Inulin alleviates metabolic dysfunction-associated steatotic liver disease-induced bone loss potentially by activating the Nrf2/GPX4 signaling pathway.

Osteoporosis is a bone disorder characterized by low bone mass density and impaired microarchitecture that is accompanied by multiple metabolic disorders, especially metabolic dysfunction-associated steatotic liver disease (MASLD). Inulin has been proposed as a treatment for MASLD, but its role in MASLD-related bone loss has not been determined. This study aimed to investigate the effect of inulin on MASLD-induced bone loss and the underlying mechanisms. To establish a MASLD model, C57BL/6 mice were fed a high-fat high-fructose high-glucose diet for 16 weeks. Inulin treatment was administered by incorporating 5% inulin into the diet. Inulin significantly ameliorated MASLD, characterized by induced weight gain, hepatic lipid accumulation, high blood lipid levels, and liver damage. After inulin treatment, MASLD-related bone loss was alleviated, as indicated by increases in the trabecular number, trabecular thickness, and the bone volume/total volume ratio and a reduction in trabecular separation, and also reduced osteoclast-associated features. Mechanistically, inulin significantly protected against ferroptosis in MASLD-related bone loss by reducing 4-hydroxynonenal (4-HNE), prostaglandin-endoperoxide synthase 2 (PTGS2) and transferrin (TF) levels and increasing solute carrier family 7 member 11 (SLC7A11) and ferritin heavy chain (FTH) levels. The elevated protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4) following inulin intervention indicate that the Nrf2/GPX4 signaling pathway may participate in the biological regulation induced by inulin. In conclusion, inulin significantly ameliorates MASLD-induced bone loss by inhibiting ferroptosis, which may be correlated with activating Nrf2/GPX4, providing new therapeutic insight into MASLD-related bone health.