The synergistic anti‐inflammatory effect of pterostilbene and honokiol on LPS‐stimulated PMA‐differentiated THP‐1 macrophages

Objective The cosmetics industry increasingly prioritizes the development of formulations that are both safe and effective. This study aimed to investigate the synergistic anti‐inflammatory effects of pterostilbene (Pt) and honokiol (Ho) in lipopolysaccharide (LPS)‐stimulated THP‐1 macrophages and to evaluate their systemic safety using the Threshold of Toxicological Concern (TTC) framework. Methods Human THP‐1 monocytes were differentiated with PMA and stimulated with LPS to model inflammatory conditions. Pt and Ho were tested individually and in combination for their ability to suppress macrophage proliferation and proinflammatory cytokine production (TNF‐α, IL‐1β, IL‐6). Synergistic effects were assessed through combination index and isobolographic analyses. NF‐κB pathway modulation was evaluated via Western blot, and molecular docking was performed to explore compound–target interactions. Maximum systemically safe concentrations were calculated using TTC values integrated with default dermal absorption percentages and product‐specific exposure parameters. Results Pt and Ho significantly inhibited LPS‐induced macrophage proliferation and cytokine production, both individually and in combination. Combination index and isobologram analyses confirmed synergistic suppression of cytokines at low, non‐cytotoxic concentrations. Both compounds attenuated NF‐κB activation; however, no statistical synergy was observed at the signalling level, indicating coordinated but distinct mechanisms. Molecular docking revealed direct binding of Pt to NF‐κB, while Ho exhibited no appreciable binding, further supporting mechanistic divergence. TTC‐based calculations established systemically safe concentration limits for Pt and Ho across various cosmetic product categories. Conclusion Pt and Ho exert synergistic anti‐inflammatory effects in macrophages and can be safely used within systemically acceptable concentration limits in cosmetic formulations. These findings support their development as a multifunctional combination targeting inflammation‐related skin conditions, while underscoring the need for further investigation into dermal safety, optimized dosing strategies and broader mechanistic pathways.