Placenta · 2025
hsa_circ_0081343 interacts with Rbm8a to inhibit NLRP3-mediated pyroptosis via the PI3K/AKT/HIF-1α pathways.
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Zheng Linmei, Tang Rong, Ahmad Fiaz, Shi Lei, Chen Xiaoju, Li Jing
Аннотация
INTRODUCTION: Pyroptosis at the maternal-fetal interface plays an important role in fetal growth restriction development. hsa_circ_0081343 can be an RNA-binding protein "sponge" regulating Rbm8a nuclear transportation through binding to Rbm8a. This study aimed to elucidate the regulatory mechanism underlying the interaction between hsa_circ_0081343 and Rbm8a in the FGR pyroptosis pathway.
METHODS: The expression levels of PI3K/AKT pathway-related components (PI3K, AKT, p-PI3K, and p-AKT), HIF-1α, NLRP3, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured using RT-qPCR, Western blot, and ELISA. RNA-seq and ChIP-seq were used to identify the downstream signaling pathways of hsa_circ_0081343 and Rbm8a in HTR8-SVneo. RNA pull-down assays, Western blot, and RT-qPCR were performed to investigate the interactions between hsa_circ_0081343 and Rbm8a.
RESULT: The placenta of FGR exhibited considerable upregulation of NLRP3 compared to normal controls. Overexpression of hsa_circ_0081343 inhibited pyroptosis and subsequent inflammatory responses in HTR-8/SVneo cells, and these effects were reversed by Rbm8a knockdown. The integration of RNA-seq and ChIP-seq showed that the PI3K/AKT and HIF-1α pathways were the targets of hsa_circ_0081343 and Rbm8a. hsa_circ_0081343 upregulation and Rbm8a downregulation was accompanied by the inhibition of the PI3K/AKT/HIF-1α signaling pathway, whereas hsa_circ_0081343 knockdown of and Rbm8a overexpression led to the opposite effect. Moreover, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence. Rbm8a overexpression significantly decreased hsa_circ_0081343 expression.
CONCLUSION: These results indicated that the interaction between hsa_circ_0081343 and Rbm8a regulates NLRP3-mediated pyroptosis through the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence and modulating hsa_circ_0081343 formation. Our results provide a new direction for further exploration of the regulatory mechanisms of circRNA-RBPs in the pathogenesis of FGR.
METHODS: The expression levels of PI3K/AKT pathway-related components (PI3K, AKT, p-PI3K, and p-AKT), HIF-1α, NLRP3, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured using RT-qPCR, Western blot, and ELISA. RNA-seq and ChIP-seq were used to identify the downstream signaling pathways of hsa_circ_0081343 and Rbm8a in HTR8-SVneo. RNA pull-down assays, Western blot, and RT-qPCR were performed to investigate the interactions between hsa_circ_0081343 and Rbm8a.
RESULT: The placenta of FGR exhibited considerable upregulation of NLRP3 compared to normal controls. Overexpression of hsa_circ_0081343 inhibited pyroptosis and subsequent inflammatory responses in HTR-8/SVneo cells, and these effects were reversed by Rbm8a knockdown. The integration of RNA-seq and ChIP-seq showed that the PI3K/AKT and HIF-1α pathways were the targets of hsa_circ_0081343 and Rbm8a. hsa_circ_0081343 upregulation and Rbm8a downregulation was accompanied by the inhibition of the PI3K/AKT/HIF-1α signaling pathway, whereas hsa_circ_0081343 knockdown of and Rbm8a overexpression led to the opposite effect. Moreover, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence. Rbm8a overexpression significantly decreased hsa_circ_0081343 expression.
CONCLUSION: These results indicated that the interaction between hsa_circ_0081343 and Rbm8a regulates NLRP3-mediated pyroptosis through the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence and modulating hsa_circ_0081343 formation. Our results provide a new direction for further exploration of the regulatory mechanisms of circRNA-RBPs in the pathogenesis of FGR.