Irish journal of medical science · 2026
Crosstalk between autophagy and ferroptosis related genes in osteoarthritis: insights from transcriptomic and in vitro analyses.
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Wang Chenhuan, Tao Xingguang, Zhang Guangming, Feng Xinying, Li Huimin, Chen Nong
Аннотация
BACKGROUND: Osteoarthritis (OA) is a prevalent musculoskeletal disorder characterized by progressive articular cartilage degradation, involving complex interactions between inflammatory and metabolic factors. Both autophagy and ferroptosis are key cellular processes implicated in OA pathogenesis, but their potential interplay remains poorly understood.
AIMS: This study aimed to explore the transcriptional crosstalk between autophagy- and ferroptosis-related genes in OA.
METHODS: We analyzed the gene expression dataset GSE207881, comprising 6 healthy and 59 OA cartilage samples, to identify differentially expressed genes (DEGs). These were intersected with established ferroptosis (from FerrDb) and autophagy (from HAMDB) gene sets, yielding 120 ferroptosis-related and 239 autophagy-related DEGs. Functional enrichment, protein-protein interaction (PPI) network, and correlation analyses were performed. Key bioinformatic predictions were validated in vitro using a TNF-α-induced inflammatory model in C28/I2 chondrocytes, assessed via qPCR, proliferation, viability, and senescence assays.
RESULTS: We identified significant co-expression networks linking ferroptosis and autophagy pathways. Functional annotations highlighted shared enrichment in oxidative stress, inflammatory response, and cellular homeostasis pathways. Core hub genes from both processes showed strong transcriptional coordination, with the most significant correlations observed between ferroptosis-related genes (ATF3, ACSL1) and autophagy-related genes (IL6, NFKBIA). In the TNF-α-induced chondrocyte model, these key genes were concordantly dysregulated, and their significant positive correlations were confirmed, reinforcing their co-regulatory relationship in an OA-relevant inflammatory context. These findings reveal a coordinated transcriptional program between autophagy and ferroptosis pathways during early OA pathogenesis.
CONCLUSION: The study identifies specific hub genes as potential interactive nodes, providing novel insights into the molecular mechanisms of chondrocyte dysfunction and highlighting candidate targets for future therapeutic investigation.
AIMS: This study aimed to explore the transcriptional crosstalk between autophagy- and ferroptosis-related genes in OA.
METHODS: We analyzed the gene expression dataset GSE207881, comprising 6 healthy and 59 OA cartilage samples, to identify differentially expressed genes (DEGs). These were intersected with established ferroptosis (from FerrDb) and autophagy (from HAMDB) gene sets, yielding 120 ferroptosis-related and 239 autophagy-related DEGs. Functional enrichment, protein-protein interaction (PPI) network, and correlation analyses were performed. Key bioinformatic predictions were validated in vitro using a TNF-α-induced inflammatory model in C28/I2 chondrocytes, assessed via qPCR, proliferation, viability, and senescence assays.
RESULTS: We identified significant co-expression networks linking ferroptosis and autophagy pathways. Functional annotations highlighted shared enrichment in oxidative stress, inflammatory response, and cellular homeostasis pathways. Core hub genes from both processes showed strong transcriptional coordination, with the most significant correlations observed between ferroptosis-related genes (ATF3, ACSL1) and autophagy-related genes (IL6, NFKBIA). In the TNF-α-induced chondrocyte model, these key genes were concordantly dysregulated, and their significant positive correlations were confirmed, reinforcing their co-regulatory relationship in an OA-relevant inflammatory context. These findings reveal a coordinated transcriptional program between autophagy and ferroptosis pathways during early OA pathogenesis.
CONCLUSION: The study identifies specific hub genes as potential interactive nodes, providing novel insights into the molecular mechanisms of chondrocyte dysfunction and highlighting candidate targets for future therapeutic investigation.