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Background <p>Pulmonary fibrosis is characterized by the excessive deposition of extracellular matrix produced from myofibroblasts in the lungs. Enhanced glycolysis has been linked to fibroblast-myofibroblast transition (FMT) during pulmonary fibrogenesis, however, there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Emerging evidence highlights Vitamin D’s anti-fibrotic potential, yet its role in modulating fibroblast glycolysis and pulmonary fibrosis remains unclear.</p> Methods <p>MRC-5 cells and mouse primary lung fibroblasts treated with TGF-β1 combined with Vitamin D were used to explore the role of vitamin D on fibroblast activation and glycolysis in vitro. Silica and bleomycin-induced pulmonary fibrosis mouse model was established to evaluate the antifibrotic effects of Vitamin D and the glycolysis inhibitor 3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one (3PO) in vivo. Cell metabolism assays were performed to determine the glycolytic rate. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which Vitamin D affects fibroblast activation and glycolysis.</p> Results <p>Transcriptomic analysis and subsequent experiments demonstrated that TK1 acts as a functional downstream effector of Vitamin D, and its expression was negatively regulated by Vitamin D. Knockdown of TK1 inhibited the profibrotic effects of TGF-β1 by reducing fibroblast glycolysis. Furthermore, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key driver of glycolysis, was identified as a target of TK1. Mechanistically, Vitamin D could reduce the expression of TK1, thereby partly blocking fibroblast glycolysis and activation by inhibiting PFKFB3. In a murine model of silica or bleomycin-induced fibrosis, both Vitamin D and 3PO treatment alleviated pulmonary fibrosis.</p> Conclusions <p>Our findings revealed that Vitamin D could attenuate pulmonary fibrosis by blocking fibroblast glycolysis and FMT through the TK1-PFKFB3 pathway. Vitamin D supplementation or targeting fibroblast glycolysis could be promising treatment strategies for pulmonary fibrosis.</p>

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Vitamin D attenuates the progression of pulmonary fibrosis via inhibiting thymidine kinase 1/PFKFB3-driven glycolysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Huanyu Yang,
  • Li Zhang,
  • Mengjia Han,
  • Keye Zhu,
  • Xianghan Guo,
  • Wenkang Yang,
  • Qi Xu

摘要

Background

Pulmonary fibrosis is characterized by the excessive deposition of extracellular matrix produced from myofibroblasts in the lungs. Enhanced glycolysis has been linked to fibroblast-myofibroblast transition (FMT) during pulmonary fibrogenesis, however, there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Emerging evidence highlights Vitamin D’s anti-fibrotic potential, yet its role in modulating fibroblast glycolysis and pulmonary fibrosis remains unclear.

Methods

MRC-5 cells and mouse primary lung fibroblasts treated with TGF-β1 combined with Vitamin D were used to explore the role of vitamin D on fibroblast activation and glycolysis in vitro. Silica and bleomycin-induced pulmonary fibrosis mouse model was established to evaluate the antifibrotic effects of Vitamin D and the glycolysis inhibitor 3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one (3PO) in vivo. Cell metabolism assays were performed to determine the glycolytic rate. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which Vitamin D affects fibroblast activation and glycolysis.

Results

Transcriptomic analysis and subsequent experiments demonstrated that TK1 acts as a functional downstream effector of Vitamin D, and its expression was negatively regulated by Vitamin D. Knockdown of TK1 inhibited the profibrotic effects of TGF-β1 by reducing fibroblast glycolysis. Furthermore, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key driver of glycolysis, was identified as a target of TK1. Mechanistically, Vitamin D could reduce the expression of TK1, thereby partly blocking fibroblast glycolysis and activation by inhibiting PFKFB3. In a murine model of silica or bleomycin-induced fibrosis, both Vitamin D and 3PO treatment alleviated pulmonary fibrosis.

Conclusions

Our findings revealed that Vitamin D could attenuate pulmonary fibrosis by blocking fibroblast glycolysis and FMT through the TK1-PFKFB3 pathway. Vitamin D supplementation or targeting fibroblast glycolysis could be promising treatment strategies for pulmonary fibrosis.