IL-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 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.