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Targeted Epigenetic Silencing of Jumonji Domain-Containing Protein 3 Alleviates Nuclear Factor-Kappa B-Mediated Inflammation in Familial Mediterranean Fever.

Ghada Nour Eldeen·Mona F Sokkar·Randa S Lotfy·Waheba A Zarouk·Hala T El-Bassyouni
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Abstract

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory condition caused by variants in the MEFV gene encoding pyrin, the essential component of the NLRP3/NF-κB complex of inflammasomes. Deregulation of nuclear factor-kappa B (NF-κB), a key proinflammatory mediator, leads to chronic inflammation in autoinflammatory/autoimmune diseases. Epigenetic modulation offers a new approach to regulate inflammasome activity, with Jumonji domain-containing protein 3 (JMJD3) being a promising target for managing inflammatory illnesses. GSK-J4 is a selective inhibitor of JMJD3, restricting pro-inflammatory cytokines and inflammation. AIM: Our research aimed to elucidate the role of JMJD3 and the NF-κB-JMJD3 signaling pathways in regulating inflammation in an in vitro model, and to investigate GSK-J4's effect in inhibiting inflammasome activation in primed peripheral blood mononuclear cells (PBMCs) isolated from FMF cases. METHODS: PBMCs were cultured and primed with LPS, and then treated with GSK-J4. JMJD3 knockdown was achieved using siRNA interference. Cellular inflammatory dynamics were assessed by Western blotting (WB) and ELISA. The qRT-PCR was used for gene expression quantification. Untreated cells served as a negative control. RESULTS: Our results showed significantly downregulated gene expression of NF-κB, NLRP3, and inflammatory cytokines in GSK-J4-treated cells compared to untreated cells, as confirmed by ELISA. WB reported a reduction of NF-κB in induced cells following GSK-J4 treatment. Knocking down JMJD3 also showed decreased levels of JMJD3, NF-κB, and inflammatory cytokines, indicating its proinflammatory role. CONCLUSION: The study showed that selective inhibition or silencing of JMJD3 significantly suppressed the inflammasome in FMF cases, suggesting its role as a therapeutic target for alleviating inflammation in various autoinflammatory diseases.

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HumansMaleFemaleChildAdolescentYoung AdultJumonji Domain-Containing Histone DemethylasesFamilial Mediterranean FeverInflammationNF-kappa BLeukocytes, MononuclearRNA InterferenceBenzazepinesPyrimidinesFamilial Mediterranean feverGSK-J4InflammasomeJMJD3siRNAJournal Article

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Ghada Nour Eldeen, Mona F Sokkar, Randa S Lotfy, Waheba A Zarouk, Hala T El-Bassyouni. 2026-05-23. Targeted Epigenetic Silencing of Jumonji Domain-Containing Protein 3 Alleviates Nuclear Factor-Kappa B-Mediated Inflammation in Familial Mediterranean Fever.. https://doi.org/10.1016/j.arcmed.2026.103440

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