Perfluorooctanoic acid (PFOA) induces adipose-derived ADMSC senescence via oxidative stress pathway

Adipose-derived Mesenchymal Stem Cells (ADMSCs) are crucial for tissue repair, immune modulation, and regenerative medicine. However, environmental pollutants, such as perfluorooctanoic acid (PFOA), pose significant risks to ADMSC functionality. This study investigates the effects of PFOA exposure on ADMSC viability, senescence, differentiation, immune regulation, and lipid metabolism. Our findings show that PFOA exposure significantly reduces ADMSC viability, accelerates cellular senescence, and impairs adipogenic and osteogenic differentiation. Moreover, PFOA disrupts ADMSC-mediated immune regulation and lipid metabolism, diminishing their ability to suppress T-cell proliferation, regulate inflammatory responses and lipid metabolism. Mechanistically, PFOA induces oxidative stress by increasing reactive oxygen species (ROS) levels, which leads to mitochondrial dysfunction. Furthermore, PFOA alters the KEAP1-NFE2L2 signaling pathway, which plays a pivotal role in regulating oxidative stress and antioxidant responses. RNA sequencing and pathway enrichment analyses identified significant alterations in antioxidant and detoxification pathways in PFOA-exposed ADMSCs. These findings demonstrate that PFOA accelerates ADMSC aging and impairs their regenerative potential, highlighting the potential risks posed by environmental pollutants to stem cell functionality. Future studies should focus on exploring therapeutic interventions, such as targeting the KEAP1-NFE2L2 pathway or utilizing antioxidant strategies, to mitigate the detrimental effects of environmental toxins on stem cell-based therapies. This study highlights the environmental impact of PFOA exposure on mesenchymal stem cells, emphasizing its role in aging, dysfunction, and impaired regenerative potential. • Reveal PFOA-induced MSC aging via ROS accumulation and mitochondrial dysfunction. • Identify KEAP1-NFE2L2 signaling dysregulation in antioxidant response impairment. • Demonstrate PFOA induces MSC senescence. • Highlight environmental pollutant risks to stem cell-based regenerative therapies.