Tagetes erecta L. polyphenols restore osteogenesis impaired by polystyrene microplastics via NRF2-mediated ER–mitochondrial homeostasis

Microplastic contamination has emerged as a pervasive environmental threat with growing implications for human health, yet its potential impact on skeletal health remains poorly understood. Here we show that polystyrene microplastics (PS-MPs) profoundly disrupt osteogenic differentiation and vertebral mineralization by triggering oxidative stress and organelle dysfunction. In preosteoblasts and zebrafish larvae, PS-MPs suppressed osteogenic regulators including RUNX2 and SP7, accompanied by excessive reactive oxygen species accumulation, activation of endoplasmic reticulum (ER) stress signaling, and disruption of mitochondrial dynamics. We further demonstrate that a polyphenol-rich extract from Tagetes erecta L. (TE) effectively restores osteogenic capacity and skeletal mineralization under PS-MP-induced stress conditions. Mechanistically, TE activates nuclear factor erythroid 2-related factor 2 (NRF2), promoting its nuclear translocation and induction of antioxidant defense pathways that reestablish redox balance and organelle homeostasis. Pharmacological inhibition of NRF2 abolishes these protective effects, identifying NRF2 as a central mediator of TE-driven osteoprotection. Together, our findings elucidate a novel mechanistic axis driven by ROS-mediated ER and mitochondrial stress and highlight T. erecta polyphenols as a potential natural strategy for protecting bone integrity in the face of increasing environmental microplastic exposure.