{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T15:04:44Z","timestamp":1773759884200,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004080","name":"Korea Drug Development Fund","doi-asserted-by":"publisher","award":["RS-2023-00283815"],"award-info":[{"award-number":["RS-2023-00283815"]}],"id":[{"id":"10.13039\/501100004080","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the pathological accumulation of collagen-rich extracellular matrix, resulting in irreversible lung remodeling and respiratory failure. The incomplete understanding of IPF pathogenesis has hindered the development of effective therapeutics. Here, we investigate the mechanism by which the actin-related protein 2\/3 complex subunit 2 (ARPC2) contributes to the fibrotic response in lung fibroblasts. Modulating of ARPC2 expression levels altered the expression of profibrotic genes, including \u03b1-smooth muscle actin (ACTA2), in TGF-\u03b21-treated MRC-5 cells at the transcriptional level. We further show that ARPC2 regulates the TGF-\u03b21-mediated nuclear translocation of myocardin-related transcription factor-A (MRTFA), a central driver of fibrotic gene induction. Our data indicate that ARPC2 plays a distinct role in profibrotic gene expression and MRTFA nuclear localization, distinguishing its function from other components of the actin-related protein 2\/3 (ARP2\/3) complex. Furthermore, ARPC2 appears to modulate the TGF-\u03b21-dependent formation of MRTFA\/G-actin complexes. Finally, transcriptomic analysis of cells depleted of ARPC2, ACTR2, or MRTFA revealed that ARPC2 and MRTFA co-regulate a specific repertoire of fibrotic genes. These observations support a profibrotic function for ARPC2 during fibroblast-to-myofibroblast transition (FMT), highlighting it as a potential therapeutic target for IPF.<\/jats:p>","DOI":"10.3390\/ijms27062729","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:42:16Z","timestamp":1773751336000},"page":"2729","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ARPC2 Promotes Pulmonary Fibrosis by Regulating MRTFA Activity Independent of the Canonical ARP2\/3 Complex"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-724X","authenticated-orcid":false,"given":"Eun Jo","family":"Du","sequence":"first","affiliation":[{"name":"SapiensBio Inc., Seongnam-si 13207, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8411-2082","authenticated-orcid":false,"given":"Hyunseong","family":"Kim","sequence":"additional","affiliation":[{"name":"SapiensBio Inc., Seongnam-si 13207, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-3783","authenticated-orcid":false,"given":"Seo-Gyeong","family":"Bae","sequence":"additional","affiliation":[{"name":"SapiensBio Inc., Seongnam-si 13207, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6217-0750","authenticated-orcid":false,"given":"Sihyeon","family":"An","sequence":"additional","affiliation":[{"name":"YD Global Life Science Co., Ltd., Seongnam-si 13207, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanghyun","family":"Ryoo","sequence":"additional","affiliation":[{"name":"SapiensBio Inc., Seongnam-si 13207, Gyeonggi-do, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1183\/09031936.00077309","article-title":"Idiopathic Pulmonary Fibrosis: A Disease with Similarities and Links to Cancer Biology","volume":"35","author":"Vancheri","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"00591-2021","DOI":"10.1183\/23120541.00591-2021","article-title":"Mortality and Survival in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis","volume":"8","author":"Zheng","year":"2022","journal-title":"ERJ Open Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1056\/NEJMoa1402584","article-title":"Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis","volume":"370","author":"Richeldi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1159\/000479976","article-title":"An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP)","volume":"94","author":"Costabel","year":"2017","journal-title":"Respiration"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MS9.0000000000004290","article-title":"Jascayd (Nerandomilast): A Novel PDE4B Inhibitor for Idiopathic Pulmonary Fibrosis","volume":"88","author":"Hujjat","year":"2026","journal-title":"Ann. Med. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3390\/arm91010005","article-title":"Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis","volume":"91","author":"Zhang","year":"2023","journal-title":"Adv. Respir. