{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:04Z","timestamp":1786121344003,"version":"build-2736575974"},"reference-count":135,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"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. Med."],"abstract":"<jats:p>\n                    Frozen shoulder, also known as adhesive capsulitis, is characterized by fibrosis, thickening, and contracture of the shoulder joint capsule. Through a systematic review of existing research, we have analyzed the complex molecular network of shoulder fibrosis. Previous studies have found that the disease begins with inflammation of the nuclear factor kappa B (NF-\u03baB) and leptin\/Janus kinase\/signal transducer and activator of transcription (JAK\u2013STAT) pathways, and the transforming growth factor-beta (TGF-\n                    <jats:italic>\u03b2<\/jats:italic>\n                    ) pathway is the key cause of fibrosis. Wingless\/Int (WNT) and potentially Hippo pathways may contribute to fibrotic progression. The phosphatidylinositol 3-kinase (PI3K)\/protein kinase B (PKB\/Akt), mitogen-activated protein kinase (MAPK), and hypoxia-inducible factor (HIF-1) pathways are also related to abnormal cell proliferation, inflammatory response, and hypoxia adaptation, respectively. Technologies such as single-cell sequencing also show the heterogeneity of fibroblasts and their role in pathological networks. We point out the current limitations of pathway interaction research and look forward to the future use of multi-omics and spatial technology to gain an in-depth understanding of the mechanism and provide a theoretical basis for the formulation of treatment strategies for key nodes.\n                  <\/jats:p>","DOI":"10.3389\/fmed.2026.1883535","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:22:23Z","timestamp":1786076543000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Signaling pathway networks in frozen shoulder fibrosis: from inflammatory initiation to fibrotic progression"],"prefix":"10.3389","volume":"13","author":[{"given":"Tianyu","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbing","family":"He","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/s41572-022-00386-2","article-title":"Frozen shoulder","volume":"8","author":"Millar","year":"2022","journal-title":"Nat Rev Dis Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1007\/s43465-024-01294-1","article-title":"Basic science research in frozen shoulder: current updates","volume":"59","author":"Kim","year":"2025","journal-title":"Indian J Orthop"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.molimm.2022.07.007","article-title":"Fibrosis in frozen shoulder: activation of Il-6 through Pi3K-Akt signaling pathway in synovial fibroblast","volume":"150","author":"Yang","year":"2022","journal-title":"Mol Immunol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.3390\/jcm14051780","article-title":"Frozen shoulder as a metabolic and immune disorder: potential roles of leptin resistance, Jak-Stat dysregulation, and fibrosis","volume":"14","author":"Navarro-Ledesma","year":"2025","journal-title":"J Clin Med"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e0215301","DOI":"10.1371\/journal.pone.0215301","article-title":"Fibroblast activation and inflammation in frozen shoulder","volume":"14","author":"Akbar","year":"2019","journal-title":"PLoS One"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1055\/s-0038-1676105","article-title":"Analytical observational study of frozen shoulder among patients with diabetes mellitus","volume":"6","author":"Alhashimi","year":"2018","journal-title":"Joints"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"23259671211069577","DOI":"10.1177\/23259671211069577","article-title":"Evaluating utilization trends in adhesive capsulitis of the shoulder: a retrospective cohort analysis of a large database","volume":"10","author":"Cogan","year":"2022","journal-title":"Orthop J Sports Med"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1177\/1758573216676786","article-title":"Adhesive capsulitis of the shoulder: review of pathophysiology and current clinical treatments","volume":"9","author":"Le","year":"2017","journal-title":"Shoulder Elbow"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1186\/s12891-021-04704-9","article-title":"The epidemiology and etiology of adhesive capsulitis in the U.S. Medicare population","volume":"22","author":"Sarasua","year":"2021","journal-title":"BMC Musculoskelet Disord"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"663703","DOI":"10.3389\/fmed.2021.663703","article-title":"A comprehensive view of frozen shoulder: a mystery