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• Metabolic alteration of articular cartilage is associated with pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors, and relevant pathways. We established a comprehensive network integrated with transcription factors, metabolism-related genes, and hallmarks. Metabolic alteration of articular cartilage is associated with the pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors (TFs), and relevant pathways. Overall, RNA sequencing profiles of articular cartilage were collected from the GEO database. Metabolism-related genes and OA-related hallmarks were collected from the MSigDB v7.1. Differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Gene Set Variation Analysis (GSVA) were conducted to identify pathways or hallmarks that were related to the pathogenesis of OA. The Pearson correlation analysis was used to establish the regulatory network among transcription factors, metabolism-related genes, and hallmarks. To further confirm the regulation of the identified transcription factors, Chromatin Immunoprecipitation-sequencing (ChIP-seq) was conducted, and single-cell sequencing was used to locate the cell clusters. Connectivity Map (CM) analysis were also conducted to identify the potential specific bioactive small molecules targeting the metabolic alteration of osteoarthritis. scTPA database was used to detect activated signaling pathways. Collectively, a total of 74 and 38 differentially expressed metabolism-related genes and TFs were retrieved. Skeletal system development, extracellular matrix, and cell adhesion molecule binding were important pathways in GO analysis. Human papillomavirus infection, PI3K-Akt signaling pathway, and Human T-cell leukemia virus 1 infection were the top 3 pathways in KEGG. 7 and 12 hallmarks were down- and up-regulated in GSVA, respectively. Ten bioactive small molecules may be potential treatments of OA by regulating the metabolism of articular cartilage. ChIP-seq analysis showed high relativity between transcription factors and their target genes. Furthermore, single-cell sequencing confirms the high expression of identified transcription factors in chondrocytes. To conclude, we established a comprehensive network integrated with transcription factors, metabolism-related genes, and hallmarks. [ABSTRACT FROM AUTHOR]

• A macrophage membrane coated curcumin-loaded biomimetic nanosponge system was designed for osteoarthritis alleviation. • This system can alleviate the progression of osteoarthritis by synergistically suppressing inflammation and ferroptosis. • We broadened the biomedical application of macrophage membrane as an anti-ferroptosis agent in OA treatment. Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the degradation of articular cartilage while sustained inflammation and ferroptosis have been demonstrated to play crucial roles in the progression of OA. It is an effective strategy to fabricate nanomedicines for OA treatment. However, current research primarily concentrates on anti-inflammation, whereas nanomedicine systems for anti-ferroptosis in OA treatment are rarely reported. Additionally, there are few studies integrating inflammation inhibition with anti-ferroptosis within a single system to ameliorate OA progression. In this study, we introduce a curcumin-loaded biomimetic nanosponge (CM@Cur-NPs) to alleviate OA by synergistically suppressing inflammation and ferroptosis. CM@Cur-NPs were obtained by encapsulating curcumin within polymeric nanoparticles and coating them with macrophage cell membranes. The in vitro and in vivo synergistic anti-inflammatory and anti-ferroptotic effects of CM@Cur-NPs were investigated. It was discovered that the CM@Cur-NPs significantly reduced pro-inflammatory cytokines (TNF-α, IL-6), iNOS, ROS, and apoptosis levels of chondrocytes while concurrently increasing the anti-inflammatory cytokine (IL-4) and extracellular matrix (ECM) content in vitro. We also found that CM@Cur-NPs decreased the expression of the ferroptosis marker Fe2+, ACSL4, and MDA, coupled with an increase in the levels of SLC7A11 and GPX4 of chondrocytes. Lipid peroxidation of chondrocytes was attenuated by CM@Cur-NPs as well. In vivo results indicated that CM@Cur-NPs effectively alleviated OA progression and achieved cartilage protection by upregulating Aggrecan and collagen II expression, along with downregulating ADAMTS5 and MMP13 expression. This study demonstrated that CM@Cur-NPs exhibited enhanced chondroprotective effects through synergistic anti-inflammatory and anti-ferroptotic actions. It is a promising approach to integrate inflammation and ferroptosis inhibition by bioactive nanomaterials for OA treatment. [ABSTRACT FROM AUTHOR]