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Here, we propose amorphous silicon oxynitride (SiONx) as a coating for the fixation devices to improve both bioactivity and bacteriostatic activity and reduce oxidative stress. We aimed to study the effect of increasing the N\/O ratio in the SiONx to fine-tune the cellular activity and the antioxidant effect via the NRF2 pathway under oxidative stress conditions. The in vitro studies involved using human mesenchymal stem cells (MSCs) to examine the effect of SiONx coatings on osteogenesis with and without toxic oxidative stress. Additionally, bacterial growth on SiONx surfaces was studied using methicillin-resistant Staphylococcus aureus (MRSA) colonies. NRF2 siRNA transfection was performed on the hMSCs (NRF2-KD) to study the antioxidant response to silicon ions. The SiONx implant surfaces showed a &gt;4-fold decrease in bacterial growth vs. bare titanium as a control. Increasing the N\/O ratio in the SiONx implants increased the alkaline phosphatase activity &gt;1.5 times, and the other osteogenic markers (osteocalcin, RUNX2, and Osterix) were increased &gt;2-fold under normal conditions. Increasing the N\/O ratio in SiONx enhanced the protective effects and improved cell viability against toxic oxidative stress conditions. There was a significant increase in osteocalcin activity compared to the uncoated group, along with increased antioxidant activity under oxidative stress conditions. In NRF2-KD cells, there was a stunted effect on the upregulation of antioxidant markers by silicon ions, indicating a role for NRF2. In conclusion, the SiONx coatings studied here displayed bacteriostatic properties. These materials promoted osteogenic markers under toxic oxidative stress conditions while also enhancing antioxidant NRF2 activity. These results indicate the potential of SiONx coatings to induce in vivo bone regeneration in a challenging oxidative stress environment.<\/jats:p>","DOI":"10.3390\/antiox13020189","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T08:44:08Z","timestamp":1706777048000},"page":"189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SiONx Coating Regulates Mesenchymal Stem Cell Antioxidant Capacity via Nuclear Erythroid Factor 2 Activity under Toxic Oxidative Stress Conditions"],"prefix":"10.3390","volume":"13","author":[{"given":"Neelam","family":"Ahuja","sequence":"first","affiliation":[{"name":"Bone-Muscle Research Center, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3621-1136","authenticated-orcid":false,"given":"Kamal","family":"Awad","sequence":"additional","affiliation":[{"name":"Bone-Muscle Research Center, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Department of Material Science and Engineering, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8494-0475","authenticated-orcid":false,"given":"He","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonios","family":"Mikos","sequence":"additional","affiliation":[{"name":"Center for Engineering Complex Tissues, Center for Excellence in Tissue Engineering, Rice University, Houston, TX 77005, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2885-1918","authenticated-orcid":false,"given":"Pranesh","family":"Aswath","sequence":"additional","affiliation":[{"name":"Department of Material Science and Engineering, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-7083","authenticated-orcid":false,"given":"Simon","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Brotto","sequence":"additional","affiliation":[{"name":"Bone-Muscle Research Center, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venu","family":"Varanasi","sequence":"additional","affiliation":[{"name":"Bone-Muscle Research Center, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Department of Material Science and Engineering, University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dimitriou, R., Jones, E., McGonagle, D., and Giannoudis, P.V. 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