{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:56:31Z","timestamp":1790610991500,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Hepatic stellate cell (HSC) transdifferentiation into myofibroblasts is a pivotal event in liver fibrosis, yet the underlying regulatory network remains elusive. This study explores the role of TMEM39A in HSC activation and its pro-fibrotic effects via the cell adhesion molecule (CAM) signaling axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An\n                      <jats:italic>in vitro<\/jats:italic>\n                      HSC activation model was established using TGF-\u03b21-stimulated LX-2 cells, combined with TMEM39A knockdown and overexpression. Cell viability, migration, and apoptosis were assessed by CCK-8, wound healing, Transwell, and flow cytometry. Fibrotic marker expression was measured at both mRNA and protein levels. RNA sequencing and bioinformatics identified the CAM pathway as a candidate downstream effector, and its pharmacological inhibitor (Alicaforsen, an ICAM-1 antagonist) was used for validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TMEM39A expression correlated positively with HSC activation. Overexpression of TMEM39A promoted LX-2 viability, migration, and upregulation of fibrotic markers (\u03b1-SMA, COL1A1) while suppressing apoptosis, whereas knockdown reversed these effects. Mechanistically, TMEM39A activated the CAM axis with specific ICAM-1 elevation. Alicaforsen treatment partially inhibited the activation of HSCs and the expression of fibrosis markers induced by TMEM39A.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      TMEM39A functions as a novel pro-fibrotic facilitator that promotes HSC activation at least partially through the CAM\/ICAM-1 signaling axis. Our findings provide mechanistic insights into liver fibrosis and suggest TMEM39A and its downstream effectors as potential candidates for further therapeutic exploration, pending rigorous\n                      <jats:italic>in vivo<\/jats:italic>\n                      and clinical validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1926987","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:15:31Z","timestamp":1790608531000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TMEM39A acts as a novel profibrotic factor to activate hepatic stellate cells partially via the cell adhesion molecule signaling axis"],"prefix":"10.3389","volume":"14","author":[{"given":"Meng","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexia","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shisong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Hospital Affiliated to Shandong University","place":["Jinan, China"]},{"name":"Department of Pediatric Surgery, Jinan Children\u2019s Hospital","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107192","DOI":"10.1016\/j.ejps.2025.107192","article-title":"Repositioning gemigliptin for the alleviation of thioacetamide-induced liver fibrosis in rats: targeting TLR4\/MAPK, SIRT1\/AMPK\/Nrf2, PI3K\/AKT\/mTOR axis and apoptosis","volume":"212","author":"Almalki","year":"2025","journal-title":"Eur. 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