PSPC1-SMAD3 axis regulates iron-induced beiging of adipocytes in white adipose tissue

Beige adipose tissue protects against obesity and related metabolic diseases by catabolizing stored energy to generate heat. While iron is essential for this process due to its role in mitochondrial function, the specific signaling mechanisms involved remain unclear. Here, we report that diet-induced obese mice exhibit a local iron deficiency in subcutaneous adipose tissue. Crucially, through integrated multi-omics approaches (RNA-seq and ATAC-seq), we identify that iron downregulates Paraspeckle component 1(PSPC1), which interacts with SMAD family member 3 (SMAD3) to promote its phosphorylation. The iron-induced reduction of PSPC1 alleviates the repressive signaling of SMAD3 on thermogenic gene expression, thereby inducing the beiging of white adipocytes. Furthermore, overexpression of Pspc1 in subcutaneous adipose tissue counteracted the iron-induced suppression of SMAD3 phosphorylation, effectively reversing iron-induced beiging of white adipocytes and its associated metabolic benefits. Collectively, our findings demonstrate that iron promotes the beiging of white adipocytes within subcutaneous adipose tissue and exerts anti-obesity effect by inhibiting PSPC1-SMAD3 axis, which may provide a potential therapeutic target for obesity and its related metabolic diseases.Graphical AbstractIron protects against diet-induced obesity by promoting the beiging of adipocytes in white adipose tissue. This study identifies a novel regulatory mechanism where iron downregulates the expression of PSPC1. The reduction in PSPC1, which interacts with SMAD3, leads to decreased SMAD3 phosphorylation, thereby relieving its inhibition on thermogenic genes.