syndrome","volume":"8","author":"Serna","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.jse.2016.04.026","article-title":"Prevalence of hypothyroidism in patients with frozen shoulder","volume":"26","author":"Schiefer","year":"2017","journal-title":"J Shoulder Elb Surg"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2325967120986808","DOI":"10.1177\/2325967120986808","article-title":"Hyperlipidemia is a risk factor of adhesive capsulitis: real-world evidence using the Taiwanese National Health Insurance Research Database","volume":"9","author":"Wang","year":"2021","journal-title":"Orthop J Sports Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1055\/s-0037-1608951","article-title":"Risk factors for shoulder stiffness: current concepts","volume":"5","author":"Cucchi","year":"2017","journal-title":"Joints"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e062377","DOI":"10.1136\/bmjopen-2022-062377","article-title":"Diabetes as a risk factor for the onset of frozen shoulder: a systematic review and meta-analysis","volume":"13","author":"Dyer","year":"2023","journal-title":"BMJ Open"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s40634-020-00307-w","article-title":"The puzzling pathophysiology of frozen shoulders\u2014a scoping review","volume":"7","author":"Kraal","year":"2020","journal-title":"J Exp Orthop"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"257","DOI":"10.2147\/Imcrj.S407723","article-title":"A case series: effect of comorbidities on the outcomes of Prolotherapy injection for frozen shoulder patients","volume":"16","author":"Sam","year":"2023","journal-title":"Int Med Case Rep J"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"258","DOI":"10.5152\/eurjrheum.2018.18044","article-title":"Musculoskeletal problems in diabetes mellitus","volume":"5","author":"Sozen","year":"2018","journal-title":"Eur J Rheumatol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1056\/Nejm195906182602503","article-title":"Peripheral entrapment neuropathies of the upper extremity","volume":"260","author":"Thompson","year":"1959","journal-title":"N Engl J Med"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"536","DOI":"10.5435\/00124635-201109000-00004","article-title":"Adhesive capsulitis of the shoulder","volume":"19","author":"Neviaser","year":"2011","journal-title":"J Am Acad Orthop Surg"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1248612","DOI":"10.3389\/fphys.2024.1248612","article-title":"A new perspective of frozen shoulder pathology; the interplay between the brain and the immune system","volume":"15","author":"Navarro-Ledesma","year":"2024","journal-title":"Front Physiol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.jse.2012.06.014","article-title":"Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder","volume":"22","author":"Lho","year":"2013","journal-title":"J Shoulder Elb Surg"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1186\/s12891-016-1190-9","article-title":"The pathophysiology associated with primary (idiopathic) frozen shoulder: a systematic review","volume":"17","author":"Ryan","year":"2016","journal-title":"BMC Musculoskelet Disord"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.jse.2006.01.002","article-title":"Expression of vascular endothelial growth factor and angiogenesis in the diabetic frozen shoulder","volume":"15","author":"Ryu","year":"2006","journal-title":"J Shoulder Elb Surg"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1016\/j.jse.2011.08.046","article-title":"Enhanced expression of neuronal proteins in idiopathic frozen shoulder","volume":"21","author":"Xu","year":"2012","journal-title":"J Shoulder Elb Surg"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1016\/j.arthro.2016.03.024","article-title":"Shoulder stiffness: current concepts and concerns","volume":"32","author":"Itoi","year":"2016","journal-title":"Arthroscopy"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1177\/0363546517744171","article-title":"The effect of corticosteroid injection into rotator interval for early frozen shoulder: a randomized controlled trial","volume":"46","author":"Sun","year":"2018","journal-title":"Am J Sports Med"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1148\/radiol.2015150888","article-title":"Elasticity of the Coracohumeral ligament in patients with adhesive capsulitis of the shoulder","volume":"278","author":"Wu","year":"2016","journal-title":"Radiology"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e28704","DOI":"10.1371\/journal.pone.0028704","article-title":"Mri findings for frozen shoulder evaluation: is the thickness of the coracohumeral ligament a valuable diagnostic