DRP1 downregulation impairs mitophagy, driving mitochondrial ROS and SASP production in rheumatoid arthritis CD4+PD-1+T cells

作者：Ziran Bai, Jinyi Ren, Jiaqing Liu, Cheng Zhang, Huina Huang, Xiangge Zhao, Xianmei Chen, Jing Wei, Jingjing Qi, Siwen Yang, Weiping Li, Yawei Tang, Guan Wang, Xia Li · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103818 · 被引用次数：11 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Biochemical and Molecular Research

T cell senescence occurs in patients with rheumatoid arthritis (RA), but the specific phenotype and its contribution to tissue-destructive inflammation remain unclear. Here, we aim to investigate whether PD-1 marks pathogenic senescent CD4 + T cells and to explore the role and mechanism of senescent CD4 + PD-1 + T cells in RA pathogenesis. Here, we identified an expanded population of CD4 + PD-1 + T cells in RA patients that exhibited hallmark senescence features, including elevated senescence-associated secretory phenotype (SASP) production. Adoptive transfer experiments demonstrated that CD4 + PD-1 + T cells significantly accelerated disease progression in collagen-induced arthritis (CIA) models. Mechanistically, we demonstrated that RA CD4 + PD-1 + T cells showed decreased expression of dynamin-related protein 1 (DRP1) and impaired mitophagy, leading to mitochondrial reactive oxygen species (MtROS) accumulation and subsequent SASP production. Importantly, PD-1 signaling transcriptionally suppressed DRP1 expression through hypoxia inducible factor 1 alpha subunit (HIF-1α) inhibition. Our findings establish CD4 + PD-1 + T cells as a pathogenic senescent subset that drives RA progression through a PD-1-DRP1-mitophagy-SASP axis.