The SRC/NF‐κB‐AKT/NOS3 axis as a key mediator of Kaempferol's protective effects against oxidative stress‐induced osteoclastogenesis.

Background: Osteoclasts are integral to the advancement of osteoporosis (OP), and their generation under conditions of oxidative stress (OS) involves various pathways. However, the specific mechanism through which the natural antioxidant kaempferol (KAE) mitigates the influence of OS on osteoclasts remains somewhat uncertain. This study aims to evaluate the effect of KAE on osteoclast formation under OS and explore its possible mechanism. Methods: Zebrafish were used to observe the effects of KAE on OP and OS. OP and OS "double disease targets" network pharmacology were used to predict the action target and mechanism of KAE on OP under OS. The effects of KAE on osteoclast differentiation induced by OS were evaluated using RWA264.7 cells induced by LPS. To elucidate the potential mechanism, we detected the expression of related factors and target genes during induction. Results: The presence of KAE exhibited potential in improving the conditions of OP and OS in zebrafish. KAE can reduce the OS of RAW 264.7 cells stimulated by LPS, inhibit the formation of osteoclasts, and change the level of related factors of OS, and reduce the increase of TRAP. The utilization of network pharmacology and target gene expression assay revealed that KAE exerted a down‐regulatory effect on the expression of proto‐oncogene tyrosine protein kinase (SRC), nuclear factor kappa‐B (NF‐κB), Serine/Threonine Kinase‐1 (AKT1), Nitric Oxide Synthase 3 (NOS3) and Matrix Metallopeptidase‐2 (MMP2). Conclusion: Based on the results of this study, KAE may effectively mitigate OS and impede the formation of osteoclasts through the SRC/NF‐κB‐AKT/NOS3 axis. [ABSTRACT FROM AUTHOR]