Discovery of Fisetin as a potent and cell-active ACVR2A inhibitor

Current weight-loss drugs, such as GLP-1 receptor agonists, are effective at reducing body weight but are often associated with concomitant loss of muscle mass. Thus, there is growing interest in developing next-generation anti-obesity agents that preserve muscle tissue. ACVR2A has emerged as a promising target in this context, as its inhibition may uncouple fat loss from muscle wasting. While several anti-ACVR2A monoclonal antibodies have advanced into clinical trials, small-molecule inhibitors remain scarcely reported. In this study, virtual screening followed by experimental validation was employed to identify the natural product fisetin as a potent ACVR2A inhibitor. Fisetin exhibited robust enzymatic inhibitory activity, with an IC₅₀ value of 0.27 ± 0.06 μM, and demonstrated high binding affinity, with a K_D of 0.12 ± 0.03 μM. Cellular assays further confirmed that fisetin suppressed TGF-β/Smad signaling and successfully protected C2C12 myotubes from Activin A-induced atrophy by downregulating atrogenes. Despite its favorable in vitro profile, fisetin showed poor pharmacokinetic properties that currently limit its in vivo application; therefore, preliminary structural modifications were explored to guide future optimization. Collectively, these findings position fisetin as a promising lead compound for the development of ACVR2A-targeted therapies aimed at combating obesity while preserving muscle mass.