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journal article·2026-07Open access

Disruption of Treg Homeostasis in Rheumatoid Arthritis via Ferroptosis‐Mediated ETC Collapse and TXK‐STAT3/PLCγ1 Activation

Jingrong Chen, Xiao Guan, Kexu Xiong, Xiaoyi Shi, Luyao Wu, Chuanxin Su, Jun Zhao, Rongzhen Liang, Huimin Wang, Junlong Dang, Ye Chen, Yiding Xiong, Chi Zhou, Futao Zhao, Zhenhang Zhu, Xiaoli Fan, Li Zhou, Nancy Olsen, Yutong Jiang, Song Guo Zheng

Advanced Science· Volume 13· Issue 41
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Source abstract

Abstract

ABSTRACT In rheumatoid arthritis (RA), regulatory T cells (Tregs) within the synovium present a paradox: they are numerically enriched yet functionally impaired, leading to a loss of immune tolerance. Here, we report that synovial iron overload establishes a ferroptosis‐permissive microenvironment that disrupts Treg homeostasis. Exposure to RA synovial fluid induced ferroptosis, autoimmune Treg‐associated metabolic shifts through lipid peroxide‐driven mitochondrial dysfunction, characterized by electron transport chain (ETC) collapse and impaired oxidative phosphorylation. Mechanistically, metabolic disturbance by ferroptotic stress or complex III blockade triggered TXK kinase upregulation, which is required for the phosphorylation of STAT3 (Tyr705) and PLCγ1 (Tyr783), activating a proinflammatory transcriptional program that destabilized Treg identity and promoted Th17‐like conversion. Crucially, this pathogenic reprogramming was reversed through iron chelation or TXK inhibition in vitro and in vivo. Our findings unveil a ferroptosis‐ETC‐TXK/STAT3 axis as a core mechanism of synovial Treg failure. Targeting synovial iron homeostasis or inhibiting TXK signaling thus represents a promising therapeutic strategy to restore immune tolerance in RA by rescuing Treg functionality.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Immune cells in cancer · Cancer Immunotherapy and Biomarkers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Division of Rheumatology Department of Medicine Songjiang Research Institute Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

Department of Immunology School of Cell and Gene Therapy Songjiang Research Institute Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

The State Key Laboratory of Innovative Immunotherapy At the Shanghai Jiao Tong University School of Medicine Shanghai China

Shenzhen Key Laboratory of Viral Oncology The Clinical Innovation & Research Center (CIRC) Shenzhen Hospital Southern Medical University Shenzhen China

Shenzhen Qianhai Shekou Free Trade Zone Hospital Shenzhen China

Department of Organ Transplantation The Affiliated Guangdong Second Provincial General Hospital of Jinan University Guangzhou China

Department of Cardiology Songjiang Research Institute Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

Department of Rheumatology Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Division of Oncology Department of Medicine Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China

Division of Rheumatology Department of Internal Medicine Penn State Hershey Medical Center Hershey Pennsylvania USA

Division of Rheumatology Department of Internal Medicine The Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou China

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