{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:07:09Z","timestamp":1791526029645,"version":"4.3.4"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT)","award":["No. 2019R1I1A1A01061403"],"award-info":[{"award-number":["No. 2019R1I1A1A01061403"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Keloids are characterized by excessive extracellular matrix (ECM) accumulation and persistent inflammation, leading to disfiguring scars and poor therapeutic outcomes. The \u03b17 nicotinic acetylcholine receptor (\u03b17nAChR) has emerged as a key modulator of inflammatory and fibrotic signaling. This study evaluated the antifibrotic effects of tropisetron, a clinically available \u03b17nAChR agonist, in keloid fibroblasts (KFs) and a rat incisional scar model. In vitro, KFs exhibited reduced \u03b17nAChR expression, which was restored by tropisetron in a dose-dependent manner. Tropisetron treatment significantly decreased KF viability, downregulated pro-fibrotic genes (COL1A1, COL3A1, \u03b1-SMA), and upregulated matrix metalloproteinases (MMP1 and MMP3). Additionally, it suppressed phosphorylation of Smad2\/3 and reduced expression of NF-\u03baB and TNF-\u03b1, indicating inhibition of both TGF-\u03b2 and inflammatory pathways. In vivo, tropisetron-treated rats showed a ~40% reduction in scar area, improved collagen organization, and increased \u03b17nAChR expression in scar tissue. Western blot analysis confirmed decreased levels of collagen I, p-Smad2\/3, \u03b1-SMA, NF-\u03baB, and TNF-\u03b1. These results indicate that tropisetron exerts dual antifibrotic and anti-inflammatory effects through \u03b17nAChR-mediated signaling and enhanced ECM remodeling. This study provides the first evidence supporting \u03b17nAChR activation as a promising therapeutic strategy for managing keloids and other fibrotic skin disorders.<\/jats:p>","DOI":"10.3390\/ijms26188868","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T07:52:28Z","timestamp":1757663548000},"page":"8868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Antifibrotic Effects of an \u03b17 Nicotinic Acetylcholine Receptor Agonist in Keloid Fibroblasts and a Rat Scar Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Hyun","family":"Roh","sequence":"first","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1313-5016","authenticated-orcid":false,"given":"Yo Han","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Jun","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Won","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Jai","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Yonsei University, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/sj.ki.5000054","article-title":"Renal fibrosis: New insights into the pathogenesis and therapeutics","volume":"69","author":"Liu","year":"2006","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79e","DOI":"10.1097\/PRS.0000000000008667","article-title":"The Most Current Algorithms for the Treatment and Prevention of Hypertrophic Scars and Keloids: A 2020 Update of the Algorithms Published 10 Years Ago","volume":"149","author":"Ogawa","year":"2022","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1097\/01.prs.0000195073.73580.46","article-title":"Keloid pathogenesis and treatment","volume":"117","author":"Mess","year":"2006","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Limandjaja, G.C., Niessen, F.B., Scheper, R.J., and Gibbs, S. (2020). The keloid disorder: Heterogeneity, histopathology, mechanisms and models. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00360"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1038\/jid.2015.50","article-title":"Keloid pathogenesis: Potential role of cellular fibronectin with the EDA domain","volume":"135","author":"Andrews","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic acetylcholine receptor \u03b17 subunit is an essential regulator of inflammation","volume":"421","author":"Wang","year":"2003","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/ni1229","article-title":"Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2\u2013STAT3 signaling pathway","volume":"6","author":"The","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1016\/j.jid.2020.04.006","article-title":"The \u03b17 nicotinic acetylcholine receptor: A promising target for the treatment of fibrotic skin disorders","volume":"140","author":"Stegemann","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/35013070","article-title":"Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin","volume":"405","author":"Borovikova","year":"2000","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1002\/art.37809","article-title":"Tropisetron Suppresses Collagen Synthesis in Skin Fibroblasts via \u03b17 Nicotinic Acetylcholine Receptor and Attenuates Fibrosis in a Scleroderma Mouse Model","volume":"65","author":"Stegemann","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ajpath.2012.04.005","article-title":"Targeting \u03b1-7 nicotinic acetylcholine receptor in the enteric nervous system: A cholinergic agonist prevents gut barrier failure after severe burn injury","volume":"181","author":"Costantini","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1046\/j.1471-4159.2004.02347.x","article-title":"Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors","volume":"89","author":"Shytle","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Xu, K., Hu, J., Wang, X., Feng, X., Li, Y., Ni, X., Wen, S., and Wang, J. (2019). Activation of Nicotinic Acetylcholine \u03b17 Receptor Attenuates Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats by Downregulating the NLRP3 Inflammasome. