Sodium Houttuybonate Promotes the Browning of White Adipose Tissue by Inhibiting Ferroptosis via the AMPK-NRF2-HO1 Pathway

The rising prevalence of obesity has resulted in an increased demand for innovative and effective treatment strategies. <i>Houttuynia cordata</i> Thunb. <i>(H. cordata)</i> has demonstrated promising potential in preventing obesity. However, the mechanism underlying the anti-obesity effects of <i>H. cordata</i> and its bioactive component, sodium houttuybonate (SH), remains unclear. Our study reveals that SH treatment promotes the browning of inguinal white adipose tissue (iWAT) and prevents the obesity induced by a high-fat diet. SH significantly mitigates ferroptosis by upregulating glutathione peroxidase 4 (<i>Gpx4</i>) and decreasing malondialdehyde (MDA) levels, while also enhancing superoxide dismutase (SOD) levels. Furthermore, SH promotes the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increases the expression of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) in the iWAT. However, the effects of SH were attenuated by ML385, an Nrf2 inhibitor. Collectively, our findings suggest that SH induces iWAT browning and prevents diet-induced obesity primarily through the AMPK/NRF2/HO-1 pathway by inhibiting ferroptosis.