Anti‐Osteoporosis Activity of Lycopene Through ESR1: Network Pharmacology, Molecular Docking, Imaging Technology, and Experimental Validation

ABSTRACT Osteoporosis is a widespread metabolic bone disorder. Lycopene (LYC), a potent antioxidant in tomatoes, has been shown to exhibit anti‐osteoporosis effects. Here, we elucidated its molecular determinants in treating osteoporosis. Network pharmacology and molecular docking were utilized to screen target proteins of LYC in osteoporosis treatment. KEGG pathway and GO enrichment analyses were used to observe biological functions of these target proteins. The osteoblastic differentiation of human marrow‐derived mesenchymal stem cells (hBMSCs) was induced and evaluated by ALP staining and activity assay, Alizarin Red S (ARS) staining, and related protein expression analysis. An osteoporotic mouse model was induced by ovariectomy (OVX). For the anti‐osteoporosis effect of LYC, network pharmacology and molecular docking showed estrogen receptor 1 (ESR1) as a potential therapeutic target, and KEGG pathway enrichment analysis suggested the involvement of the PI3K/AKT pathway. LYC promoted osteogenic differentiation of hBMSCs and increased ESR1 expression in the hBMSC osteogenic differentiation process in vitro. LYC diminished bone loss and increased ESR1 expression in OVX mice. Reduction of ESR1 attenuated LYC‐induced osteogenic differentiation of hBMSCs. Moreover, LYC activated the PI3K/AKT pathway in the hBMSC osteogenic differentiation process by upregulating ESR1. Our findings suggest that LYC induces osteogenic differentiation of hBMSCs by the ESR1/PI3K/AKT pathway, thereby contributing to its anti‐osteoporosis effect. Our study provides a molecular basis for the potential application of LYC as a therapeutic agent in osteoporosis.