Hinokiflavone resists HFD-induced obesity by promoting apoptosis in an IGF2BP2-mediated Bim m6A modification dependent manner

Obesity has emerged as a major health risk on a global scale. Natural small molecules, such as hinokiflavone (HF) extracted from plants like cypress, exhibit diverse chemical structures and low synthesis costs. Using HFD-induced obese mice models, we found that HF suppresses obesity by inducing apoptosis in adipose tissue. Adipocyte apoptosis helps maintain tissue health by removing aging, damaged, or excess fat cells, crucial in preventing obesity and metabolic diseases. We found that HF can specifically bind to insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to promote the stability of N6-methyladenosine (m6A) -modified Bim, inducing mitochondrial outer membrane permeabilization (MOMP). MOMP leads to Caspase9/3-mediated adipocyte mitochondrial pathway apoptosis, alleviating obesity induced by a high-fat diet. HF offers a controlled means of adipocyte apoptosis for weight loss. This study reveals the potential of small molecules like HF in developing new therapeutic approaches in drug development and biomedical research. Overall design: To investigate the effects and mechanisms of HF on obesity-induced mice with a high-fat diet and 3T3-L1 cells during adipogenesis, RNA-seq and RIP-seq of IGF2BP2 were conducted.