Hepatocyte ferroportin drives liver cirrhosis-induced skeletal deterioration via systemic iron overload

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ID: 329566
2026
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Ranked #72 of 133 articles by views in journal of bone and mineral research : the official journal of the american society for bone and mineral research

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Abstract
Chronic liver disease frequently leads to debilitating bone fractures, yet the mechanistic link between liver injury and skeletal fragility remains elusive. This study aimed to investigate a liver-bone axis where dysregulated iron flux, mediated by hepatocyte ferroportin (FPN), drives osteoporosis during the progression of cirrhosis. We utilized a mouse model of progressive liver disease and generated hepatocyte-specific FPN deletion mice to examine systemic iron homeostasis. Bone quality and microarchitecture were evaluated via micro-computed tomography and histological analysis. To assess fracture risk and mechanical integrity, we employed engineering-based finite element simulations and physical mechanical testing. Our data reveal a critical window during liver fibrosis where compensatory mechanisms counteract iron toxicity. However, upon progression to cirrhosis, this homeostatic balance collapses, leading to massive toxic iron accumulation in the skeleton. This creates a pro-inflammatory environment that suppresses bone formation and accelerates resorption. Biomechanical simulations and testing demonstrate that combined deficits in bone material properties and architecture create distinct stress concentration zones, markedly reducing load-bearing capacity. Strikingly, hepatocyte-specific deletion of FPN attenuated liver fibrosis and restored systemic iron balance, thereby preserving bone microarchitecture and mechanical performance. Hepatocyte FPN-regulated iron homeostasis is a central mediator of the liver-bone axis. Cirrhosis-induced iron overload is a major contributor to skeletal mechanical failure, identifying FPN as a key regulator of bone health in chronic liver disease.
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Authors Liangliang Xiang, Kaili Deng, Zixiang Gao, Qingjiang Pang, Alan Wang, Justin Fernandez, Li Chen, Gu Yaodong
Journal journal of bone and mineral research : the official journal of the american society for bone and mineral research
Year 2026
DOI
10.1093/jbmr/zjag138
URL
https://doi.org/10.1093/jbmr/zjag138
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