Heterobifunctional degraders emerge as a novel pharmacologic strategy to treat inflammatory conditions. Previous data have indicated that inflammatory signaling via the myddosome complex is critical for kidney injury and fibrosis development. Within the myddosome, modulation of interleukin-1 receptor associated kinase 4 (IRAK4) by small molecule kinase inhibitors has been shown to reduce fibrosis, but has limited anti-inflammatory effect. Here we used a novel strategy to abrogate IRAK4 by means of targeted ubiquitination triggering proteasomal degradation. We tested the antifibrotic and anti-inflammatory activity of the small molecule IRAK4 degrader KTX-545 in vitro and in vivo in a model of acute kidney injury. Our results indicated that incubation with degrader resulted in abrogation of IRAK4 protein levels, and reduced formation of myddosome complex in primary kidney fibrogenic cells. In human kidney organoids, IRAK4 degradation reduced both extracellular matrix deposition, as well as fibrogenic gene expression caused by tubular damage. Further, the treatment resulted in inhibition of NF-kB activation and downstream inflammatory cytokine expression. In vivo, KTX-545 showed increased efficacy compared to the small molecule IRAK4 kinase inhibitor CA-4948 in ameliorating fibrosis following ischemia/reperfusion injury. Collectively, our results indicate that targeted degradation of IRAK4 is a new promising therapeutic approach for the treatment of renal fibrosing disorders.

This study evaluates how titanium and polymethyl methacrylate (PMMA) Boston Keratoprosthesis backplate substrates influence human corneal fibroblast proliferation, cytotoxicity, morphology, activation phenotype, and mechanotransductive signaling. Human corneal fibroblasts were cultured on titanium and PMMA, with tissue culture plastic or glass as controls. Proliferation was assessed over 7 days using metabolic assays, and cytotoxicity was measured by lactate dehydrogenase release. Cell morphology and surface coverage were examined by scanning electron microscopy, while immunofluorescence quantified fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin (α-SMA). Gene expression of α-SMA, collagen I, FSP-1, and focal adhesion kinase (FAK) was analyzed by quantitative PCR. Cells cultured on both substrates maintained stable viability with modest increases in estimated cell numbers and comparable proliferation curves, indicating preserved metabolic activity without growth suppression. Cytotoxicity remained low and similar between groups. SEM demonstrated broader and more continuous cell spreading on titanium, whereas cells on PMMA were more sparsely distributed. Immunofluorescence showed higher FSP-1 expression on titanium and increased α-SMA on PMMA. Gene expression analysis revealed higher FAK transcripts on PMMA, with no significant differences in α-SMA, FSP-1, or collagen I. These results confirm the cytocompatibility of both titanium and PMMA backplates with human corneal fibroblasts and support their use with the Boston Keratoprosthesis.