A novel hnRNPA2B1 stabilizer HMS-01 promotes weight loss by modulating Orm1 mRNA in an m6A-dependent manner

Obesity is one of the greatest healthcare challenges of our time; however, only a few anti- obesity medications have been launched successfully. It still necessitates innovative and alternative targets together with new treatment options. We previously reported a novel anti- obesity target, orosomucoid1 (ORM1), which was elevated in response to obesity and exerted beneficial effects in a negative feedback way. Here, we report a novel small molecule HMS- 01, a non-antibiotic derivative of erythromycin that effectively up-regulated ORM1, could effectively reduce body weight in obese murine models. In this study, we show that HMS-01 effectively reduces body mass and food intake in obese mice through elevating ORM1 level. At the mechanistic level, HMS-01 could bind and stabilize RNA binding protein hnRNPA2B1, which mediated its regulation on stabilizing Orm1 mRNA in a m6A RNA methylation manner. Furthermore, loss-of function study proved that hnRNPA2B1 was essential to mediate the weight loss effect of HMS-01. These findings suggest that HMS-01 is a promising drug with novel target to mitigate obesity.