tool?","volume":"6","author":"Li","year":"2011","journal-title":"PLoS One"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nrrheum.2016.213","article-title":"Inflammatory mechanisms in tendinopathy\u2014towards translation","volume":"13","author":"Millar","year":"2017","journal-title":"Nat Rev Rheumatol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/cr.2010.171","article-title":"Structural studies of Nf-kappaB signaling","volume":"21","author":"Zheng","year":"2011","journal-title":"Cell Res"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1126\/science.3140380","article-title":"I kappa B: a specific inhibitor of the Nf-kappa B transcription factor","volume":"242","author":"Baeuerle","year":"1988","journal-title":"Science"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1126\/science.7878466","article-title":"Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation","volume":"267","author":"Brown","year":"1995","journal-title":"Science"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nrm1368","article-title":"Shaping the nuclear action of NF-kappaB","volume":"5","author":"Chen","year":"2004","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41392-024-01757-9","article-title":"Nf-kappaB in biology and targeted therapy: new insights and translational implications","volume":"9","author":"Guo","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"11 9D 1","DOI":"10.1002\/0471142735.im1109ds87","article-title":"Traf-mediated Tnfr-family signaling","volume":"11","author":"Ha","year":"2009","journal-title":"Curr Protoc Immunol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1126\/science.8096091","article-title":"Nf-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway","volume":"259","author":"Sun","year":"1993","journal-title":"Science"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/0092-8674(90)90806-p","article-title":"Purified human I kappa B can rapidly dissociate the complex of the Nf-kappa B transcription factor with its cognate Dna","volume":"61","author":"Zabel","year":"1990","journal-title":"Cell"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1177\/0363546517741127","article-title":"Alarmins in frozen shoulder: a molecular association between inflammation and pain","volume":"46","author":"Cher","year":"2018","journal-title":"Am J Sports Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"8434","DOI":"10.1038\/s41598-018-26501-6","article-title":"Profibrogenic effect of high-mobility group box protein-1 in human dermal fibroblasts and its excess in keloid tissues","volume":"8","author":"Lee","year":"2018","journal-title":"Sci Rep"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3062","DOI":"10.3892\/mmr.2017.6364","article-title":"Hmgb1 induces lung fibroblast to myofibroblast differentiation through Nf-kappaB-mediated Tgf-beta1 release","volume":"15","author":"Wang","year":"2017","journal-title":"Mol Med Rep"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"5118","DOI":"10.1073\/pnas.2102715118","article-title":"Translational targeting of inflammation and fibrosis in frozen shoulder: molecular dissection of the T cell\/IL-17A axis","volume":"118","author":"Akbar","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"12183","DOI":"10.1073\/pnas.1900355116","article-title":"Intraarticular injection of relaxin-2 alleviates shoulder arthrofibrosis","volume":"116","author":"Blessing","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"27149","DOI":"10.1038\/srep27149","article-title":"Il-17A mediates inflammatory and tissue remodelling events in early human tendinopathy","volume":"6","author":"Millar","year":"2016","journal-title":"Sci Rep"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1016\/j.jse.2020.01.076","article-title":"Rage-dependent Nf-kB inflammation processes in the capsule of frozen shoulders","volume":"29","author":"Yano","year":"2020","journal-title":"J Shoulder Elb Surg"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/jpi.12302","article-title":"Melatonin: the dawning of a treatment for fibrosis?","volume":"60","author":"Hu","year":"2016","journal-title":"J Pineal Res"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The Jak\/Stat signaling pathway: from bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3109\/08977194.2012.660936","article-title":"Biology and significance of the Jak\/Stat signalling pathways","volume":"30","author":"Kiu","year":"2012","journal-title":"Growth Factors"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1069057","DOI":"10.3389\/fendo.2022.1069057","article-title":"The potential roles of Jak\/Stat signaling in the progression of