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Objective <p>Postmenopausal osteoporosis (PMOP) is characterized by bone loss attributed to estrogen deficiency; however, the involvement of ferroptosis in its pathogenesis has yet to be fully elucidated. The objective of this study was to explore the regulatory mechanism of the CEBPA/ALOX15B axis in PMOP, with a focus on modulating ferroptosis.</p> Methods <p>Four gene expression datasets (GSE56116, GSE56814, GSE56815, GSE230665) were analyzed to identify differentially expressed genes (DEGs) and ferroptosis-related genes (FRGs) in PMOP. In vitro experimental approaches, including cell viability, apoptosis, ferroptosis marker detection, and osteogenic differentiation assays, were conducted in hFOB 1.19 cells with ALOX15B/CEBPA knockdown/overexpression. The AMPK/mTOR pathway was validated using Western blot and pharmacological inhibitors. In vivo, ALOX15B knockout mice were subjected to ovariectomy (OVX) to establish a PMOP model, and bone mineral density (BMD), micro-CT, and histopathological analyses were performed.</p> Results <p>ALOX15B was significantly upregulated in PMOP patients, negatively correlating with estrogen levels. ALOX15B knockdown in hFOB 1.19 cells suppressed ferroptosis (reduced Fe²⁺, MDA, ROS, and PTGS2; increased GSH/GSSG and GPX4) and promoted osteoblast differentiation (elevated ALP, RUNX2, OCN). Mechanistically, CEBPA directly bound to the ALOX15B promoter to transcriptionally activate it. CEBPA/ALOX15B regulated ferroptosis and osteogenesis via the AMPK/mTOR axis. In OVX mice, ALOX15B knockout ameliorated bone loss (increased BMD, BV/TV, Tb.Th; reduced Tb.Sp) and ferroptosis (decreased iron deposition, 4-HNE; increased GPX4).</p> Conclusion <p>The CEBPA/ALOX15B axis promotes osteoblast ferroptosis in PMOP by inhibiting the AMPK/mTOR pathway, providing a novel therapeutic target for PMOP treatment.</p>

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Targeting CEBPA/ALOX15B attenuates postmenopausal osteoporosis by inhibiting ferroptosis through the AMPK/mTOR signaling pathway

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Tingting Wang,
  • Jingyi Li,
  • Chong Li,
  • Zhifang Wang,
  • Lixia Zhang,
  • Chao Han,
  • Guangzhao Qi,
  • Lijun Xu,
  • Lili Zheng

摘要

Objective

Postmenopausal osteoporosis (PMOP) is characterized by bone loss attributed to estrogen deficiency; however, the involvement of ferroptosis in its pathogenesis has yet to be fully elucidated. The objective of this study was to explore the regulatory mechanism of the CEBPA/ALOX15B axis in PMOP, with a focus on modulating ferroptosis.

Methods

Four gene expression datasets (GSE56116, GSE56814, GSE56815, GSE230665) were analyzed to identify differentially expressed genes (DEGs) and ferroptosis-related genes (FRGs) in PMOP. In vitro experimental approaches, including cell viability, apoptosis, ferroptosis marker detection, and osteogenic differentiation assays, were conducted in hFOB 1.19 cells with ALOX15B/CEBPA knockdown/overexpression. The AMPK/mTOR pathway was validated using Western blot and pharmacological inhibitors. In vivo, ALOX15B knockout mice were subjected to ovariectomy (OVX) to establish a PMOP model, and bone mineral density (BMD), micro-CT, and histopathological analyses were performed.

Results

ALOX15B was significantly upregulated in PMOP patients, negatively correlating with estrogen levels. ALOX15B knockdown in hFOB 1.19 cells suppressed ferroptosis (reduced Fe²⁺, MDA, ROS, and PTGS2; increased GSH/GSSG and GPX4) and promoted osteoblast differentiation (elevated ALP, RUNX2, OCN). Mechanistically, CEBPA directly bound to the ALOX15B promoter to transcriptionally activate it. CEBPA/ALOX15B regulated ferroptosis and osteogenesis via the AMPK/mTOR axis. In OVX mice, ALOX15B knockout ameliorated bone loss (increased BMD, BV/TV, Tb.Th; reduced Tb.Sp) and ferroptosis (decreased iron deposition, 4-HNE; increased GPX4).

Conclusion

The CEBPA/ALOX15B axis promotes osteoblast ferroptosis in PMOP by inhibiting the AMPK/mTOR pathway, providing a novel therapeutic target for PMOP treatment.