Programmed cell death-related gene S100A9 promotes macrophage M1 polarization and chondrocyte apoptosis in rheumatoid arthritis.

Authors

Qingyuan Xu, Jinfu Liu, Qiang Ding, Canbin Zhao, Weiwei Wang, Hao Li, Chicheng Niu, Wei Chen, Ping Zeng, Donghui Guan, Ronghua Zhang

Published in

Biology direct. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

Rheumatoid arthritis (RA) is a heterogeneous chronic autoimmune disease. Its high disability rate has a serious impact on individuals and society. Programmed cell death (PCD) patterns play a key role in several diseases. However, the significance of the interplay between PCD and RA remains underexplored.
In total, 18 PCD patterns were analyzed for the model construction. Single-cell RNA-seq transcriptome (scRNA-seq) and bulk RNA-seq data were collected from the GSE200815, GSE1919, GSE77298, GSE206848, GSE89408, GSE12021, GSE55235, and GSE55457 cohorts to validate the model. In vivo and in vitro experiments were performed to determine the role of S100A9 in RA.
We developed a programmed cell death-related (PCDR) model for RA using 113 combinations of 12 machine learning algorithms and significant PCD signatures; 2 RA clusters were identified. A significant difference was noted in the macrophage numbers between the two groups. Macrophages were identified as key effector cells that play a central role in RA pathogenesis through cellular communication and the transition of cell states. S100A9 was identified as a key gene in the PCDR model, and its knockdown significantly slowed RA progression by reducing joint synovitis and cartilage damage. M1 macrophage polarization was accompanied by the overexpression of S100A9 in the synovial tissues of RA model mice. Compared with RA mice, AAV-shRNA-mediated S100A9 knockdown mice showed decreased M1 macrophage polarization, attenuated severity of synovitis, and elevated expression of the cartilage phenotype proteins-collagen II and BCL-2. Additionally, S100A9 knockdown inhibited M1 macrophage polarization in vitro. Hence, S100A9 inhibition may be a promising therapeutic strategy for RA treatment.
We established a novel PCDR model by comprehensively analyzing diverse cell death patterns. S100A9 inhibition may be a promising therapeutic strategy for RA treatment.

PMID:
42351193
Bibliographic data and abstract were imported from PubMed on 26 Jun 2026.

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