osteoarthritis","volume":"13","author":"Zhou","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"887","DOI":"10.3390\/ijms21165887","article-title":"Role of leptin in inflammation and vice versa","volume":"21","author":"Perez-Perez","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/nm1195-1155","article-title":"Leptin levels in human and rodent: measurement of plasma leptin and Ob Rna in obese and weight-reduced subjects","volume":"1","author":"Maffei","year":"1995","journal-title":"Nat Med"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/372425a0","article-title":"Positional cloning of the mouse obese gene and its human homologue","volume":"372","author":"Zhang","year":"1994","journal-title":"Nature"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1161\/Circresaha.107.156596","article-title":"Leptin signaling and obesity: cardiovascular consequences","volume":"101","author":"Yang","year":"2007","journal-title":"Circ Res"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1124\/pr.119.018440","article-title":"Targeting Janus kinases and signal transducer and activator of transcription 3 to treat inflammation, fibrosis, and Cancer: rationale, Progress, and caution","volume":"72","author":"Bharadwaj","year":"2020","journal-title":"Pharmacol Rev"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1172\/Jci122462","article-title":"Tgf-beta-induced epigenetic deregulation of Socs3 facilitates Stat3 signaling to promote fibrosis","volume":"130","author":"Dees","year":"2020","journal-title":"J Clin Invest"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3390\/biom13010119","article-title":"The role of Jak\/Stat pathway in fibrotic diseases: molecular and cellular mechanisms","volume":"13","author":"Liu","year":"2023","journal-title":"Biomolecules"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1136\/annrheumdis-2013-204256","article-title":"Inhibition of casein kinase ii reduces Tgfbeta induced fibroblast activation and ameliorates experimental fibrosis","volume":"74","author":"Zhang","year":"2015","journal-title":"Ann Rheum Dis"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.3390\/antiox11071394","article-title":"Macrophage polarization and reprogramming in acute inflammation: a redox perspective","volume":"11","author":"Perez","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"59","DOI":"10.3389\/fmed.2015.00059","article-title":"Signaling in fibrosis: Tgf-beta, Wnt, and Yap\/Taz converge","volume":"2","author":"Piersma","year":"2015","journal-title":"Front Med (Lausanne)"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.burns.2011.08.013","article-title":"Effect of tetrandrine on the Tgf-beta-induced smad signal transduction pathway in human hypertrophic scar fibroblasts in vitro","volume":"38","author":"Zunwen","year":"2012","journal-title":"Burns"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"337","DOI":"10.33549\/physiolres.932289","article-title":"Wnt\/beta-catenin signaling: a promising new target for fibrosis diseases","volume":"61","author":"Guo","year":"2012","journal-title":"Physiol Res"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3390\/cells11132065","article-title":"New insights into hippo\/Yap signaling in fibrotic diseases","volume":"11","author":"Mia","year":"2022","journal-title":"Cells"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1002\/jor.24920","article-title":"Pathological changes of frozen shoulder in rat model and the therapeutic effect of Ppar-gamma agonist","volume":"39","author":"Chen","year":"2021","journal-title":"J Orthop Res"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"3681645","DOI":"10.1155\/2017\/3681645","article-title":"A study of IL-1beta, MMP-3, TGF-beta1, and GDF5 polymorphisms and their association with primary frozen shoulder in a Chinese Han population","volume":"2017","author":"Chen","year":"2017","journal-title":"Biomed Res Int"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/7274517","article-title":"Biological aspect of pathophysiology for frozen shoulder","volume":"2018","author":"Cho","year":"2018","journal-title":"Biomed Res Int"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"325","DOI":"10.6061\/clinics\/2016(06)07","article-title":"The roles of tenascin C and fibronectin 1 in adhesive capsulitis: a pilot gene expression study","volume":"71","author":"Cohen","year":"2016","journal-title":"Clinics (Sao Paulo)"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1186\/s12891-025-08706-9","article-title":"Influence of the metabolic and inflammatory profile in patients with frozen shoulder\u2014systematic review and meta-analysis","volume":"26","author":"Hamed-Hamed","year":"2025","journal-title":"BMC Musculoskelet