IL-38 attenuates vascular calcification by upregulating GPX3-mediated antioxidant defense via the PPAR-γ/NRF2 axis
Year: 2025
Type: article
Abstract: 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.
Authors: 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
Institutions: Xijing Hospital, Air Force Medical University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,290
Award: G1435708471
OpenAlex ID: W4416768406