Astaxanthin Reverses Oxidative Stress‐Induced Dysfunction in Human Periodontal Ligament Stem Cells by Activating the Nrf2/ARE Pathway

Background Oxidative stress plays a crucial role in the pathogenesis of periodontitis and compromises the regenerative potential of human periodontal ligament stem cells (hPDLSCs). Astaxanthin (ASX), a potent natural antioxidant with both lipophilic and hydrophilic properties, has been shown to scavenge reactive oxygen species (ROS). However, its protective effects on hPDLSCs under oxidative stress remain largely unexplored. Methods hPDLSCs were isolated and characterized. An oxidative stress model was established by exposing cells to 300 μM H 2 O 2 for 6 h, followed by treatment with 10 μM ASX. Cellular viability, cytoskeletal integrity, ROS accumulation, inflammatory cytokine expression, osteogenic differentiation, and activation of the Nrf2/ARE pathway were assessed. Results ASX significantly reduced intracellular and mitochondrial ROS levels, preserved mitochondrial membrane potential, and inhibited H 2 O 2 ‐induced expression of TNF‐ α , IL‐1 β , IL‐6, and MCP‐1. Moreover, ASX promoted osteogenic differentiation, as evidenced by enhanced alkaline phosphatase (ALP) activity, increased mineralized nodule formation, and upregulation of RUNX2, OCN, and COL1. Mechanistically, ASX activated the Nrf2/ARE pathway, leading to increased expression of Nrf2 and its downstream antioxidant enzymes (HO‐1, NQO‐1, and GCLC). Conclusion These findings demonstrate that ASX ameliorates oxidative stress‐induced injury in hPDLSCs via the Nrf2/ARE signaling pathway, exerting antioxidative, anti‐inflammatory, and pro‐osteogenic effects. This suggests its therapeutic potential for promoting periodontal regeneration under oxidative microenvironments.