HDAC3 inhibition stabilizes the IL-37 receptor module to enhance anti-inflammatory signaling in cystic fibrosis airway epithelium

Ueno-Shuto, K.; Fukuyama, A.; Nakajima, K.; Hitora, Y.; Tsukamoto, S.; Kishimoto, T.; Kawano, K.; Nishi, K.; Suico, M. A.; Shuto, T.

doi:10.64898/2026.06.02.729465

bioRxiv · 10.64898/2026.06.02.729465

HDAC3 inhibition stabilizes the IL-37 receptor module to enhance anti-inflammatory signaling in cystic fibrosis airway epithelium

Ueno-Shuto, K.·Fukuyama, A.·Nakajima, K.·Hitora, Y.·Tsukamoto, S.·Kishimoto, T.·Kawano, K.·Nishi, K.·Suico, M. A.·Shuto, T.

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Abstract

Airway inflammation in cystic fibrosis (CF) persists despite advances in CFTR modulator therapy. IL-37b suppresses innate immune signaling through a receptor complex containing IL-18R and wild-type SIGIRR (WT-SIGIRR; IL-1R8), but this pathway is compromised in CF airway epithelial cells by the dominant-negative exon 8-skipped SIGIRR isoform ({Delta}8-SIGIRR). Here, a natural-product screen identified short-chain fatty acids as preferential enhancers of WT-SIGIRR. Pan-HDAC inhibition with panobinostat increased WT-SIGIRR, reduced {Delta}8-SIGIRR, and restored IL-37b-dependent suppression of the TLR3 ligand poly(I:C)-induced IL-8 production. Isoform-selective inhibitor screening and siRNA knockdown identified HDAC3 as a regulator of the IL-37 receptor module. Low concentrations of RGFP966 and HDAC3 silencing increased WT-SIGIRR and IL-18R protein abundance without inducing their mRNA levels. HDAC3 inhibition delayed proteasome-dependent WT-SIGIRR turnover and stabilized IL-18R, thereby enhancing IL-37b-mediated anti-inflammatory signaling in CF airway epithelial cells.

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Ueno-Shuto, K., Fukuyama, A., Nakajima, K., Hitora, Y., Tsukamoto, S., Kishimoto, T., Kawano, K., Nishi, K., Suico, M. A., Shuto, T.. 2026-06-05. HDAC3 inhibition stabilizes the IL-37 receptor module to enhance anti-inflammatory signaling in cystic fibrosis airway epithelium. https://doi.org/10.64898/2026.06.02.729465

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