AbstractObjectivesThe objectives of current study were to investigate the role and related mechanism of Ginsenoside Rb1 (GRb1) on regulating apical periodontitis (AP) prognosis.Materials and MethodsClinical specimens were used to determine the involvement of calcium overload‐induced macrophage pyroptosis in periapical tissues. Next, a calcium ion‐chelating agent (BAPTA‐AM) was applied to detect the suppression of intracellular calcium overload in macrophage pyroptosis. Then, network pharmacology, western blot (WB) analysis, and Fluo‐4 calcium assay were conducted to explore the role of GRb1 on intracellular calcium overload. To gain a better understanding of GRb1 in calcium overload‐induced macrophage pyroptosis linked AP, GRb1‐treated AP models were established.ResultsWe discovered clinically and experimentally that calcium overload‐dependent macrophage pyroptosis is involved in AP pathogenesis, and reducing calcium overload greatly decreased macrophage pyroptosis in an AP cell model. Next, based on GRb1's inhibitory role in aberrant intracellular calcium accumulation, we discovered that GRb1 alleviates AP by suppressing calcium‐dependent macrophage pyroptosis in both in vitro and in vivo models.ConclusionsGRb1 is an effective therapeutic strategy to rescue the periapical tissues from inflammation due to its anti‐pyroptosis function. Thus, the present study supports further investigation of GRb1 as an adjuvant therapy for AP.