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<p>Vascular calcification is a pathological process commonly associated with cardiovascular diseases, diabetes, and renal insufficiency, driven by inflammation, oxidative stress, and endoplasmic reticulum stress. IL-38, a member of the IL-1 cytokine family, has shown anti-inflammatory, antioxidant, and anti-fibrotic effects in cardiovascular contexts. However, its role in vascular calcification remains unknown. This study demonstrated significantly reduced IL-38 expression in human calcified coronary tissues, patient plasma, and experimental models. IL-38 knockout mice exhibited aggravated vascular calcification, while treatment with recombinant IL-38 protein markedly suppressed calcification. RNA sequencing revealed that IL-38 alleviates oxidative stress by upregulating glutathione peroxidase 3 (GPX3). siRNA-mediated knockdown of GPX3 abolished the protective effects of IL-38, confirming its essential role as a downstream mediator. Further mechanistic studies established that IL-38 activates the PPAR-γ/NRF2 signaling axis to regulate GPX3 expression, as evidenced by pharmacological inhibition. These results identify IL-38 as a novel endogenous inhibitor of vascular calcification operating through the PPAR-γ/NRF2/GPX3 pathway, providing mechanistic insight and suggesting a potential therapeutic strategy.</p> Graphical abstract <p> IL-38 is revealed as a novel anti-vascular calcification molecule that alleviates calcification primarily by upregulating GPX3 and its mediated antioxidant effects through the PPAR-γ/NRF2 axis (Created in <a href="https://BioRender.com">https://BioRender.com</a>).</p> <p></p>

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IL-38 attenuates vascular calcification by upregulating GPX3-mediated antioxidant defense via the PPAR-γ/NRF2 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Lei Zhu,
  • Qiang Wang,
  • Bingliang Shang,
  • Jun Cui,
  • Yujie Song,
  • Bing Zhang,
  • Wenlong Chen,
  • Jialin Xin,
  • Yang Cui,
  • Rui Liu,
  • Panpan Li,
  • Lanrui Jing,
  • Haitao Zhou,
  • Wangxia Tang,
  • Yang Sun,
  • Wei Yi

摘要

Vascular calcification is a pathological process commonly associated with cardiovascular diseases, diabetes, and renal insufficiency, driven by inflammation, oxidative stress, and endoplasmic reticulum stress. IL-38, a member of the IL-1 cytokine family, has shown anti-inflammatory, antioxidant, and anti-fibrotic effects in cardiovascular contexts. However, its role in vascular calcification remains unknown. This study demonstrated significantly reduced IL-38 expression in human calcified coronary tissues, patient plasma, and experimental models. IL-38 knockout mice exhibited aggravated vascular calcification, while treatment with recombinant IL-38 protein markedly suppressed calcification. RNA sequencing revealed that IL-38 alleviates oxidative stress by upregulating glutathione peroxidase 3 (GPX3). siRNA-mediated knockdown of GPX3 abolished the protective effects of IL-38, confirming its essential role as a downstream mediator. Further mechanistic studies established that IL-38 activates the PPAR-γ/NRF2 signaling axis to regulate GPX3 expression, as evidenced by pharmacological inhibition. These results identify IL-38 as a novel endogenous inhibitor of vascular calcification operating through the PPAR-γ/NRF2/GPX3 pathway, providing mechanistic insight and suggesting a potential therapeutic strategy.

Graphical abstract

IL-38 is revealed as a novel anti-vascular calcification molecule that alleviates calcification primarily by upregulating GPX3 and its mediated antioxidant effects through the PPAR-γ/NRF2 axis (Created in https://BioRender.com).