Multi-target effects of bergapten in a vitro periodontitis-mimicking model: suppressing inflammation and oxidative stress while promoting osteogenesis

Background Bergapten (BG) is a natural furanocoumarin found in various botanical drugs including Citrus bergamia , Angelica archangelica , and Citrus medica , and it’s a bioactive constituent of Peucedanum guangxiense , an indigenous species in Guangxi, China. Although BG exhibits anti-inflammatory and osteoprotective properties, its effects relevant to periodontitis-mimicking microenvironment remains unexplored. Methods This study integrated network analysis with in vitro experimental validation to investigate the multi-target effects of BG in a Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) -induced periodontitis-mimicking in vitro model. Results Network analysis and molecular docking identified the PI3K/Akt pathway as a candidate pathway, along with predicted binding to CAT, BMP-2, TNF-α, IL-6 and IL-1β. BG at concentration of 5–30 μM did not reduce cell viability in human periodontal ligament stem cells (h-PDLSCs) or RAW264 .7 macrophages under the tested conditions. BG at concentrations of 7.5–30 μM directly promoted osteogenic differentiation of h-PDLSCs beyond baseline levels in the normal-mimicking microenvironment, as evidenced by increased ALP activity, mineralization, and expression of osteogenic markers ( RUNX2, COL-I, OCN , and OPN ). Under inflammatory conditions, BG reduced intracellular oxidative activity across concentrations of 7.5–30 μM, suppressed pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), down-regulated M1 macrophages polarization associated markers ( iNOS, CD86 ) and NF-κB components (IκBα, p65), while up-regulating anti-inflammatory cytokines (IL-4, IL-10), M2 macrophages polarization-associated markers (Arg-1, CD206) and antioxidant genes ( HO-1,CAT, SOD ). Moreover, BG-treated macrophages conditioned medium partially rescued the osteogenic capacity of h-PDLSCs in inflammation condition, though not to the level of the normal control. The effects might associate with increased phosphorylation levels of PI3K and Akt, and with decreased mRNA expression of NF-κB pathway components. Conclusion Collectively, BG was associated with multi-modal effects relevant to periodontitis-mimicking microenvironment, including alleviating oxidative stress, suppressing NF-κB driven inflammation, promoting PI3K/Akt associated osteogenesis, and shifting macrophage polarization-associated markers toward an M2-like profile. Our in vitro findings suggest that BG possess multi-modal activities relevant to periodontitis-mimicking microenvironment, warranting further in vivo investigation to assess its pharmacological relevance.