{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:08:18Z","timestamp":1789549698719,"version":"build-2803163510"},"reference-count":74,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Mesenchymal stem cells (MSCs) hold considerable therapeutic promise in regenerative medicine, yet precise control over lineage fate remains critical for reproducible clinical outcomes. This review examines the Nrf2\u2013Keap1 (nuclear factor erythroid 2\u2013related factor 2\u2013Kelch\u2010like ECH\u2010associated protein 1) signaling axis as a redox\u2010sensitive rheostat governing the balance between osteogenic and adipogenic differentiation. Physiological reactive oxygen species (ROS) support osteogenesis in a dose\u2010 and context\u2010dependent manner, whereas sustained oxidative stress drives cellular senescence and adipogenic bias; emerging evidence also indicates that Nrf2 hyperactivation can itself impair osteogenic differentiation, pointing to an optimal activation window rather than a simple \u201cmore is better\u201d relationship. Conventional plant\u2010derived Nrf2 activators are limited by poor bioavailability and metabolic stability. Phytofabricated metal oxide nanoparticles (MONPs), synthesized using plant extracts as capping and stabilizing agents, offer a biocompatible, \u201cgreen\u201d delivery alternative. We propose that these hybrid systems may act through a dual\u2010stimulus mechanism \u2014 phytochemical\u2010mediated electrophilic modification of Keap1 cysteines alongside metal\u2010oxide\u2010core\u2010derived, sub\u2010cytotoxic ROS consistent with mitohormetic signaling \u2014 that together could promote Nrf2 nuclear translocation, ARE\u2010driven antioxidant gene expression, and downstream epigenetic reinforcement of osteogenic commitment. This dual\u2010stimulus framework, however, remains a mechanistic hypothesis: no study to date has directly demonstrated Keap1 modification, Nrf2 activation, and resulting lineage bias by phytofabricated MONPs within MSCs. Preclinical studies support the efficacy of phytofabricated MONPs in bone defect models and suggest potential for restoring function in senescent MSCs, but direct mechanistic validation in MSC systems remains an essential next step before these insights can guide rational nanoplatform design for bone regeneration.<\/jats:p>","DOI":"10.1002\/jbt.71091","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:49:50Z","timestamp":1788245390000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nrf2\u2013Keap1 Axis Modulation by Phytofabricated Metal Oxide Nanoparticles in Mesenchymal Stem Cell Lineage Bias"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5615-0142","authenticated-orcid":false,"given":"Muhammad","family":"Irfan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Gujrat Gujrat Pakistan"},{"name":"Institute of Veterinary Medicine and Animal Husbandry, Chair of Veterinary Biomedicine and Food Hygiene Estonian University of Life Sciences  Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7435-5944","authenticated-orcid":false,"given":"Muhammad","family":"Taha","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Gujrat Gujrat Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Muhammad Faizan","family":"Asghar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Gujrat Gujrat Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Raza","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology University of Gujrat Gujrat 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