Objective To explore the therapeutic effect and related mechanism of citronellol on methicillin-resistant Staphylococcus aureus (MRSA)-induced skin infections in mice via NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway. Methods The minimum inhibitory concentration (MIC) of citronellol against standard MRSA strains was determined using the microbroth dilution method. A full-thickness skin MRSA infection model was established in female C57BL/6 mice, control group, model group, positive control (2% mupirocin) group, citronellol low-, medium- and high-dose (0.75%, 1.50%, 3.00% citronellol gel) groups were set up. Local administration was performed for 7 d. Wound healing rates were dynamically monitored, hematoxylin-eosin (HE) staining was used to observe histopathological changes in skin tissues, and ELISA was used to detect levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD) and malondialdehyde (MDA) in skin tissues. Masson staining was used to observe collagen fiber deposition in skin tissues. RNA-seq transcriptome sequencing, qRT-PCR and Western blotting were employed to analyze the expressions of NLRP3 inflammasome pathway-related genes and proteins in skin tissues, while molecular docking was used to predict the binding affinity of citronellol to relevant inflammatory targets. The lactate dehydrogenase (LDH) release assay was used to evaluate the effect of citronellol on pyroptosis in MRSA-infected immortalized keratinocytes. Results Citronellol exhibited significant antibacterial activity against MRSA, with an MIC ranging from 0.312 5—0.625 0 mg/mL. In vivo experiments revealed that compared with model group, citronellol significantly accelerated wound healing, reduced inflammatory cell infiltration and tissue edema, decreased IL-1β and TNF-α levels in skin tissues (P < 0.05, 0.01, 0.001), markedly increased collagen fiber deposition at wound sites (P < 0.05, 0.01), and inhibited the activation of NLRP3 inflammasome-cell pyroptosis pathway (P < 0.05, 0.01, 0.001). Molecular docking results indicated that citronellol could bind to target proteins such as IL-1β. In vitro experiments demonstrated that citronellol significantly suppressed LDH release in MRSA-infected HaCaT cells (P < 0.05, 0.01). Conclusion Citronellol exerts significant antibacterial, anti-inflammatory and wound repair-promoting effects on MRSA-induced skin infections in mice. Its mechanism may be related to inhibiting NLRP3 inflammasome-cell pyroptosis pathway, reducing the release of pro-inflammatory cytokines, improving the local immune microenvironment, and promoting collagen deposition.

citronellol  /  methicillin-resistant Staphylococcus aureus  /  skin infection  /  NLRP3 inflammasome  /  cell pyroptosis