Although different types of drugs are available for postmenopausal osteoporosis,the limita-tions of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERα modulators from crude extracts of several plant en-dophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERα modulator.NOR directly bound to ERα with an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-El precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast forma-tion in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERα and TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariec-tomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endome-trial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERα with substantial anti-osteoporosis but less estrogenic activity.