Inulin alleviates metabolic dysfunction-associated steatotic liver disease-induced bone loss potentially by activating the Nrf2/GPX4 signaling pathway.
Gu Shaobo, Wang Junzhuo, Zhong Kangpeng, Yao Xuejie, Wen Jinfeng, Chen Dahua, Yan Deyi, Zhang Zongkai, Chen Honghui, Ding Xiaoyun, Yu Siyi, Chen Yi, Li Chunxiao
Abstract
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.
Key Findings
- Inulin treatment significantly ameliorated MASLD-induced bone loss by improving bone microarchitecture parameters such as trabecular number, thickness, and bone volume/total volume ratio.
- Inulin reduced markers of ferroptosis including 4-hydroxynonenal (4-HNE), PTGS2, and transferrin (TF) while increasing levels of SLC7A11 and ferritin heavy chain (FTH).
- The protective effects of inulin were associated with activation of the Nrf2/GPX4 signaling pathway, indicating its role in inhibiting ferroptosis in MASLD-related bone loss.
Clinical Significance
This study suggests that inulin may serve as a therapeutic agent to prevent bone loss in patients with metabolic dysfunction-associated steatotic liver disease by targeting ferroptosis through the Nrf2/GPX4 pathway.
Citation
Gu Shaobo, Wang Junzhuo, Zhong Kangpenget al.. Inulin alleviates metabolic dysfunction-associated steatotic liver disease-induced bone loss potentially by activating the Nrf2/GPX4 signaling pathway. Molecular and cellular biochemistry. 2026-Aug-28.