Disord"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1097\/Jsa.0000000000000324","article-title":"Arthrofibrosis nightmares: prevention and management strategies","volume":"30","author":"Lee","year":"2022","journal-title":"Sports Med Arthrosc Rev"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1186\/s13018-021-02705-x","article-title":"Recombinant Tsg-6 protein inhibits the growth of capsule fibroblasts in frozen shoulder via suppressing the Tgf-beta\/Smad2 signal pathway","volume":"16","author":"Liu","year":"2021","journal-title":"J Orthop Surg Res"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40824-022-00286-2","article-title":"Si-Tgfbr1-loading liposomes inhibit shoulder capsule fibrosis via mimicking the protective function of exosomes from patients with adhesive capsulitis","volume":"26","author":"Sun","year":"2022","journal-title":"Biomater Res"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"e0158093","DOI":"10.1371\/journal.pone.0158093","article-title":"The treatment of fibrosis of joint synovium and frozen shoulder by Smad4 gene silencing in rats","volume":"11","author":"Xue","year":"2016","journal-title":"PLoS One"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"111700","DOI":"10.1016\/j.biopha.2021.111700","article-title":"Tetrandrine inhibits the occurrence and development of frozen shoulder by inhibiting inflammation, angiogenesis, and fibrosis","volume":"140","author":"Zhao","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/jor.1100150316","article-title":"Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder","volume":"15","author":"Rodeo","year":"1997","journal-title":"J Orthop Res"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"Tgf-beta: the master regulator of fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.omtn.2018.04.005","article-title":"miR-24 and miR-122 negatively regulate the transforming growth factor-beta\/Smad signaling pathway in skeletal muscle fibrosis","volume":"11","author":"Sun","year":"2018","journal-title":"Mol Ther Nucleic Acids"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"742","DOI":"10.3390\/ijms20225742","article-title":"Microrna-29a mitigates subacromial Bursa fibrosis in rotator cuff lesion with shoulder stiffness","volume":"20","author":"Ko","year":"2019","journal-title":"Int J Mol Sci"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.2147\/Jir.S304555","article-title":"The serum from patients with secondary frozen shoulder following rotator cuff repair induces shoulder capsule fibrosis and promotes macrophage polarization and fibroblast activation","volume":"14","author":"Sun","year":"2021","journal-title":"J Inflamm Res"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.3892\/etm.2020.8431","article-title":"Effects of tetrandrine combined with acetylcysteine on exercise tolerance, pulmonary function and serum Tnf-beta1 and Mmp-7 in silicosis patients","volume":"19","author":"Zhang","year":"2020","journal-title":"Exp Ther Med"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3390\/ijms21145141","article-title":"Pro-fibrotic phenotype in a patient with segmental stiff skin syndrome via Tgf-beta signaling overactivation","volume":"21","author":"Fusco","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"30121","DOI":"10.1038\/srep30121","article-title":"Tsg-6 secreted by human umbilical cord-Mscs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and Jnk signaling","volume":"6","author":"Liu","year":"2016","journal-title":"Sci Rep"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/j.jse.2015.10.015","article-title":"Advanced glycation end products in idiopathic frozen shoulders","volume":"25","author":"Hwang","year":"2016","journal-title":"J Shoulder Elb Surg"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.2106\/Jbjs.25.00090","article-title":"Involvement of oxidative stress and glycation stress in frozen shoulder","volume":"107","author":"Tsurukami","year":"2025","journal-title":"J Bone Joint Surg Am"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"3520581","DOI":"10.1155\/2017\/3520581","article-title":"Distinct roles of Wnt\/beta-catenin signaling in the pathogenesis of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis","volume":"2017","author":"Shi","year":"2017","journal-title":"Mediat Inflamm"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40591-015-0038-2","article-title":"The Wnt\/beta-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target","volume":"3","author":"Enzo","year":"2015","journal-title":"Mol Cell Ther"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"G39","DOI":"10.1152\/ajpgi.00263.2007","article-title":"Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis","volume":"294","author":"Cheng","year":"2008","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"101063","DOI":"10.1016\/j.arr.2020.101063","article-title":"Wnt