Combination of Isoliquiritigenin and Vancomycin Alleviates Staphylococcus aureus‐Induced Bone Infection in Rats

ABSTRACT Staphylococcus aureus ( S. aureus )‐induced osteomyelitis presents therapeutic challenges due to antibiotic resistance. Isoliquiritigenin (ISL), a licorice‐derived chalcone, exhibits antibacterial and anti‐inflammatory properties. This study evaluated vancomycin (VAN) combined with ISL against methicillin‐resistant S. aureus (MRSA)‐induced implant‐related osteomyelitis. A rat model was established by tibial MRSA inoculation with simultaneous Kirschner wire implantation. Four weeks postinfection, rats were divided into five groups: normal, model, VAN (50 mg/kg), ISL (100 mg/kg), and VAN + ISL. After 14 days of treatment, combined therapy significantly reduced bone infection severity and histopathological scores versus monotherapies ( p < 0.001), decreased serum inflammatory markers (IL‐6, TNF‐α, IL‐1β, and CRP; p < 0.001), and reduced bacterial loads in bone/wire ( p < 0.001). In vitro, ISL (50 μM) attenuated MRSA‐induced inflammatory response in MC3T3‐E1 osteoblasts by suppressing NF‐κB and MAPK signaling, while promoting osteogenesis via increased Runx2/BMP2/ALP expression, activated BMP/Smad signaling, and enhanced mineralization. Overall, VAN + ISL combination therapy outperforms monotherapy by concurrently eradicating MRSA, suppressing inflammation, and promoting bone repair, representing a promising synergistic strategy for recalcitrant osteomyelitis.