Connective tissue research · 2026
Overexpression of NSUN3 suppresses ferroptosis in osteoarthritis chondrocytes by reducing m5C modification and expression of PCBP1 mRNA.
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Mahan Wuluhan, Ayiheng Yelinaer, Xie Zengru
Аннотация
PURPOSE: Osteoarthritis (OA) is a degenerative joint disease, with chondrocyte ferroptosis a key pathogenic mechanism in its progression. The role of RNA 5-methylcytosine (m5C) modification in OA chondrocyte ferroptosis remains unclear. This study investigates the involvement and mechanisms of m5C-related regulatory factors in OA chondrocyte ferroptosis.
MATERIALS AND METHODS: Differentially expressed genes (DEGs) between healthy and damaged knee cartilages were analyzed using GSE129147. Mouse chondrocytes were treated with Interleukin-1β (IL-1β) to induce in vitro OA model. Ferroptosis was evaluated by measuring malondialdehyde (MDA), Fe2+, glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), glutathione (GSH) levels, and ACSL4, SLC7A11, GPX4 protein levels. The mechanism was investigated via methylated RNA immunoprecipitation (MeRIP), RIP, and dual luciferase activity.
RESULTS: NSUN3 was downregulated in damaged human knee cartilage and IL-1β-induced mouse chondrocytes. IL-1β promoted chondrocyte death and ferroptosis, which was reversed by NSUN3 overexpression. NSUN3 expression positively correlated with PCBP1. NSUN3 increased PCBP1 expression and RNA stability via m5C modification. PCBP1 knockdown abolished the enhancing effects of NSUN3 on ferroptosis and cell death under IL-1β stimulation.
CONCLUSIONS: NSUN3 overexpression inhibited ferroptosis in IL-1β-induced mouse chondrocytes by promoting PCBP1 expression via increased m5C modification on PCBP1. These in vitro findings offer preliminary insights into potential epigenetic regulatory mechanisms underlying chondrocyte ferroptosis in OA, although further in vivo validation is required.
MATERIALS AND METHODS: Differentially expressed genes (DEGs) between healthy and damaged knee cartilages were analyzed using GSE129147. Mouse chondrocytes were treated with Interleukin-1β (IL-1β) to induce in vitro OA model. Ferroptosis was evaluated by measuring malondialdehyde (MDA), Fe2+, glutathione peroxidase 4 (GPX4), superoxide dismutase (SOD), glutathione (GSH) levels, and ACSL4, SLC7A11, GPX4 protein levels. The mechanism was investigated via methylated RNA immunoprecipitation (MeRIP), RIP, and dual luciferase activity.
RESULTS: NSUN3 was downregulated in damaged human knee cartilage and IL-1β-induced mouse chondrocytes. IL-1β promoted chondrocyte death and ferroptosis, which was reversed by NSUN3 overexpression. NSUN3 expression positively correlated with PCBP1. NSUN3 increased PCBP1 expression and RNA stability via m5C modification. PCBP1 knockdown abolished the enhancing effects of NSUN3 on ferroptosis and cell death under IL-1β stimulation.
CONCLUSIONS: NSUN3 overexpression inhibited ferroptosis in IL-1β-induced mouse chondrocytes by promoting PCBP1 expression via increased m5C modification on PCBP1. These in vitro findings offer preliminary insights into potential epigenetic regulatory mechanisms underlying chondrocyte ferroptosis in OA, although further in vivo validation is required.