{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:15:26Z","timestamp":1788671726577,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Keloids are characterized by fibrosis and chronic inflammation, but links between mitochondrial dysfunction and keloid pathogenesis remain unclear. This study examined whether impaired PINK1\/Parkin-dependent mitophagy is associated with mitochondrial DNA (mtDNA)-mediated innate immune activation and fibrosis in keloids, and evaluated mitochondrial transplantation as a potential therapeutic strategy. Primary keloid fibroblasts (KFs), normal skin fibroblasts (NFs), adipose-derived stem cells (ADSCs), human keloid tissues, and human keloid xenografts in immunodeficient BALB\/c nude mice were analyzed using ultrastructural, molecular, and functional approaches. Freshly isolated NF-derived mitochondria (nMito) and ADSC-derived mitochondria (aMito) were compared at protein-equivalent doses. KFs exhibited mitochondrial abnormalities, impaired oxidative phosphorylation, increased reactive oxygen species, mtDNA leakage, and cGAS\/STING pathway activation. Elevated PINK1 expression, reduced Parkin expression and p62 accumulation were consistent with impaired downstream mitophagic clearance. Both nMito and aMito were associated with improved mitochondrial function, changes in mitophagy-related markers, reduced cytosolic mtDNA and cGAS\/STING signaling, and attenuated fibroblast activation, with greater aMito-associated changes in selected endpoints. In xenografts, intralesional administration of either mitochondria improved collagen organization and reduced fibrotic and inflammatory signaling. Together, these findings link altered PINK1\/Parkin-dependent mitophagy to mtDNA-driven inflammation and fibrosis and support mitochondrial transplantation as a potential organelle-based therapeutic approach.<\/jats:p>","DOI":"10.3390\/antiox15091120","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial Transplantation Suppresses mtDNA-cGAS\/STING-Mediated Innate Immunity by Enhancing PINK1\/Parkin-Dependent Mitophagy to Attenuate Keloid Fibrosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0728-6526","authenticated-orcid":false,"given":"Wenjing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-5880","authenticated-orcid":false,"given":"Yuanbo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Jipeng","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"},{"name":"Department of Aesthetic Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing 102208, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5303-7837","authenticated-orcid":false,"given":"Zouzou","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Zixiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"given":"Hu","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, H.J., and Kim, Y.H. (2024). Comprehensive Insights into Keloid Pathogenesis and Advanced Therapeutic Strategies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168776"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/exd.14414","article-title":"The Epigenetics of Keloids","volume":"30","author":"Stevenson","year":"2021","journal-title":"Exp. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79e","DOI":"10.1097\/PRS.0000000000008667","article-title":"The Most Current Algorithms for the Treatment and Prevention of Hypertrophic Scars and Keloids: A 2020 Update of the Algorithms Published 10 Years Ago","volume":"149","author":"Ogawa","year":"2022","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/ijd.15159","article-title":"Keloids: A Review of Therapeutic Management","volume":"60","author":"Ekstein","year":"2021","journal-title":"Int. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12964-026-02807-1","article-title":"Lipid Droplet-Mediated Macrophage Reprogramming Drives Fibroblast Activation in Keloid-Associated Inflammation","volume":"24","author":"Shao","year":"2026","journal-title":"Cell Commun. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.burns.2021.03.003","article-title":"Warburg Effect in Keloids: A Unique Feature Different from Other Types of Scars","volume":"48","author":"Su","year":"2022","journal-title":"Burns"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/s41556-018-0124-1","article-title":"The Multifaceted Contributions of Mitochondria to Cellular Metabolism","volume":"20","author":"Spinelli","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Feng, L., Chen, X., Huang, Y., Zhang, X., Zheng, S., and Xie, N. (2023). Immunometabolism Changes in Fibrosis: From Mechanisms to Therapeutic Strategies. