文献类型：期刊文献

英文题名：N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) induces osteoporosis by a mechanism involving CX43-mediated mitochondrial autophagy dysfunction in bone marrow mesenchymal stem cells

作者：Zhang, Haitao[1,2];Chen, Chaofeng[3,4];Wang, Dayu[5];Huang, Yiwei[6];Liu, Yang[7];Wang, Zhiyuan[5];Fu, Furui[8];Wang, Hongyu[8];Shi, Senjie[8];Li, Yijin[5];Zeng, Jianchun[1,2];Shen, Caiping[1,2];Zhong, Chudan[1,2];Liu, Xiaozhou[9];Chen, Jinlun[1,2];Li, Jie[1,2];Liu, Shufen[8];Huang, Jin[8,10];Zeng, Yirong[1,2];Feng, Wenjun[1,2]

第一作者：Zhang, Haitao

通信作者：Zeng, YR[1];Feng, WJ[1];Liu, SF[2];Huang, J[2]

机构：[1]Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou, Peoples R China;[2]Guangdong Prov Hosp Tradit Chinese Med, Guangzhou, Peoples R China;[3]Guangzhou Univ Chinese Med, Clin Med Sch 1, Guangzhou, Peoples R China;[4]Panyu Hosp Chinese Med, Guangzhou, Peoples R China;[5]Guangzhou Univ Chinese Med, Guangzhou, Peoples R China;[6]Zhongshan Hosp Tradit Chinese Med, Zhongshan, Peoples R China;[7]Nanchang Med Coll, Nanchang, Peoples R China;[8]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Shanghai, Peoples R China;[9]Huizhou Tradit Chinese Med Hosp, Huizhou, Peoples R China;[10]Gansu Univ Chinese Med, Lanzhou, Peoples R China

第一机构：Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou, Peoples R China

通信机构：[1]corresponding author), Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou, Peoples R China;[2]corresponding author), Shanghai Univ Tradit Chinese Med, Longhua Hosp, Shanghai, Peoples R China.

年份：2026

卷号：311

外文期刊名：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY

收录：;Scopus(收录号：2-s2.0-105031631363);WOS:【SCI-EXPANDED(收录号:WOS:001692117300001)】；

基金：This work was supported in part by the National Natural Science Foundation of China (Grant No. 82374484) , National Research Project for the Transmission and Innovation of Traditional Chinese Medicine at Guangzhou University of Chinese Medicine (Grant No. 2022QN16) , Guangzhou University of Chinese Medicine Joint University-Research Innovation Fund (Grant No. GZYZS2024G42) , Guangzhou University of Chinese Medicine Joint University-Research Innovation Fund (Grant No. GZYHZ2025Y06) , Guangzhou Science and Technology Plan Project (Grant No. 2025A04J2851) , Guangdong Provincial Administration of Traditional Chinese Medicine Research Platform Special Project (Grant No. 20254038) , Young and Middle-aged Key Talent Training Project of the First Affiliated Hospital of Guangzhou University of Chinese Medicine "Young and Excellent Talent", Jin-Tian-Ge Young and Middle-aged Research Training Fund, Guangdong Province Traditional Chinese Medicine Research Project (Grant No. 20232061) , and Guangdong Province Traditional Chinese Medicine Research Project (Grant No. 20232061, 20232128) .

语种：英文

外文关键词：6PPD-Q; Osteoporosis; CX43; Mitophagy

摘要：As an emerging environmental contaminant, N-(1,3-dimethylbutyl)-N '-phenyl-p-phenylenediamine-quinone (6PPD-Q) poses a potential threat to public health. However, the potential link between 6PPD-Q exposure and bone health remains largely unexplored. This study aims to systematically investigate the toxic effects of 6PPD-Q on bone metabolism and elucidate the underlying mechanisms by integrating transcriptomic sequencing, network toxicology, single-cell RNA, Molecular docking, molecular dynamics with both in vivo and in vitro experiments. Integrative analysis converged on mitophagy as a central mechanism in 6PPD-Q-induced osteoporosis, with single-cell sequencing identifying bone marrow-derived mesenchymal stem cells (BMSCs) as the key cell type and revealing CX43, MMP2, PDGFRB, and FYN as the principal targets. Molecular docking and MD simulations confirmed the targeted binding of 6PPD-Q to CX43. RNA-seq analysis of rat tibiae validated the differential expression of CX43 and the critical role of mitophagy. Both in vivo and in vitro experiments demonstrated that 6PPD-Q-induced bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. In conclusion, this study elucidates that 6PPD-Q induces bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. Our work establishes a comprehensive mechanistic framework for 6PPD-Q-induced bone damage and offers novel insights for future research into its bone toxicity. The 1 or 10 mg/kg dose used in this study, although higher than the typical environmental exposure level, is consistent with the effects observed in cadmium exposure and is close to the 8 mg/kg dose used in studies on mouse bone toxicity. Additionally, the 5 ng/mL concentration of 6PPD-Q used in the in vitro experiments is comparable to the concentration detected in freshwater, indicating its environmental relevance.