Zhang RQ, Chu WH, Bai JB, Lei YH, Zhou D. Selenoprotein P attenuates oxidative senescence and ferroptosis-associated lipid peroxidation in dental pulp stem cells through a FOXM1-dependent program. World J Stem Cells 2026; 18(6): 119118 [DOI: 10.4252/wjsc.119118]
Corresponding Author of This Article
Dai Zhou, PhD, Full Professor, Post-doctoral Researcher, Changsha Hospital for Maternal and Child Health Care, Hunan Normal University, No. 416 Chengnan Road, Changsha 410000, Hunan Province, China. zhoudai@hunnu.edu.cn
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Dentistry, Oral Surgery & Medicine
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research-article
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Zhang RQ, Chu WH, Bai JB, Lei YH, Zhou D. Selenoprotein P attenuates oxidative senescence and ferroptosis-associated lipid peroxidation in dental pulp stem cells through a FOXM1-dependent program. World J Stem Cells 2026; 18(6): 119118 [DOI: 10.4252/wjsc.119118]
World J Stem Cells. Jun 26, 2026; 18(6): 119118 Published online Jun 26, 2026. doi: 10.4252/wjsc.119118
Selenoprotein P attenuates oxidative senescence and ferroptosis-associated lipid peroxidation in dental pulp stem cells through a FOXM1-dependent program
Ruo-Qi Zhang, Wei-Hao Chu, Jun-Bo Bai, Yong-Hua Lei, Dai Zhou
Ruo-Qi Zhang, Yong-Hua Lei, Department of Orthodontics and Prosthodontics, Center of Stomatology, Central South University, Changsha 410000, Hunan Province, China
Wei-Hao Chu, Jun-Bo Bai, School of Stomatology, Hunan University of Chinese Medicine, Changsha 410000, Hunan Province, China
Dai Zhou, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha 410000, Hunan Province, China
Co-corresponding authors: Yong-Hua Lei and Dai Zhou.
Author contributions: Zhou D and Lei YH conceived and designed the research, edited and revised the manuscript; they contributed equally to this manuscript and are co-corresponding authors; Zhang RQ, Chu WH, and Bai JB performed experiments; Zhang RQ and Chu WH analyzed data; Zhang RQ, Lei YH, and Zhou D interpreted experimental results; Zhang RQ prepared figures and drafted the manuscript. All authors approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 82201771; Natural Science Foundation of Hunan Province, No. 2024JJ6083; Health Research Project of Hunan Provincial Health Commission, No. W20243143; and Natural Science Foundation of Changsha, No. kq2202491.
Institutional review board statement: This study was conducted in accordance with the Declaration of Helsinki, reviewed and approved by the Medical Ethics Review Committee of Xiangya Hospital Central South University (Approval No. 2025122275). Informed consent was obtained from all participants or their legal guardians.
Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Corresponding author: Dai Zhou, PhD, Full Professor, Post-doctoral Researcher, Changsha Hospital for Maternal and Child Health Care, Hunan Normal University, No. 416 Chengnan Road, Changsha 410000, Hunan Province, China. zhoudai@hunnu.edu.cn
Received: January 20, 2026 Revised: February 21, 2026 Accepted: April 2, 2026 Published online: June 26, 2026 Processing time: 157 Days and 2.2 Hours
Abstract
BACKGROUND
Aging impairs dental pulp regeneration, but upstream mechanisms driving dental pulp stem cell (DPSC) vulnerability remain unclear. Selenium-dependent antioxidant homeostasis is essential for redox control, and selenoprotein P (SEPP1) is a major extracellular selenium transport protein. We hypothesized that age-related loss of SEPP1 contributes to oxidative stress susceptibility in DPSCs and that restoring selenium transport support reduces senescence-associated injury.
AIM
To determine whether SEPP1 and selenium supplementation protect DPSCs from oxidative senescence injury.
METHODS
Single-cell RNA sequencing data from young and aged human dental pulp were integrated. Human DPSCs were exposed to hydrogen peroxide (100 μmol/L, 4 hours), then treated for 48 hours with recombinant SEPP1 (50 ng/mL), sodium selenite (100 nmol/L), or both. Senescence, proliferation, redox injury, and ferroptosis-associated lipid peroxidation were assessed. Ferrostatin-1 rescue and forkhead box protein M1 (FOXM1) knockdown were performed. Bulk RNA sequencing and tissue validation were included.
RESULTS
Aged pulp showed reduced DPSC abundance and weakened selenium-related antioxidant signatures. Combined SEPP1 and sodium selenite treatment reduced senescence-associated changes, improved proliferation, and preserved stemness-related markers after oxidative injury. The combined treatment produced stronger viability rescue than either treatment alone. It also reduced ferrous iron accumulation, glutathione imbalance, glutathione peroxidase 4 downregulation, and lipid peroxidation. Ferrostatin-1 improved viability after oxidative injury, supporting ferroptosis-associated injury involvement. Transcriptome analysis identified FOXM1-centered cell cycle and antioxidant programs, and FOXM1 knockdown attenuated the protective effects. Aged human pulp tissues showed reduced SEPP1 and FOXM1 expression.
CONCLUSION
SEPP1 and selenium co-treatment mitigates oxidative senescence and ferroptosis-associated lipid peroxidation in DPSCs through a FOXM1-dependent protective program.
Core Tip: Aging-associated decline of dental pulp stem cells is linked to impaired selenium-dependent antioxidant defense. This study integrates single-cell transcriptomics, oxidative stress modeling, and human tissue validation to show that selenoprotein P and sodium selenite co-treatment reduces senescence and ferroptosis-associated lipid peroxidation in dental pulp stem cells. The combined treatment is more effective than either agent alone, and ferrostatin-1 rescue supports ferroptosis-related injury involvement. Transcriptomic and knockdown analyses identify a forkhead box protein M1-dependent protective program downstream of selenoprotein P/selenium support, highlighting a candidate strategy for preserving dental pulp vitality during aging.