signaling pathway in aging-related tissue fibrosis and therapies","volume":"60","author":"Hu","year":"2020","journal-title":"Ageing Res Rev"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"E262","DOI":"10.25011\/cim.v37i4.21733","article-title":"Igf2-expression and \u03b2-catenin levels are increased in frozen shoulder syndrome","volume":"37","author":"Raykha","year":"2014","journal-title":"Clin Invest Med"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.2106\/Jbjs.21.01407","article-title":"Genome-wide association study of adhesive capsulitis suggests significant genetic risk factors","volume":"104","author":"Kulm","year":"2022","journal-title":"J Bone Joint Surg Am"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1242\/dev.045500","article-title":"Hippo signaling: growth control and beyond","volume":"138","author":"Halder","year":"2011","journal-title":"Development"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.devcel.2015.06.020","article-title":"Crumbs3-mediated polarity directs airway epithelial cell fate through the hippo pathway effector Yap","volume":"34","author":"Szymaniak","year":"2015","journal-title":"Dev Cell"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","article-title":"Hippo pathway in organ size control, tissue homeostasis, and Cancer","volume":"163","author":"Yu","year":"2015","journal-title":"Cell"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1038\/ncb2303","article-title":"The hippo pathway in organ size control, tissue regeneration and stem cell self-renewal","volume":"13","author":"Zhao","year":"2011","journal-title":"Nat Cell Biol"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.devcel.2014.06.004","article-title":"Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells","volume":"30","author":"Zhao","year":"2014","journal-title":"Dev Cell"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"16364","DOI":"10.1074\/jbc.Ra118.004073","article-title":"Yap\/Taz mediates mtorc2-stimulated fibroblast activation and kidney fibrosis","volume":"293","author":"Gui","year":"2018","journal-title":"J Biol Chem"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"L344","DOI":"10.1152\/ajplung.00300.2014","article-title":"Mechanosignaling through Yap and Taz drives fibroblast activation and fibrosis","volume":"308","author":"Liu","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1093\/cvr\/cvab205","article-title":"Loss of Yap\/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function","volume":"118","author":"Mia","year":"2022","journal-title":"Cardiovasc Res"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/j.cmet.2020.03.010","article-title":"Cholesterol stabilizes Taz in hepatocytes to promote experimental non-alcoholic steatohepatitis","volume":"31","author":"Wang","year":"2020","journal-title":"Cell Metab"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1186\/s13287-024-04011-9","article-title":"Emerging role and function of hippo-Yap\/Taz signaling pathway in musculoskeletal disorders","volume":"15","author":"Han","year":"2024","journal-title":"Stem Cell Res Ther"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/s41598-023-50904-9","article-title":"Proteomics and phosphoproteomics to study Tuina reverses capsule fibrosis in frozen shoulder: a research report based on rats","volume":"14","author":"Qiao","year":"2024","journal-title":"Sci Rep"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"106701","DOI":"10.1016\/j.jsbmb.2025.106701","article-title":"Mechanistic insights into the anti-fibrotic effects of estrogen via the Pi3K-Akt pathway in frozen shoulder","volume":"249","author":"Wang","year":"2025","journal-title":"J Steroid Biochem Mol Biol"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.7150\/ijms.98505","article-title":"Exploring pathogenic genes in frozen shoulder through weighted gene co-expression network analysis and Mendelian randomization","volume":"21","author":"Wen","year":"2024","journal-title":"Int J Med Sci"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"1230174","DOI":"10.3389\/fphar.2023.1230174","article-title":"Salvianolic acid B attenuates inflammation and prevent pathologic fibrosis by inhibiting Cd36-mediated activation of the Pi3K-Akt signaling pathway in frozen shoulder","volume":"14","author":"Yan","year":"2023","journal-title":"Front Pharmacol"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"3278","DOI":"10.1681\/asn.2015121354","article-title":"Yap\/Taz deletion in Gli+ cell-derived Myofibroblasts attenuates