Inhibition of salt-inducible kinase 1 attenuates the inflammatory response via the JAK–STAT pathway in hidradenitis suppurativa: A preliminary mechanistic study

Objective: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder. Salt-inducible kinase 1 (SIK1) has been implicated in the regulation of inflammation; however, its role and underlying mechanisms in HS pathogenesis remain poorly defined. The present study aimed to address this gap. Methods: Immunohistochemistry was used to assess SIK1 expression in lesions from 3 patients with HS and in 3 murine HS models. An ex vivo skin explant Transwell culture system was established, and multiplex secretome analysis was performed to quantify inflammatory mediators of 10 patients with HS after treatment with a SIK1 inhibitor. The therapeutic effects of SIK1 inhibition were then evaluated in murine models. RNA sequencing was conducted to identify differentially expressed genes and associated signaling pathways in lesional skin of 5 patients with HS after SIK1 inhibition. Protein expression patterns of key pathway components were subsequently analyzed in 3 patients with HS. Results: SIK1 expression was increased in HS lesional skin and in murine models. Pharmacological inhibition of SIK1 reduced the secretion of interleukin (IL)-6, C-X-C motif chemokine ligand (CXCL) 8 ( P ＜0.01), and tumor necrosis factor-α ( P ＜0.01) in HS skin explants ( P ＜0.01) and alleviated pathological features in murine HS models Following SIK1 inhibitor treatment, the epidermal thickness (33.2 µm vs 62.4 µm, P ＜0.05) at the lesional sites in murine models was significantly reduced and the expression of CXCL1 and IL-6 was decreased. Transcriptomic analysis indicated suppression of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway, accompanied by reduced levels of phosphorylated STAT3. Conclusion: These findings provide preliminary evidence that SIK1 inhibition attenuates HS-associated inflammation by reducing proinflammatory cytokine production and downregulating the JAK–STAT pathway, highlighting SIK1 as a potential therapeutic target for HS.