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00128"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.2119\/molmed.2016.00083","article-title":"Deficiency of \u03b17 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice","volume":"23","author":"Sun","year":"2017","journal-title":"Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Su, Y., Zhang, W., Zhang, R., Yuan, Q., Wu, R., Liu, X., Wuri, J., Li, R., and Yan, T. (2022). Activation of Cholinergic Anti-Inflammatory Pathway Ameliorates Cerebral and Cardiac Dysfunction After Intracerebral Hemorrhage Through Autophagy. Front. Immunol, 13.","DOI":"10.3389\/fimmu.2022.870174"},{"key":"ref_18","first-page":"646","article-title":"Activation of the Alpha 7 Nicotinic Acetylcholine Receptor by GTS-21 Mitigates Contrast Nephropathy in a Rat Model","volume":"49","author":"Akcay","year":"2024","journal-title":"Kidney Blood Press. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit","volume":"334","author":"Olofsson","year":"2011","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.neulet.2004.12.025","article-title":"Molecular Dissection of Tropisetron, an Alpha7 Nicotinic Acetylcholine Receptor-Selective Partial Agonist","volume":"378","author":"Papke","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_21","first-page":"836","article-title":"The \u03b17 Nicotinic Acetylcholine Receptor Agonist Tropisetron Counteracts Ultraviolet A-Mediated Oxidative Stress in Human Dermal Fibroblasts","volume":"29","author":"Stegemann","year":"2020","journal-title":"Exp. Dermatol."},{"key":"ref_22","first-page":"222","article-title":"Tropisetron Sensitizes \u03b17-Containing Nicotinic Receptors to Low Levels of Acetylcholine in Vitro and Improves Memory-Related Task Performance in Young and Aged Animals","volume":"112","author":"Callahan","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lee, H.J., and Jang, Y.J. (2018). Recent Understandings of Biology, Prophylaxis and Treatment Strategies for Hypertrophic Scars and Keloids. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030711"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1089\/wound.2014.0581","article-title":"Metalloproteinases and Wound Healing","volume":"4","author":"Caley","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1254\/jphs.94.334","article-title":"Nicotinic acetylcholine receptor alpha7 subunit mediates migration of vascular smooth muscle cells toward nicotine","volume":"94","author":"Li","year":"2004","journal-title":"J. Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1111\/jdi.12964","article-title":"Nicotinic Alpha-7 Acetylcholine Receptor Deficiency Exacerbates Hepatic Inflammation and Fibrosis in a Mouse Model of Non-Alcoholic Steatohepatitis","volume":"10","author":"Kimura","year":"2019","journal-title":"J. Diabetes Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s00418-011-0798-y","article-title":"Nicotinic acetylcholine receptor \u03b17 subunit is time-dependently expressed in distinct cell types during skin wound healing in mice","volume":"135","author":"Fan","year":"2011","journal-title":"Histochem. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00414-014-1001-5","article-title":"The time-dependent expression of \u03b17 nicotinic acetylcholine receptor during skeletal muscle wound healing in rats","volume":"128","author":"Fan","year":"2014","journal-title":"Int. J. Legal Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00403-004-0487-y","article-title":"Activation of NF-\u03baB signal pathways in keloid fibroblasts","volume":"296","author":"Messadi","year":"2004","journal-title":"Arch. Dermatol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"502","DOI":"10.3892\/etm.2021.9933","article-title":"Increased sensitivity to TNF-\u03b1 promotes keloid fibroblast hyperproliferation by activating the NF-\u03baB, JNK and p38 MAPK pathways","volume":"21","author":"Li","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2401027","DOI":"10.1155\/2017\/2401027","article-title":"Stimulation of \u03b17 nicotinic acetylcholine receptor attenuates nicotine induced upregulation of MMP, MCP 1, and RANTES through modulating ERK1\/2\/AP 1 signaling in RAW264.7 and MOVAS cells","volume":"2017","author":"Liu","year":"2017","journal-title":"Mediators Inflamm."},{"key":"ref_32","first-page":"2287","article-title":"\u03b17-nAChR agonist GTS-21 reduces radiation-induced lung injury","volume":"40","author":"Mei","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.32607\/actanaturae.27494","article-title":"Peptide Mimicking Loop II of the Human Epithelial Protein SLURP-2 Enhances the Viability and Migration of Skin Keratinocytes","volume":"16","author":"Shlepova","year":"2024","journal-title":"Acta Naturae"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1134\/S1068162024030014","article-title":"Human Epithelial Protein SLURP-2 as a Prototype of Drugs for Wound Healing","volume":"50","author":"Bychkov","year":"2024","journal-title":"Russ. J. Bioorg. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8868\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:15Z","timestamp":1760035455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8868"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":34,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26188868"],"URL":"https:\/\/doi.org\/10.3390\/ijms26188868","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,11]]}}}