{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:45:37Z","timestamp":1774633537956,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"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><jats:title>Introduction<\/jats:title><jats:p>Congenital microtia is a birth defect characterized by auricular underdevelopment, with unclear pathogenesis and unidentified pathogenic genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Differential expression analysis, weighted co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks and support vector machine recursive feature elimination (SVM-RFE) identified the key biomolecules in microtia. Single-cell and intercellular communication analysis were used to decipher the key intercellular signaling pathway. We extracted primary cells and conducted Immuno precipitation mass spectrometry (IP-MS), co-Immuno precipitation (Co-IP) and RNA-sequencing (RNA-seq) to confirmed the mechanism. The intercellular communication network was confirmed through the cell co-culture system. Organoid and animal models further validated the role of key biomolecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that IL-6 may be the key biomolecule in microtia. Normal ear cartilage tissue is mainly composed of chondrocytes, but microtia auricular ear tissue contained chondrocytes and stem cells. IL-6 signaling pathway is the main intercellular communication pathways in microtia. We extracted primary chondrocytes and stem cells, and proved that IL-6 promotes the growth and migration of primary cells. The binding of IL-6 and IL-6R and Glycoprotein 130 (GP130) and the activation of their downstream were confirmed. Furthermore, IL-6 signaling pathway was proved to involve in the intercellular communication of microtia. Cartilage microspheres demonstrated the role of IL-6 in regeneration of ear cartilage. The preventive intervention of adeno-associated virus (AAV) on pregnant mice confirmed the role of IL-6 <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IL-6 signaling is the key biomolecule in the development and regeneration of auricular cartilage in microtia. IL-6 is a potential biomarker and preventive and therapeutic target for microtia patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1625058","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T05:28:40Z","timestamp":1753853320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["IL-6 signaling is required for the development and regeneration of ear cartilage in microtia"],"prefix":"10.3389","volume":"13","author":[{"given":"Wenkang","family":"Luan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shujun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanyi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongwen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinxiu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leren","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","article-title":"Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage","volume":"20","author":"Aran","year":"2019","journal-title":"Nat. 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