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1243675"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41580-024-00730-2","article-title":"Fundamentals of Redox Regulation in Biology","volume":"25","author":"Sies","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41422-025-01203-7","article-title":"Mitophagy in the Pathogenesis and Management of Disease","volume":"36","author":"Wang","year":"2026","journal-title":"Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101815","DOI":"10.1016\/j.redox.2020.101815","article-title":"Altered Glucose Metabolism and Cell Function in Keloid Fibroblasts under Hypoxia","volume":"38","author":"Wang","year":"2021","journal-title":"Redox Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/s41556-024-01513-9","article-title":"The Role of PINK1-Parkin in Mitochondrial Quality Control","volume":"26","author":"Narendra","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16601","DOI":"10.1002\/jcp.28332","article-title":"Inactivating the Ubiquitin Ligase Parkin Suppresses Cell Proliferation and Induces Apoptosis in Human Keloids","volume":"234","author":"Lei","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.immuni.2025.03.005","article-title":"Mitochondrial DNA Released by Senescent Tumor Cells Enhances PMN-MDSC-Driven Immunosuppression Through the cGAS-STING Pathway","volume":"58","author":"Lai","year":"2025","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.cell.2020.09.020","article-title":"TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS\/STING in ALS","volume":"183","author":"Yu","year":"2020","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e13622","DOI":"10.1111\/acel.13622","article-title":"Defective Mitophagy in Aged Macrophages Promotes Mitochondrial DNA Cytosolic Leakage to Activate STING Signaling During Liver Sterile Inflammation","volume":"21","author":"Zhong","year":"2022","journal-title":"Aging Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41577-021-00524-z","article-title":"The cGAS-STING Pathway as a Therapeutic Target in inflammatory diseases","volume":"21","author":"Decout","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41586-023-06537-z","article-title":"The Power and Potential of Mitochondria Transfer","volume":"623","author":"Borcherding","year":"2023","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41586-024-07340-0","article-title":"Mitochondrial Transfer Mediates Endothelial Cell Engraftment Through Mitophagy","volume":"629","author":"Lin","year":"2024","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/s13287-025-04619-5","article-title":"From Mitochondria to Immune Networks: New Mesenchymal Stem Cell Strategies to Treat Periodontitis","volume":"16","author":"Wang","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1186\/s13287-024-03938-3","article-title":"The Effect of Exogenous Mitochondria in Enhancing the Survival and Volume Retention of Transplanted Fat Tissue in a Nude Mice Model","volume":"15","author":"Li","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41419-025-07643-8","article-title":"Mitochondrial Transplantation: Adaptive Bio-Enhancement","volume":"16","author":"Lu","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7131","DOI":"10.1111\/jocd.15416","article-title":"An Improved Explants Culture Method: Sustainable Isolation of Keloid Fibroblasts with Primary Characteristics","volume":"21","author":"He","year":"2022","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, T., Huang, T., Li, J., Li, A., Li, C., Huang, X., and Zhou, Y. (2023). Optimization of Differentiation and Transcriptomic Profile of THP-1 Cells into Macrophage by PMA. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0286056"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1111\/bph.15673","article-title":"The STING Antagonist H-151 Ameliorates Psoriasis via Suppression of STING\/NF-\u03baB-Mediated Inflammation","volume":"178","author":"Pan","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1080\/15548627.2025.2589909","article-title":"Mitochondrial NAD+-Mediated Mitophagy Alleviates Type I Interferon Response to the Cytosolic Mitochondrial DNA","volume":"22","author":"Lan","year":"2026","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1097\/SAP.0000000000002090","article-title":"Triamcinolone Acetonide Suppresses Keloid Formation Through Enhancing Apoptosis in a Nude Mouse Model","volume":"83","author":"Chen","year":"2019","journal-title":"Ann. Plast. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1038\/s41598-018-21539-y","article-title":"Delivery of Exogenous Mitochondria via Centrifugation Enhances Cellular Metabolic Function","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1038\/s41467-025-58189-4","article-title":"Mitochondria Transplantation Transiently Rescues Cerebellar Neurodegeneration Improving Mitochondrial Function and Reducing Mitophagy in Mice","volume":"16","author":"Li","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1016\/j.jid.2020.01.036","article-title":"Hypoxia and HIF-1\u03b1 Regulate Collagen Production in Keloids","volume":"140","author":"Kang","year":"2020","journal-title":"J. Invest. