{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:04:28Z","timestamp":1790813068398,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Zerone Cellvane Inc.","award":["B20220018"],"award-info":[{"award-number":["B20220018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is widely used to treat osteoporosis and bone metastases. However, its clinical application is limited by adverse effects, notably bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is associated with cytotoxicity in oral mucosal cells. Polydeoxyribonucleotide (PDRN), a salmon sperm-derived DNA polymer with regenerative and anti-inflammatory properties, has shown therapeutic potential in tissue repair; however, its ability to mitigate ZA-induced cytotoxicity remains poorly understood. Here, we investigated the molecular mechanisms of ZA-induced toxicity in HGF-1 cells, a human gingival fibroblast line, and evaluated the protective effects of PDRN. ZA treatment (50 \u00b5M, 48 h) significantly inhibited HGF-1 cell growth, accompanied by reduced phosphorylation of protein kinase B (PKB) and signal transducer and activator of transcription 3 (STAT-3), along with increased phosphorylation of TANK-binding kinase 1 (TBK1). TBK1 silencing restored cell growth under ZA exposure, whereas silencing PKB or STAT-3 further suppressed cell growth even without ZA. Co-treatment with PDRN (100 \u00b5g\/mL) effectively prevented and reversed ZA-induced HGF-1 cytotoxicity. Mechanistically, PDRN inhibited ZA-induced TBK1 phosphorylation and partially restored PKB phosphorylation, though it did not reverse the reduction in p-STAT-3. Additionally, ZA significantly elevated intracellular reactive oxygen species (ROS) levels at 8 h, which were attenuated by PDRN. The antioxidant N-acetylcysteine (NAC) similarly reduced ZA-induced ROS and p-TBK1 levels and improved cell growth, although it had limited effects on p-PKB at 8 h. Importantly, delayed PDRN treatment following ZA exposure reversed ZA-induced cell growth inhibition and TBK1 activation in a dose- and time-dependent manner. In summary, these findings demonstrate that ZA suppresses HGF-1 cell growth through ROS production, TBK1 activation, and inhibition of PKB and STAT-3, whereas PDRN counteracts these effects primarily by suppressing TBK1 activation and oxidative stress.<\/jats:p>","DOI":"10.3390\/ijms262311367","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T08:50:20Z","timestamp":1764060620000},"page":"11367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Mitigating Effect and Mechanism of Polydeoxyribonucleotide Against Zoledronic Acid-Induced Growth Suppression of Human Gingival Fibroblasts"],"prefix":"10.3390","volume":"26","author":[{"given":"Shailashree","family":"Pachhapure","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2045-2234","authenticated-orcid":false,"given":"Young-Min","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Dentistry, School of Medicine, Dongsan Hospital, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duk Gyu","family":"Kim","sequence":"additional","affiliation":[{"name":"Zerone Cellvane Inc., Cheonan 31035, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Rak","family":"Choi","sequence":"additional","affiliation":[{"name":"Zerone Cellvane Inc., Cheonan 31035, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-IL","family":"Yun","sequence":"additional","affiliation":[{"name":"Yeon Dental Clinic, Seoul 04363, Republic of Korea"},{"name":"Dental R&D Center, Zerone Cellvane Inc., Seoul 04363, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hong","family":"Kim","sequence":"additional","affiliation":[{"name":"Dental R&D Center, Zerone Cellvane Inc., Seoul 04363, Republic of Korea"},{"name":"Seoul Top Dental Clinic, Namyangju-si 12232, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong-Churl","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/jcb.25266","article-title":"Risks and benefits of bisphosphonate therapies","volume":"117","author":"Reyes","year":"2016","journal-title":"J. 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