Siwei Dihuang Pill ameliorates postmenopausal osteosarcopenia: Multi-omics insights into arachidonic acid metabolism and PTGER4/CREB/SIRT1-related signaling in gut-bone-muscle crosstalk.

Abstract

Siwei Dihuang Pill (SWDHP), a traditional Chinese herbal formula, has shown beneficial effects on estrogen deficiency-associated osteosarcopenia (OS), but its systemic mechanisms remain unclear. To investigate the effects of SWDHP on postmenopausal OS and the associated mechanisms from the perspective of gut-bone-muscle crosstalk. An ovariectomized rat model was used to evaluate SWDHP efficacy. Serum-absorbed compounds were characterized by UHPLC-Q-Orbitrap HRMS. Integrated multi-omics analyses were combined with targeted LC-MS/MS quantification of fecal arachidonic acid (AA) and PGE2, cAMP measurement, molecular docking, molecular dynamics simulations, SPR, RT-qPCR, and Western blotting. SWDHP alleviated bone loss, skeletal muscle atrophy, and colonic inflammation. Multi-omics analyses revealed coordinated changes in gut microbiota, Th17/Treg-associated immune markers, oxidative stress-related indices, and osteoclast differentiation, and highlighted AA metabolism as a pathway associated with OS-related multisystem dysfunction. SWDHP increased PTGER4 expression and cAMP levels, accompanied by enhanced PKA/CREB phosphorylation, increased SIRT1 expression, and reduced NF-κB signaling. Kaempferol showed favorable predicted interactions with PTGER4 and SIRT1, while SPR demonstrated direct binding to SIRT1 (KD = 15.73 μM). SWDHP alleviates postmenopausal OS, accompanied by coordinated alterations in gut microbiota, AA metabolism, and PTGER4/CREB/SIRT1-related signaling across the gut-bone-muscle axis.

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