fibrosis","volume":"28","author":"Liang","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41392-024-02011-y","article-title":"Overexpression of Stx11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the Pi3K\/Akt\/mtor pathway","volume":"9","author":"Huang","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.apsb.2021.07.023","article-title":"Targeting Pi3K\/Akt signaling for treatment of idiopathic pulmonary fibrosis","volume":"12","author":"Wang","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"Pi3K\/Akt\/mtor signaling transduction pathway and targeted therapies in cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol Cancer"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41568-019-0216-7","article-title":"The Pi3K-Akt network at the interface of oncogenic signalling and cancer metabolism","volume":"20","author":"Hoxhaj","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"104787","DOI":"10.1016\/j.yexmp.2022.104787","article-title":"The Pi3K\/Akt signaling pathway in cancer: molecular mechanisms and possible therapeutic interventions","volume":"127","author":"Khezri","year":"2022","journal-title":"Exp Mol Pathol"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"1222099","DOI":"10.3389\/fphys.2023.1222099","article-title":"The pathology of oxidative stress-induced autophagy in a chronic rotator cuff enthesis tear","volume":"14","author":"Prasetia","year":"2023","journal-title":"Front Physiol"},{"key":"ref109","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3390\/antiox13010086","article-title":"Hypoxia-inducible factor and oxidative stress in tendon degeneration: a molecular perspective","volume":"13","author":"Shahid","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"984950","DOI":"10.1155\/2012\/984950","article-title":"Regulation of hypoxia-induced cell death in human tenocytes","volume":"2012","author":"Liang","year":"2012","journal-title":"Adv Orthop"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"766080","DOI":"10.3389\/fphys.2021.766080","article-title":"The role of vascular endothelial growth factor in tendon healing","volume":"12","author":"Liu","year":"2021","journal-title":"Front Physiol"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1136\/ard.2011.154229","article-title":"Hypoxia: a critical regulator of early human tendinopathy","volume":"71","author":"Millar","year":"2012","journal-title":"Ann Rheum Dis"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1002\/jor.22147","article-title":"Impaired biomechanical properties correlate with neoangiogenesis as well as Vegf and Mmp-3 expression during rat patellar tendon healing","volume":"30","author":"Sahin","year":"2012","journal-title":"J Orthop Res"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1089\/wound.2018.0796","article-title":"Vascular endothelial growth factor and cutaneous scarring","volume":"8","author":"Wilgus","year":"2019","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"ref115","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1093\/rheumatology\/kead493","article-title":"Inhibition of Tlr4 signalling to dampen joint inflammation in osteoarthritis","volume":"63","author":"Bartels","year":"2024","journal-title":"Rheumatology (Oxford)"},{"key":"ref116","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s11658-022-00318-8","article-title":"Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses","volume":"27","author":"Li","year":"2022","journal-title":"Cell Mol Biol Lett"},{"key":"ref117","doi-asserted-by":"publisher","first-page":"3437","DOI":"10.1093\/eurheartj\/ehv544","article-title":"Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans","volume":"36","author":"Wenzel","year":"2015","journal-title":"Eur Heart J"},{"key":"ref118","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1186\/s12920-024-02011-5","article-title":"Bioinformatics analysis of ferroptosis in frozen shoulder","volume":"17","author":"Zhang","year":"2024","journal-title":"BMC Med Genet"},{"key":"ref119","doi-asserted-by":"publisher","first-page":"e14386","DOI":"10.1111\/cns.14386","article-title":"Global analysis of iron metabolism-related genes identifies potential mechanisms of gliomagenesis and reveals novel targets","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci Ther"},{"key":"ref120","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.21037\/atm-21-1595","article-title":"Mechanisms and pharmacological applications of ferroptosis: a narrative review","volume":"9","author":"Zhang","year":"2021","journal-title":"Ann Transl Med"},{"key":"ref121","doi-asserted-by":"publisher","first-page":"113828","DOI":"10.1016\/j.expneurol.2021.113828","article-title":"Inhibition