Nuclear receptors meet natural sesquiterpenes: From preclinical mechanisms to therapeutic potential

Nuclear receptors (NRs) are ligand-activated transcription factors that have been extensively studied since their discovery due to their broad regulatory roles in diverse biological processes. Plant-derived natural sesquiterpenes are numerous and possess distinct biological activities; consequently, natural sesquiterpenes provide a stable compound library for pharmaceutical research and development. We examine the growing evidence demonstrating that specific plant-derived sesquiterpenes act as potent modulators of NRs. We highlight compelling in vitro and in vivo examples where these sesquiterpenoids exert therapeutic effects against various diseases primarily through their interactions with specific NRs. Furthermore, this review synthesizes the distinct advantages and therapeutic potential of natural sesquiterpenes as NR-targeting agents, emphasizing their structural diversity, often favorable safety profiles, multi-target potential, and natural origins. Finally, we discuss the current challenges and perspectives to fully exploit the giant potential of plant sesquiterpenes in the development of novel, NR-target therapeutics. This review reveals the significant promise of natural sesquiterpenes as a rich source for innovative drugs targeting NR pathways.