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1164\/rccm.201306-1141WS","article-title":"Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report","volume":"189","author":"Blackwell","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1378\/chest.06-2568","article-title":"Molecular Targets in Pulmonary Fibrosis: The Myofibroblast in Focus","volume":"132","author":"Scotton","year":"2007","journal-title":"CHEST"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5088","DOI":"10.1172\/JCI139519","article-title":"Contributions of Alveolar Epithelial Cell Quality Control to Pulmonary Fibrosis","volume":"130","author":"Katzen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s40139-013-0017-8","article-title":"Regulation and Relevance of Myofibroblast Responses in Idiopathic Pulmonary Fibrosis","volume":"1","author":"Moore","year":"2013","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pccm.2024.08.003","article-title":"Understanding Myofibroblast Origin in the Fibrotic Lung","volume":"2","author":"Zabihi","year":"2024","journal-title":"Chin. Med. J. Pulm. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1146\/annurev-pathol-042320-030240","article-title":"Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis","volume":"17","author":"Moss","year":"2022","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.jmb.2003.12.017","article-title":"Identification of Functionally Important Residues of Arp2\/3 Complex by Analysis of Homology Models from Diverse Species","volume":"336","author":"Beltzner","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2206722119","DOI":"10.1073\/pnas.2206722119","article-title":"Mechanism of Actin Filament Branch Formation by Arp2\/3 Complex Revealed by a High-Resolution Cryo-EM Structureof the Branch Junction","volume":"119","author":"Chou","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"jcs227900","DOI":"10.1242\/jcs.227900","article-title":"The Myofibroblast at a Glance","volume":"133","author":"Pakshir","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.trsl.2011.05.004","article-title":"Actin Cytoskeleton in Myofibroblast Differentiation: Ultrastructure Defining Form and Driving Function","volume":"158","author":"Sandbo","year":"2011","journal-title":"Transl. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/s41419-025-07573-5","article-title":"Inhibition of Rho GEFs Attenuates Pulmonary Fibrosis through Suppressing Myofibroblast Activation and Reprogramming Profibrotic Macrophages","volume":"16","author":"Luo","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/bph.15675","article-title":"Inhibition of the Arp2\/3 Complex Represses Human Lung Myofibroblast Differentiation and Attenuates Bleomycin-Induced Pulmonary Fibrosis","volume":"179","author":"Mergault","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"L838","DOI":"10.1152\/ajplung.00012.2014","article-title":"Forkhead Box F1 Represses Cell Growth and Inhibits COL1 and ARPC2 Expression in Lung Fibroblasts in Vitro","volume":"307","author":"Tadbiri","year":"2014","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Meltzer, E.B., Barry, W.T., D\u2019Amico, T.A., Davis, R.D., Lin, S.S., Onaitis, M.W., Morrison, L.D., Sporn, T.A., Steele, M.P., and Noble, P.W. (2011). Bayesian Probit Regression Model for the Diagnosis of Pulmonary Fibrosis: Proof-of-Principle. BMC Med. Genom., 4.","DOI":"10.1186\/1755-8794-4-70"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14871","DOI":"10.1073\/pnas.261419298","article-title":"Arp2\/3 Complex Requires Hydrolyzable ATP for Nucleation of New Actin Filaments","volume":"98","author":"Dayel","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2306165120","DOI":"10.1073\/pnas.2306165120","article-title":"Transition State of Arp2\/3 Complex Activation by Actin-Bound Dimeric Nucleation-Promoting Factor","volume":"120","author":"Boczkowska","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.devcel.2017.08.003","article-title":"Arp2\/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility","volume":"42","author":"Rotty","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1182\/bloodadvances.2017006973","article-title":"Deletion of the Arp2\/3 Complex in Megakaryocytes Leads to Microthrombocytopenia in Mice","volume":"1","author":"Paul","year":"2017","journal-title":"Blood Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/S1097-2765(01)00393-8","article-title":"Reconstitution of Human Arp2\/3 Complex Reveals Critical Roles of Individual Subunits in Complex Structure and Activity","volume":"8","author":"Gournier","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2202723119","DOI":"10.1073\/pnas.2202723119","article-title":"Structure of Arp2\/3 Complex at a Branched Actin Filament Junction Resolved by Single-Particle Cryo-Electron Microscopy","volume":"119","author":"Ding","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"44116","DOI":"10.1074\/jbc.M111.276931","article-title":"Myocardin-Related Transcription Factor-A Complexes Activate Type I Collagen Expression in Lung Fibroblasts","volume":"286","author":"Luchsinger","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1007\/s12265-012-9397-0","article-title":"The Actin\u2013MRTF\u2013SRF Gene Regulatory Axis and Myofibroblast Differentiation","volume":"5","author":"Small","year":"2012","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1161\/CIRCRESAHA.110.223172","article-title":"Myocardin-Related Transcription Factor-A Controls Myofibroblast Activation and Fibrosis in Response to Myocardial Infarction","volume":"107","author":"Small","year":"2010","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1177\/1535370219854669","article-title":"Nucleoskeletal Regulation of Transcription: Actin on MRTF","volume":"244","author":"Sidorenko","year":"2019","journal-title":"Exp. