Chao Song,1,2 Weijun Song,1,3 Yong Liu,1 Daqian Zhou,1 Weiye Cai,1 Yongliang Mei,1 Fei Liu,1,2 Feng Jiang,1 Feng Chen,1,2 Zongchao Liu1,4 

1Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, People’s Republic of China; 2Department of Orthopedics, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 3Department of Orthopedics, Affiliated Sport Hospital of CDSU, Chengdu, Sichuan Province, People’s Republic of China; 4Luzhou Longmatan District People’s Hospital, Luzhou, Sichuan Province, People’s Republic of China

Correspondence: Zongchao Liu; Feng Chen, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, No. 182 Chunhui Road, Longmatan District, Luzhou City, Sichuan Province, People’s Republic of China, Email lzcxnykdx@swmu.edu.cn; chenf1986@gxtcmu.edu.cn

Background: Osteoarthritis (OA) is a widespread chronic inflammatory disease in orthopedics, and its molecular mechanisms are still poorly understood.
Objective: The purpose of this work was to detect the immunological infiltration of OA and the manner of cell death utilizing bioinformatics and single-cell analysis in order to provide guidelines for clinical therapy and medicine.
Methods: Ferroptosis -associated genes were sourced from the ferroptosis Database, single-cell and bioinformatic expression profiles were chosen from the Gene Expression Comprehensive Database, and OA gene information was taken from GeneCards. To ascertain the categorization status of OA cells, single-cell analysis was conducted. Protein-protein interaction networks were established by SRING analysis, and functional enrichment was examined in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. The important proteins of immune-ferroptosis death in OA were elucidated through co-analysis. Last but not least, network pharmacology and molecular docking support the mechanism by which resveratrol controls Ferroptosis in OA.
Results: The development of OA was found to be tightly related to chondrocytes and immune cells, particularly T and macrophage cells, according to single-cell analysis profile. In patients with OA, immune infiltration also revealed a notable infiltration of T cells, B cells, NK cells, monocytes, and macrophages. The hub genes were shown to be enriched in immunological responses, chemokine-mediated signaling pathways, and inflammatory responses, according to enrichment analysis. The main signaling pathways included autophagy, ferroptosis, the HIF-1 signaling pathway, the PI3K-Akt signaling pathway, and the FoxO signaling pathway. Ferroptosis is a significant cell death mechanism that contributes to the advancement of osteoarthritis. Ferroptosis in chondrocytes is lessened by resveratrol regulation of GPX4, TFRC, and SLC7A11.
Conclusion: Various immune cell infiltrates, especially T cells and macrophages, play an important role in the progression of OA, and resveratrol ameliorates OA by modulating chondrocyte ferroptosis.

Keywords: osteoarthritis, immune infiltration, macrophages, T cells, ferroptosis, resveratrol