芍药苷通过p53/SLC7A11/GPX4途径抑制软骨细胞铁下垂，减轻铁超载诱导的骨关节炎

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-06-19 DOI:10.1016/j.intimp.2025.115111

Boyu Wu , Zhiqiang Luo , Zehua Chen , Yifan Lu , Jianhui Duan , Zhuo Yang , Guoliang Lu

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引用次数: 0

摘要

软骨细胞中的铁下垂越来越被认为是骨关节炎（OA）进展的关键驱动因素。虽然芍药苷（PAE）在多种疾病模型中显示出有效的抗炎和抗氧化特性，但其通过铁下垂调节OA的作用尚不清楚。目的探讨PAE通过p53/溶质载体家族7成员11 (SLC7A11)/谷胱甘肽过氧化物酶4 （GPX4）信号通路对铁超载诱导的OA （IOOA）的保护作用。方法体外实验采用柠檬酸铁铵在软骨细胞中建立铁超载模型，体外实验采用右旋糖酐铁注射液破坏内侧半月板稳定诱导小鼠体内IOOA模型。随后的评估包括细胞活力、软骨基质代谢、铁积累、氧化应激标志物和线粒体功能。为了研究其潜在的机制，采用Western blot、免疫荧光（IF）和Nutlin-3（一种p53激活剂）干预来评估p53/SLC7A11/GPX4通路的参与。体内评估包括显微计算机断层成像、组织学分析和IF。结果spae能显著提高铁超载条件下软骨细胞活力，恢复基质代谢，减少铁积累和氧化应激，保护线粒体功能。在机制上，PAE下调p53，上调SLC7A11和GPX4的表达，从而抑制铁下垂。坚果素-3部分逆转了这些保护作用。在体内，PAE减轻软骨下骨丢失和软骨破坏，减少铁沉积，恢复GPX4和II型胶原（COL2）表达，同时降低基质金属蛋白酶13 （MMP13）水平。结论pae通过调控p53/SLC7A11/GPX4通路抑制铁沉，减轻铁超载诱导的OA进展，为铁沉靶向OA治疗提供了新的思路。

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Paeoniflorin mitigates iron overload-induced osteoarthritis by suppressing chondrocyte ferroptosis via the p53/SLC7A11/GPX4 pathway

Background

Ferroptosis in chondrocytes is increasingly recognized as a key driver of osteoarthritis (OA) progression. Although paeoniflorin (PAE) has demonstrated potent anti-inflammatory and antioxidant properties in multiple disease models, its role in modulating OA through ferroptosis remains unclear.

Purpose

This study aimed to investigate the protective role of PAE against iron overload-induced OA (IOOA) via the p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway.

Methods

An iron overload model was established in chondrocytes using ferric ammonium citrate for in vitro experiments, while an in vivo IOOA model was induced in mice via destabilization of the medial meniscus combined with iron dextran injection. Subsequent evaluations included cell viability, cartilage matrix metabolism, iron accumulation, oxidative stress markers, and mitochondrial function. To investigate the underlying mechanism, Western blot, immunofluorescence (IF), and Nutlin-3 (a p53 activator) intervention were employed to assess the involvement of the p53/SLC7A11/GPX4 pathway. In vivo assessments included micro-computed tomography imaging, histological analysis, and IF.

Results

PAE significantly improved chondrocyte viability, restored matrix metabolism, reduced iron accumulation and oxidative stress, and protected mitochondrial function under iron overload conditions. Mechanistically, PAE downregulated p53 and upregulated SLC7A11 and GPX4 expression, thereby suppressing ferroptosis. Nutlin-3 partially reversed these protective effects. In vivo, PAE mitigated subchondral bone loss and cartilage destruction, reduced iron deposition, and restored GPX4 and type II collagen (COL2) expression while lowering matrix metalloproteinase 13 (MMP13) levels.

Conclusion

PAE alleviates iron overload-induced OA progression by inhibiting ferroptosis through regulation of the p53/SLC7A11/GPX4 pathway, offering new insights into ferroptosis-targeted OA therapy.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.