biostudies-literatureZhu LKey Research and Development Program of Shaanxi ProvinceHealth Research and Innovation Capacity Enhancement Program of Shaanxi ProvinceNational Natural Science Foundation of China19https://www.ebi.ac.uk/biostudies/studies/S-EPMC12748425biostudies-literatureUnknown83(1)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 peroxidasCellular and molecular life sciences : CMLSIL-38 attenuates vascular calcification by upregulating GPX3-mediated antioxidant defense via the PPAR-γ/NRF2 axis.PMC127484252023-ZDLSF-39821703362024TD-05Shang BJing LCui JLi PLiu RSun YYi WXin JWang QZhu LCui YChen WTang WZhang BZhou HSong YfalseIL-38 attenuates vascular calcification by upregulating GPX3-mediated antioxidant defense via the PPAR-γ/NRF2 axis.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 peroxidas2025-01-01T00:00:00Z2025 Nov2026-06-06T09:31:40.171Z2026-05-28T03:12:01.922ZS-EPMC127484254130765410.1007/s00018-025-05990-5