A small-molecule lycorine derivative protects from obesity by targeting Na ⁺ /K ⁺ -ATPase <i>α</i> 3 independent of food intake suppression

Abstract

ABSTRACT Obesity remains a severe global public health challenge, with contemporary therapeutic approaches primarily focusing on appetite suppression. Here, we discovered HLY72, a lycorine-derived small molecule that potently counteracts obesity in mice at doses without affecting food intake, by promoting sympathetic activation-mediated lipolysis and thermogenesis in adipose tissues. Mass spectrometry identified Na + /K + -ATPase (NKA) α3, the brain-specific isoform, as HLY72’s target. Only blood-brain barrier-permeable NKA inhibitors reproduce HLY72’s anti-obesity effects, and resistance to HLY72 treatment occurs specifically in NKA α3 (not α1) knockin mice harboring a HLY72-binding mutation. Similar to the chemical inhibition by HLY72, genetic inhibition of NKA α3 also effectively protects mice from diet-induced obesity. These findings point NKA α3 as a potent anti-obesity drug target and highlight HLY72’s potential in treating and preventing obesity independent of appetite control.