{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:51:04Z","timestamp":1781715064566,"version":"3.54.5"},"reference-count":56,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071126"],"award-info":[{"award-number":["82071126"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2025,11]]},"abstract":"ABSTRACT<\/jats:title>Aim<\/jats:title>To investigate the role and mechanism of progranulin (PGRN) in reparative dentinogenesis and inflammation control for rat pulpitis and inflammatory human dental pulp stem cells (hDPSCs).<\/jats:p><\/jats:sec>Methodology<\/jats:title>Eight\u2010week\u2010old male Wistar rats with irreversible pulpitis were treated with pulpotomy and divided into five groups: No treatment; Control; iRoot BP plus (BP); GelMA and recombinant human PGRN (rhPGRN)\u2009+\u2009GelMA (rhPGRN). Micro\u2010computed tomography (Micro\u2010CT) scans and histological and immunohistochemical staining were conducted to evaluate rhPGRN' anti\u2010inflammation and pro\u2010healing properties. The effects of rhPGRN on hDPSC inflammatory response, proliferation and dentinogenic differentiation and potential signalling pathways were assessed through CCK\u20108, alkaline phosphatase (ALP) staining, alizarin red staining, quantitative reverse transcription polymerase chain reaction (qRT\u2010PCR), enzyme\u2010linked immunosorbent assay (ELISA), immunofluorescence staining and western blotting.<\/jats:p><\/jats:sec>Results<\/jats:title>In vivo, PGRN expression obviously increased in both the Control and GelMA groups compared to healthy pulp (p<\/jats:italic>\u2009<\u20090.05). The BP and rhPGRN groups showed a significant decrease in inflammatory scores and expression of M1 macrophage markers CD86 and tumour necrosis factor alpha (TNF\u2010\u03b1) while increasing M2 markers CD206 and interleukin 10 (IL\u201010) compared with the controls (p<\/jats:italic>\u2009<\u20090.05). Enhanced dentine bridge formation and dentine sialophosphoprotein (DSPP) expression were observed in the BP and rhPGRN groups versus the controls (p<\/jats:italic>\u2009<\u20090.05). Moreover, the rhPGRN group presented higher expressions of CD206, IL\u201010 and DSPP than the BP group (p<\/jats:italic>\u2009<\u20090.05). In\u00a0vitro, PGRN expression significantly increased in lipopolysaccharide (LPS)\u2010stimulated hDPSCs (p<\/jats:italic>\u2009<\u20090.05). rhPGRN significantly reduced the release of TNF\u2010\u03b1, interleukin 1 beta (IL\u20101\u03b2) and IL\u20106 in LPS\u2010stimulated hDPSCs and enhanced ALP activity, mineralized nodule formation and expression of ALP, Runt\u2010related transcription factor 2 (RUNX2) and DSPP in LPS\u2010stimulated or unstimulated hDPSCs (p<\/jats:italic>\u2009<\u20090.05). Mechanistically, co\u2010immunoprecipitation showed that PGRN bound to tumour necrosis factor receptor\u20102 (TNFR2), interacting with 14\u20103\u20103 epsilon (14\u20103\u20103\u03b5) in hDPSCs. PGRN significantly inhibited LPS\u2010activated phosphorylation of NF\u2010\u03baB\/p65 and its nuclear translocation, and the use of a TNFR2 neutralising antibody or the 14\u20103\u20103 protein inhibitor R18 reversed these effects (p<\/jats:italic>\u2009<\u20090.05).<\/jats:p><\/jats:sec>Conclusion<\/jats:title>These findings suggest that PGRN plays a crucial role in anti\u2010inflammation, immunomodulation and reparative dentinogenesis in rat pulpitis via the TNFR2\/14\u20103\u20103\u03b5\u2010NF\u2010\u03baB pathway, highlighting its potential as a strategy for vital pulp therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.70000","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T08:30:28Z","timestamp":1753691428000},"page":"1725-1737","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Progranulin (PGRN<\/scp>) Facilitates Anti\u2010Inflammation and Pulpitis Repair In\u00a0Vivo and In\u00a0Vitro Through TNFR2<\/scp>\/14\u20103\u20103\u03b5 Signalling Complex"],"prefix":"10.1111","volume":"58","author":[{"given":"Jinhong","family":"Ju","sequence":"first","affiliation":[{"name":"Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caijiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, School and Hospital of Stomatology, Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fujiao","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases Jinan 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Oral Diseases Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4800-3396","authenticated-orcid":false,"given":"Yi","family":"Du","sequence":"additional","affiliation":[{"name":"Yantai & Department of Endodontics, Jinan Stomatological Hospital Binzhou Medical University Jinan 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