Liu_2025_Free.Radic.Biol.Med_243_466

OBJECTIVE: This study aimed to investigate whether liver-specific soluble epoxide hydrolase (sEH) mediates osteoclast differentiation by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, thereby contributing to molecular mechanisms underlying bone homeostasis imbalance. METHODS: Clinical samples, an ovariectomy (OVX)-induced mouse osteoporosis model, and in vitro osteoclast induction experiments were systematically employed to evaluate the role of sEH in osteoclast differentiation. RESULTS: Osteoporosis patients exhibited decreased plasma levels of 14,15-epoxyeicosatrienoic acid (14,15-EET), increased levels of 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), and elevated pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta). OVX mice demonstrated enhanced osteoclast differentiation associated with upregulated hepatic sEH expression, decreased plasma 14,15-EET, increased 14,15-DHET, and elevated pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta). Treatment with sEH inhibitors or liver-specific sEH knockdown ameliorated osteoclast differentiation by restoring 14,15-EET and 14,15-DHET levels and reducing pro-inflammatory cytokine concentrations. Transcriptome sequencing revealed that sEH inhibitors suppress osteoclast differentiation by activating the Nrf2-antioxidant response element (ARE) signaling pathway. Furthermore, 14,15-EET directly inhibited osteoclast differentiation in an Nrf2-dependent manner, underscoring a direct link between the metabolite and the antioxidant transcription factor. CONCLUSION: This study reveals, for the first time, a novel regulatory mechanism of bone metabolism mediated by the "liver-bone axis." Liver-derived sEH remotely modulates the Nrf2-ARE signaling pathway in bone tissue by controlling circulating levels of 14,15-EET, 14,15-DHET, and pro-inflammatory cytokines, thereby influencing osteoclast differentiation and bone homeostasis. These findings provide new insights into the pathogenesis of osteoporosis.