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The following is a summary of “IRAK4 Is Overexpressed in Hidradenitis Suppurativa Skin and Correlates with Inflammatory Biomarkers,” published in the February 2025 issue of Journal of Investigative Dermatology by McDonald et al.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving painful nodules, abscesses, and tunnels, with IRAK4 playing a key role in its pathogenesis through the IL-1R/toll-like receptor pathway.
Researchers conducted a retrospective study to assess IRAK4 expression in blood and skin samples from patients with HS and evaluate the effects of KT-474, a targeted IRAK4 degrader, on immune cells.
They enrolled 30 patients with HS (NCT04440410) and measured IRAK4 expression in blood and lesional, perilesional, and nonlesional skin biopsies and PBMCs were analyzed for IRAK4 levels, and ex vivo treatment with KT-474 was performed to assess its effects on IRAK4 degradation and cytokine production.
The results showed that PBMCs expressed IRAK4, with higher levels in monocytes (P ≤ .0001). Treatment with KT-474 reduced IRAK4 levels in all immune cell types from both healthy volunteers and patients with HS. In toll-like receptor–stimulated monocytes, KT-474 decreased IRAK4 protein levels and inhibited inflammatory cytokine production. The IRAK4 expression was elevated in HS lesional skin compared to nonlesional tissue (P ≤ .0001), with IRAK4-positive immune infiltrates increasing with disease severity. Multiple inflammatory mediators were upregulated in HS lesional skin, correlating with IRAK4 overexpression.
Investigators concluded the confirmed role of the IL-1R/toll-like receptor pathway in HS pathogenesis and supported further clinical evaluation of KT-474 as a potential HS treatment.
Source: jidonline.org/article/S0022-202X(24)01899-2/fulltext
