PFOS Exposure Triggers NRF2-Mediated Senescence in Bone Marrow Mesenchymal Stem Cells to Attenuate Their Chondrogenic Potential

The widespread application of per- and polyfluoroalkyl substances (PFASs) has established perfluorooctanesulfonic acid (PFOS), a representative PFAS, as a critical environmental pollutant. Although PFOS exposure causes significant bioaccumulation and potential myelotoxicity, its specific impact on the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) remains to be elucidated. In this study, we established a murine model of PFOS exposure to isolate primary BMSCs and investigated this issue through in vitro differentiation assays, cellular senescence evaluations, and an in vivo subcutaneous implantation model using gelatin methacryloyl (GelMA) hydrogel scaffolds. Our results demonstrated that PFOS exposure triggered intracellular reactive oxygen species (ROS) accumulation and induced a senescent phenotype in BMSCs, characterized by restricted cellular proliferation and the release of senescence-associated secretory phenotype (SASP) factors, thereby markedly suppressing their chondrogenic capacity. Mechanistically, the inhibition of the Nrf2 signaling pathway by PFOS was identified as the principal driver of this process. Furthermore, both in vitro and in vivo assays confirmed that pharmacological activation using the Nrf2 agonist sulforaphane (SFN) effectively mitigated the senescent phenotype and restored the chondrogenic potential of PFOS-exposed BMSCs. Altogether, these findings elucidate the specific mechanisms of PFOS-induced stem cell toxicity and offer a potential strategy to overcome the resulting limitations in BMSC-based cartilage regeneration.