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"ra40","DOI":"10.1126\/scisignal.2001750","article-title":"Structure of a Pentavalent G-Actin\u2022MRTF-A Complex Reveals How G-Actin Controls Nucleocytoplasmic Shuttling of a Transcriptional Coactivator","volume":"4","author":"Mouilleron","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0092-8674(03)00278-2","article-title":"Actin Dynamics Control SRF Activity by Regulation of Its Coactivator MAL","volume":"113","author":"Miralles","year":"2003","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1128\/MCB.01623-07","article-title":"RPEL Motifs Link the Serum Response Factor Cofactor MAL but Not Myocardin to Rho Signaling via Actin Binding","volume":"28","author":"Guettler","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ar41","DOI":"10.1091\/mbc.E20-08-0536","article-title":"Fibroblast to Myofibroblast Transition Is Enhanced by Increased Cell Density","volume":"32","author":"Doolin","year":"2021","journal-title":"Mol. Biol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1002\/ijc.35246","article-title":"ARP2\/3 Complex Affects Myofibroblast Differentiation and Migration in Pancreatic Ductal Adenocarcinoma","volume":"156","author":"Sun","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1016\/j.yexcr.2007.07.008","article-title":"Reorganization of the Actin Cytoskeleton via Transcriptional Regulation of Cytoskeletal\/Focal Adhesion Genes by Myocardin-Related Transcription Factors (MRTFs\/MAL\/MKLs)","volume":"313","author":"Morita","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrm2890","article-title":"Linking Actin Dynamics and Gene Transcription to Drive Cellular Motile Functions","volume":"11","author":"Olson","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1101\/gad.239327.114","article-title":"Rho-Actin Signaling to the MRTF Coactivators Dominates the Immediate Transcriptional Response to Serum in Fibroblasts","volume":"28","author":"Esnault","year":"2014","journal-title":"Genes Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7288","DOI":"10.1073\/pnas.96.13.7288","article-title":"Genetic Dissection of the Budding Yeast Arp2\/3 Complex: A Comparison of the in Vivo and Structural Roles of Individual Subunits","volume":"96","author":"Winter","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18205","DOI":"10.1038\/s41598-022-22982-8","article-title":"CRISPR-Cas9 Arabidopsis Mutants of Genes for ARPC1 and ARPC3 Subunits of ARP2\/3 Complex Reveal Differential Roles of Complex Subunits","volume":"12","author":"Bellinvia","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Dimchev, V., Lahmann, I., Koestler, S.A., Kage, F., Dimchev, G., Steffen, A., Stradal, T.E.B., Vauti, F., Arnold, H.-H., and Rottner, K. (2021). Induced Arp2\/3 Complex Depletion Increases FMNL2\/3 Formin Expression and Filopodia Formation. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.634708"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4588","DOI":"10.1242\/dev.156323","article-title":"Knockout of the Arp2\/3 Complex in Epidermis Causes a Psoriasis-like Disease Hallmarked by Hyperactivation of Transcription Factor Nrf2","volume":"144","author":"Song","year":"2017","journal-title":"Development"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3788","DOI":"10.1111\/cas.14205","article-title":"Pimozide Suppresses Cancer Cell Migration and Tumor Metastasis through Binding to ARPC2, a Subunit of the Arp2\/3 Complex","volume":"110","author":"Choi","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_44","first-page":"2311","article-title":"Adenovirus Type 5 Substituted with Type 11 or 35 Fiber Structure Increases Its Infectivity to Human Cells Enabling Dual Gene Transfer in CD46-Dependent and -Independent Manners","volume":"27","author":"Yu","year":"2007","journal-title":"Anticancer. Res."},{"key":"ref_45","unstructured":"R Core Team (2021). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s11336-013-9328-2","article-title":"A Nondegenerate Penalized Likelihood Estimator for Variance Parameters in Multilevel Models","volume":"78","author":"Chung","year":"2013","journal-title":"Psychometrika"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2729\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T12:44:25Z","timestamp":1773751465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2729"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062729"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062729","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,17]]}}}