of Tlr4 prevents hippocampal hypoxic-ischemic injury by regulating ferroptosis in neonatal rats","volume":"345","author":"Zhu","year":"2021","journal-title":"Exp Neurol"},{"key":"ref122","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1186\/s12891-024-08068-8","article-title":"The link between osteoporosis and frozen shoulder: exploring the therapeutic effect of Tak715 on reversing fibrosis and protecting against osteoporosis via the p38 Mapk signaling pathway","volume":"25","author":"Li","year":"2024","journal-title":"BMC Musculoskelet Disord"},{"key":"ref123","doi-asserted-by":"publisher","first-page":"723","DOI":"10.2147\/Jir.S348491","article-title":"p38mapk signaling pathway in osteoarthritis: pathological and therapeutic aspects","volume":"15","author":"Li","year":"2022","journal-title":"J Inflamm Res"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"5966","DOI":"10.1021\/jm050165o","article-title":"Novel inhibitor of p38 map kinase as an anti-Tnf-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (Tak-715) as a potent and orally active anti-rheumatoid arthritis agent","volume":"48","author":"Miwatashi","year":"2005","journal-title":"J Med Chem"},{"key":"ref125","doi-asserted-by":"publisher","first-page":"101979","DOI":"10.1016\/j.mtbio.2025.101979","article-title":"Antioxidant RuCo nanosheet attenuates capsule fibrosis in adhesive capsulitis of shoulder by p38 Mapk signaling pathway inhibition","volume":"33","author":"Qi","year":"2025","journal-title":"Mater Today Bio"},{"key":"ref126","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41467-023-44451-0","article-title":"A genome-wide association meta-analysis implicates hedgehog and notch signaling in Dupuytren's disease","volume":"15","author":"Riesmeijer","year":"2024","journal-title":"Nat Commun"},{"key":"ref127","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1080\/03008207.2019.1648445","article-title":"Biomarkers associated with idiopathic frozen shoulder: a systematic review","volume":"61","author":"Andronic","year":"2020","journal-title":"Connect Tissue Res"},{"key":"ref128","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1002\/jor.24228","article-title":"Genetic variants involved in extracellular matrix homeostasis play a role in the susceptibility to frozen shoulder: a case-control study","volume":"37","author":"Cohen","year":"2019","journal-title":"J Orthop Res"},{"key":"ref129","doi-asserted-by":"publisher","first-page":"1075395","DOI":"10.3389\/fimmu.2023.1075395","article-title":"Role of immune cell infiltration and small molecule drugs in adhesive capsulitis: novel exploration based on bioinformatics analyses","volume":"14","author":"Liu","year":"2023","journal-title":"Front Immunol"},{"key":"ref130","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1186\/s12891-022-05762-3","article-title":"Characteristics of gene expression in frozen shoulder","volume":"23","author":"Nishimoto","year":"2022","journal-title":"BMC Musculoskelet Disord"},{"key":"ref131","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41586-019-1263-7","article-title":"Distinct fibroblast subsets drive inflammation and damage in arthritis","volume":"570","author":"Croft","year":"2019","journal-title":"Nature"},{"key":"ref132","doi-asserted-by":"publisher","first-page":"14852","DOI":"10.1038\/ncomms14852","article-title":"Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions","volume":"8","author":"Frank-Bertoncelj","year":"2017","journal-title":"Nat Commun"},{"key":"ref133","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41586-020-2222-z","article-title":"Notch signalling drives synovial fibroblast identity and arthritis pathology","volume":"582","author":"Wei","year":"2020","journal-title":"Nature"},{"key":"ref134","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1172\/Jci149538","article-title":"Fibroblast pathology in inflammatory diseases","volume":"131","author":"Wei","year":"2021","journal-title":"J Clin Invest"},{"key":"ref135","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1038\/s41467-024-45341-9","article-title":"A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution","volume":"15","author":"Ng","year":"2024","journal-title":"Nat Commun"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1883535\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:22:24Z","timestamp":1786076544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1883535\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":135,"alternative-id":["10.3389\/fmed.2026.1883535"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1883535","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]},"article-number":"1883535"}}