{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:04:33Z","timestamp":1784174673337,"version":"3.55.0"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100011789","name":"Department of Science and Technology of Jilin Province","doi-asserted-by":"publisher","award":["20250203025SF"],"award-info":[{"award-number":["20250203025SF"]}],"id":[{"id":"10.13039\/501100011789","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":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Midkine (MK) protein plays a critical regulatory role in tooth development and odontogenic differentiation, and has been shown to significantly promote reparative dentine formation. However, the direct application of recombinant MK protein as a pulp capping material presents clinical challenges and may increase medical costs. In contrast, peptides offer a cost\u2010effective and feasible alternative by overcoming many of the limitations associated with full\u2010length proteins. This study aimed to develop a novel MK\u2010derived peptide for use in vital pulp therapy (VPT).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>The human MK protein sequence was appropriately cleaved, resulting in the generation of multiple MK\u2010derived peptides. The peptide with the highest mineralisation potential was identified through quantitative polymerase chain reaction (qPCR) and alizarin red S (ARS) staining. Cell proliferation, live\/dead cell staining and apoptosis assays were conducted to evaluate the in\u00a0vitro biosafety of MK\u2010derived peptide. The optimal concentration of MK\u2010derived peptide for promoting cell migration and odontogenic differentiation was determined using cell migration assays, qPCR, Western blotting, alkaline phosphatase staining and ARS staining. RNA sequencing, bioinformatics analysis, transmission electron microscopy and siRNA were used to explore the potential mechanism by which MK\u2010derived peptide promotes odontogenesis. A rat pulp capping model was established, and in\u00a0vivo evaluation was conducted through Micro\u2010CT, H&amp;E, Masson and immunohistochemical staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following appropriate cleavage of the human MK protein, a total of 15 peptides were generated, among which MK\u201012 (KARYNAQCQETI) exhibited the highest mineralisation potential. MK\u201012 demonstrated favourable in\u00a0vitro biocompatibility at concentrations below 200\u2009\u03bcg\/mL, with the optimal effect on promoting cell migration and odontogenic differentiation observed at 100\u2009\u03bcg\/mL. RNA\u2010sequencing and functional analyses revealed that MK\u201012 was closely associated with autophagy and mammalian target of rapamycin (mTOR) signalling pathways. Subsequent experiments demonstrated that MK\u201012 modulates the mTOR pathway and autophagy by upregulating the expression of DNA damage\u2010inducible transcript 4 (DDIT4). In\u00a0vivo studies confirmed that MK\u201012 effectively promoted the formation of reparative dentine and exhibited favourable biocompatibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MK\u201012, a peptide derived from midkine, was found to promote reparative dentine formation via DDIT4\/mTOR pathway\u2013mediated activation of autophagy, thereby providing a mechanistic basis for its potential clinical application in VPT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.70149","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:11:00Z","timestamp":1774426260000},"page":"1645-1663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Midkine\u2010Derived Peptide Promotes Reparative Dentine Formation via\n                    <scp>DDIT4<\/scp>\n                    \/\n                    <scp>mTOR<\/scp>\n                    Pathway\u2010Mediated Activation of Autophagy"],"prefix":"10.1111","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9256-6770","authenticated-orcid":false,"given":"Shuwei","family":"Qiao","sequence":"first","affiliation":[{"name":"Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Wang","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-6758","authenticated-orcid":false,"given":"Hamed","family":"Alshawwa","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Zou","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Si","sequence":"additional","affiliation":[{"name":"Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology Nanjing University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-0215","authenticated-orcid":false,"given":"Xi","family":"He","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6935-9490","authenticated-orcid":false,"given":"Song","family":"Zhu","sequence":"additional","affiliation":[{"name":"Hospital of Stomatology Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114376"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma14040874"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.13128"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2017.06.031"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034515610768"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.13449"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.b.33934"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/iej.12906"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031480"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-022-01665-6"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep36889"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2005.08.016"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.10.095"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.2341\/09-132-0"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/002203458506400403"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1349-0079(06)80026-5"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73939"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ma13204618"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.896893"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-022-00948-5"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.08.005"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2022.100344"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1590\/0103-6440201701135"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2014.07.019"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/pep2.24145"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.153"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.05.530"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.129.1.267"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1599207"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdsr.2018.09.001"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2015.03.017"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2009.09.009"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221101506"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034520925427"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.655498"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/rb\/rbab004"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym12092125"},{"key":"e_1_2_11_39_1","article-title":"Development of a Direct Pulp\u2010Capping Model for the Evaluation of Pulpal Wound Healing and Reparative Dentin Formation in Mice","volume":"119","author":"Song M.","year":"2017","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2018.01.018"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(90)91189-Y"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345241253526"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04550-4"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221135766"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.22203\/eCM.v042a26"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.01.016"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02107-5"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2023.06.010"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.12.006"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.605609"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23179686"}],"container-title":["International Endodontic Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/iej.70149","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/iej.70149","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/iej.70149","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:26:38Z","timestamp":1784172398000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/iej.70149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/iej.70149"],"URL":"https:\/\/doi.org\/10.1111\/iej.70149","archive":["Portico"],"relation":{},"ISSN":["0143-2885","1365-2591"],"issn-type":[{"value":"0143-2885","type":"print"},{"value":"1365-2591","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"assertion":[{"value":"2025-08-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}