{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:06:55Z","timestamp":1791515215517,"version":"4.3.4"},"reference-count":55,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Patients with diabetes are at a higher risk of developing acute pancreatitis compared to those without diabetes. Therefore, it is essential to investigate the effects of metformin, a primary treatment for type 2 diabetes, on the progression of pancreatitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Network pharmacology was employed to investigate the potential effects of metformin on pancreatitis and to predict its underlying molecular mechanisms. Pharmacological and mechanistic studies of metformin were conducted utilising mtDNA depletion (\u03c10) of 266\u20106 acinar cells, knockout mouse models and experimental models of both acute and chronic pancreatitis. The mitochondrial homeostasis and plasma membrane integrity were examined through phase\u2010contrast microscopy and time\u2010lapse video imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Network pharmacology analysis revealed that metformin possesses significant potential to modulate the pathogenesis of pancreatitis, likely through its regulation of mitochondrial function and cell membrane morphology. Further, the results revealed that metformin augmented the release of oxidised mitochondrial DNA (Ox\u2010mtDNA) by enhancing NINJ1\u2010mediated plasma membrane rupture, which subsequently ignited a cascade of acinar cell necrosis. Metformin exacerbated mitochondrial iron imbalance by suppressing Frataxin, thereby worsening mitochondrial homeostasis disruption and Ox\u2010mtDNA generation. NINJ1 knockout eliminated the metformin\u2010induced acinar cell necrosis and elevation of Ox\u2010mtDNA levels, and mtDNA depletion reversed the effect of metformin on acinar cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Metformin exacerbates both acute and chronic pancreatitis, possibly because of increased release of Ox\u2010mtDNA via modulation of mitochondrial iron homeostasis and NINJ1\u2010mediated plasma membrane rupture, suggesting that extreme caution should be exercised when using metformin in diabetic patients with pancreatitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70065","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T09:14:34Z","timestamp":1746782074000},"page":"3952-3968","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)\/ninjurin 1 (NINJ1) signalling pathway"],"prefix":"10.1111","volume":"182","author":[{"given":"Guang","family":"Xin","sequence":"first","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qilong","family":"Zhou","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Wan","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxian","family":"Yu","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Li","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Li","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuman","family":"Dong","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilan","family":"Wang","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Feng","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Wen","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, Natural and Biomimetic Medicine Research Center, Tissue\u2010Orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01729-w"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16177"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/derm.23792"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/15563650701355314"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107246"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/000456329102800105"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409230600846058"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.10.012"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-023-00595-3"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000329999"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.25116"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05991-z"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106114"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2010.01231.x"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.09.043"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02032904"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pan.2016.05.001"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2014.00117"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.7562216"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03218-7"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2016.61"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2020.10.013"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241411554"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/BPH.15178"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05623-4"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.09.008"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05052-2"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4822"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.2003.011957"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-308553"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051035"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.243"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710539200"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.03.041"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.14242"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2925-1"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.050"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2457"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2022.5212"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2022.155223"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200302000-00029"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1177\/875512251202800507"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-018-5227-9"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2023.01.006"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.06.007"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep36222"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02012-7"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.07.002"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.01.065"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0372-z"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116690"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.70065","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:57:59Z","timestamp":1752505079000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.70065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":55,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1111\/bph.70065"],"URL":"https:\/\/doi.org\/10.1111\/bph.70065","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"assertion":[{"value":"2024-09-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}