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Background: Rosacea is a chronic inflammatory skin disease with immunological dysfunction. Supramolecular salicylic acid (SSA) has the properties of keratolytic, antibacterial, and anti-inflammatory. However, the mechanism of SSA in the treatment of rosacea is still unclear., Objective: To investigate the efficiencies and molecular mechanisms of SSA in rosacea., Methods: Forty mice were randomly divided into four groups (10 in each group): control, LL-37, LL-37 + azelaic acid (AzA), and LL-37 + SSA. Forty μl LL-37 (320 μM) was administered intradermally into the dorsal skin of the mice in the latter 3 groups every 12 h and 4 times altogether (0 h, 12 h, 24 h, 36 h). Twenty % AzA was applied on the eruptions after the first and third LL-37 injection (0 h, 24 h) in LL-37 + AzA group, while 30 % SSA was applied after the first injection (0 h) in LL-37 + SSA group. The redness score and redness area were evaluated. The skin barrier function was measured by the transepidermal water loss (TEWL) and pH. The infiltration of inflammatory cells was evaluated by hematoxylin-eosin staining, and the inflammatory biomarkers were analyzed by RT-PCR and immunohistochemistry., Results: SSA alleviated LL-37-induced rosacea-like inflammation. The increased TEWL and pH induced by LL-37 were also reversed by SSA. In addition, SSA reduced inflammatory cell infiltration and suppressed the production of Toll-like receptor 2, Matrix metallopeptidase 9, kallikrein 5, LL-37 associated with rosacea, and inhibited LL-37-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3)-mediated inflammasome activation in mice., Conclusions: Our findings indicated that SSA ameliorated LL-37-induced rosacea-like lesions by suppressing NLRP3-mediated inflammasome activation in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)