"J. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.cell.2012.02.035","article-title":"Mitochondria: In sickness and in health","volume":"148","author":"Nunnari","year":"2012","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/CIRCRESAHA.108.184663","article-title":"Hemizygous deficiency of Kruppel-like factor 2 augments experimental atherosclerosis","volume":"103","author":"Atkins","year":"2008","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1111\/jphp.13098","article-title":"An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites","volume":"71","author":"Attia","year":"2019","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1007\/s00018-016-2223-0","article-title":"Role of Nrf2\/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism","volume":"73","author":"Loboda","year":"2016","journal-title":"Cell. Mol. Life Sci."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/2\/111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T09:51:46Z","timestamp":1767693106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/2\/111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["biology15020111"],"URL":"https:\/\/doi.org\/10.3390\/biology15020111","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]}}}