Nrf2-Keap1 Axis Modulation by Phytofabricated Metal Oxide Nanoparticles in Mesenchymal Stem Cell Lineage Bias

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-Keap1 (nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1) signaling axis as a redox-sensitive rheostat governing the balance between osteogenic and adipogenic differentiation. Physiological reactive oxygen species (ROS) support osteogenesis in a dose- and context-dependent 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 "more is better" relationship. Conventional plant-derived 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, "green" delivery alternative. We propose that these hybrid systems may act through a dual-stimulus mechanism - phytochemical-mediated electrophilic modification of Keap1 cysteines alongside metal-oxide-core-derived, sub-cytotoxic ROS consistent with mitohormetic signaling - that together could promote Nrf2 nuclear translocation, ARE-driven antioxidant gene expression, and downstream epigenetic reinforcement of osteogenic commitment. This dual-stimulus 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.