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3892\/or.2026.9117","article-title":"PINK1-Mediated Mitophagy Enhances Breast Cancer Proliferation through Metabolic Reprogramming","volume":"55","author":"Guo","year":"2026","journal-title":"Oncol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1089\/ars.2018.7534","article-title":"Mitochondrial Morphofunction in Mammalian Cells","volume":"30","author":"Bulthuis","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41577-022-00760-x","article-title":"Mitochondrial Control of Inflammation","volume":"23","author":"Marchi","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1093\/cvr\/cvae238","article-title":"PINK1-Mediated Mitophagy Attenuates Pathological Cardiac Hypertrophy by Suppressing the mtDNA Release-Activated cGAS-STING Pathway","volume":"121","author":"Zhou","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.cell.2015.12.057","article-title":"NF-\u03baB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria","volume":"164","author":"Zhong","year":"2016","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1146\/annurev-cellbio-021820-101354","article-title":"Mitochondrial Quality Control and Restraining Innate Immunity","volume":"36","author":"Moehlman","year":"2020","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10777","DOI":"10.2147\/JIR.S541656","article-title":"Advances in cGAS-STING Signaling in Fibrosis Diseases: Therapeutic Target in Pathological Scars","volume":"18","author":"Zhao","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eabj0324","DOI":"10.1126\/scitranslmed.abj0324","article-title":"NF-\u03baB Perturbation Reveals Unique Immunomodulatory Functions in Prx1+ Fibroblasts That Promote Development of Atopic Dermatitis","volume":"14","author":"Ko","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/s41577-025-01186-x","article-title":"The Spatial and Temporal Activation of Macrophages During Fibrosis","volume":"25","author":"Behmoaras","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1093\/jimmun\/vkaf136","article-title":"Stromal Cell-Derived Chemokines Modulate Immune Cells in Inflammation: New Findings and Future Perspectives","volume":"214","author":"Zhang","year":"2025","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s41584-025-01259-0","article-title":"Fibroblasts in Immune Responses, Inflammatory Diseases and Therapeutic Implications","volume":"21","author":"Zou","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4717","DOI":"10.1016\/j.cell.2022.11.004","article-title":"Fibroblast Inflammatory Priming Determines Regenerative Versus Fibrotic Skin Repair in Reindeer","volume":"185","author":"Sinha","year":"2022","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41467-024-55170-5","article-title":"Macrophage STING Signaling Promotes Fibrosis in Benign Airway Stenosis via an IL6-STAT3 Pathway","volume":"16","author":"Chen","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1016\/j.cell.2024.04.037","article-title":"Mitochondria at the Crossroads of Health and Disease","volume":"187","author":"Suomalainen","year":"2024","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1248\/bpb.b25-00716","article-title":"Structural and Functional Diversity of Mitochondria Isolated from Different Cell Types","volume":"49","author":"Endo","year":"2026","journal-title":"Biol. Pharm. Bull."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13287-025-04164-1","article-title":"Enhanced Mitochondrial Function and Delivery from Adipose-Derived Stem Cell Spheres via the EZH2-H3K27me3-PPAR\u03b3 Pathway for Advanced Therapy","volume":"16","author":"Chang","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ceccarelli, S., Pontecorvi, P., Anastasiadou, E., Napoli, C., and Marchese, C. (2020). Immunomodulatory Effect of Adipose-Derived Stem Cells: The Cutting Edge of Clinical Application. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00236"},{"key":"ref_48","first-page":"4","article-title":"Recent Advances in Mitochondrial Transplantation to Treat Disease","volume":"6","author":"Li","year":"2025","journal-title":"Biomater. Transl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e2207334","DOI":"10.1002\/advs.202207334","article-title":"An Update on Adipose-Derived Stem Cells for Regenerative Medicine: Where Challenge Meets Opportunity","volume":"10","author":"Qin","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H94","DOI":"10.1152\/ajpheart.00567.2008","article-title":"Injection of Isolated Mitochondria during Early Reperfusion for Cardioprotection","volume":"296","author":"McCully","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Hayashida, K., Takegawa, R., Endo, Y., Yin, T., Choudhary, R.C., Aoki, T., Nishikimi, M., Murao, A., Nakamura, E., and Shoaib, M. (2023). Exogenous Mitochondrial Transplantation Improves Survival and Neurological Outcomes after Resuscitation from Cardiac Arrest. BMC Med., 21.","DOI":"10.1186\/s12916-023-02759-0"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"112534","DOI":"10.1016\/j.jphotobiol.2022.112534","article-title":"Structural Integrity Is Essential for the Protective Effect of Mitochondrial Transplantation against UV-Induced Cell Death","volume":"234","author":"Hu","year":"2022","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"H966","DOI":"10.1152\/ajpheart.00883.2012","article-title":"Transplantation of Autologously Derived Mitochondria Protects the Heart from Ischemia-Reperfusion Injury","volume":"304","author":"Masuzawa","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:38:50Z","timestamp":1788669530000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":53,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["antiox15091120"],"URL":"https:\/\/doi.org\/10.3390\/antiox15091120","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}