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Peer-reviewedCC BYGenes & diseases

Betaine alleviates renal osteodystrophy by stabilizing ABCG1 mRNA to inhibit HMOX1-mediated ferroptosis in BMSCs.

  • Xinhang Li1,2
  • Yi Xie1
  • Wenyan Ren3,4,5
  • Qing Liu6,7
  • Qiming Pang1
  • Wenting Liu2,8
  • Xin Li2,8
  • Bin He1
  • Dongmei He2,8
  • Xinyue Wan2,8
  • Jia Liu2,8
  • Jie Cai2,9
3 more authors
  • Baicheng He2,8
  • Wei Huang1
  • Fang He1
9 affiliations
  1. 1Departments of Nephrology, Orthopedics, Urological Metabolism and Immunoecology Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  2. 2Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.
  3. 3Department of Pharmacy, Beijing Anzhen Nanchong Hospital, Capital Medical University & Nanchong Central Hospital, Nanchong, Sichuan 637000, China.
  4. 4Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  5. 5Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan 637000, China.
  6. 6Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  7. 7National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China.
  8. 8Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  9. 9The Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
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Abstract

Renal osteodystrophy is a debilitating complication of chronic kidney disease characterized by deteriorated bone microarchitecture and impaired bone formation, leading to increased fracture risk. Despite the pressing need for anabolic therapies, the cellular mechanisms by which uremic stress compromises osteoprogenitor function remain poorly defined. Here, metabolomic profiling of renal osteodystrophy patient cohorts revealed a profound depletion of circulating betaine. We show that betaine supplementation not only rescued the osteogenic differentiation of bone marrow-derived mesenchymal stem cells challenged with the uremic toxin indoxyl sulfate but also ameliorated skeletal deterioration in a rat model of chronic kidney disease. Mechanistically, we demonstrated that indoxyl sulfate triggered ferroptosis in bone marrow-derived mesenchymal stem cells-characterized by iron-dependent lipid peroxidation and aberrant HMOX1 up-regulation-thereby arresting osteogenesis. Betaine mitigates this ferroptotic stress through a novel post-transcriptional mechanism. Specifically, betaine down-regulated the RNA-binding protein hnRNP A1, preventing the recruitment of the CNOT1 deadenylase complex. This inhibition stabilized Abcg1 mRNA, leading to restored ABCG1 expression. Functional perturbation studies confirmed that the ABCG1-HMOX1 axis was indispensable for the anti-ferroptotic and osteoprotective effects of betaine. Collectively, our findings delineate a Betaine-hnRNP A1/CNOT1-ABCG1-HMOX1 signaling cascade that links metabolic deficiency to ferroptosis-driven osteogenic failure, positioning betaine as a promising anabolic therapeutic strategy for renal osteodystrophy.

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Cite

BibTeXRIS
BibTeX
@article{li2026betaine,
  title = {{Betaine alleviates renal osteodystrophy by stabilizing ABCG1 mRNA to inhibit HMOX1-mediated ferroptosis in BMSCs.}},
  author = {Xinhang Li and Yi Xie and Wenyan Ren and Qing Liu and Qiming Pang and Wenting Liu and Xin Li and Bin He and Dongmei He and Xinyue Wan and Jia Liu and Jie Cai and Baicheng He and Wei Huang and Fang He},
  journal = {Genes \& diseases},
  year = {2026},
  month = sep,
  doi = {10.1016/j.gendis.2026.102444},
  url = {https://europepmc.org/article/MED/42899164},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Betaine alleviates renal osteodystrophy by stabilizing ABCG1 mRNA to inhibit HMOX1-mediated ferroptosis in BMSCs.
AU  - Xinhang Li
AU  - Yi Xie
AU  - Wenyan Ren
AU  - Qing Liu
AU  - Qiming Pang
AU  - Wenting Liu
AU  - Xin Li
AU  - Bin He
AU  - Dongmei He
AU  - Xinyue Wan
AU  - Jia Liu
AU  - Jie Cai
AU  - Baicheng He
AU  - Wei Huang
AU  - Fang He
PY  - 2026
DA  - 2026/09/04
JO  - Genes & diseases
DO  - 10.1016/j.gendis.2026.102444
UR  - https://europepmc.org/article/MED/42899164
AB  - Renal osteodystrophy is a debilitating complication of chronic kidney disease characterized by deteriorated bone microarchitecture and impaired bone formation, leading to increased fracture risk. Despite the pressing need for anabolic therapies, the cellular mechanisms by which uremic stress compromises osteoprogenitor function remain poorly defined. Here, metabolomic profiling of renal osteodystrophy patient cohorts revealed a profound depletion of circulating betaine. We show that betaine supplementation not only rescued the osteogenic differentiation of bone marrow-derived mesenchymal stem cells challenged with the uremic toxin indoxyl sulfate but also ameliorated skeletal deterioration in a rat model of chronic kidney disease. Mechanistically, we demonstrated that indoxyl sulfate triggered ferroptosis in bone marrow-derived mesenchymal stem cells-characterized by iron-dependent lipid peroxidation and aberrant HMOX1 up-regulation-thereby arresting osteogenesis. Betaine mitigates this ferroptotic stress through a novel post-transcriptional mechanism. Specifically, betaine down-regulated the RNA-binding protein hnRNP A1, preventing the recruitment of the CNOT1 deadenylase complex. This inhibition stabilized Abcg1 mRNA, leading to restored ABCG1 expression. Functional perturbation studies confirmed that the ABCG1-HMOX1 axis was indispensable for the anti-ferroptotic and osteoprotective effects of betaine. Collectively, our findings delineate a Betaine-hnRNP A1/CNOT1-ABCG1-HMOX1 signaling cascade that links metabolic deficiency to ferroptosis-driven osteogenic failure, positioning betaine as a promising anabolic therapeutic strategy for renal osteodystrophy.
SN  - 2352-4820
SN  - 2352-3042
ER  -