Therapeutic potential of 20-Hydroxyecdysone in pulmonary arterial hypertension: involvement of Mas receptor and PI3K–Akt pathway

Abstract Background 20-Hydroxyecdysone (20E), a natural polyhydroxylated steroid found in various edible plants, exhibits diverse pharmacological effects. Pulmonary arterial hypertension (PAH) remains challenging to treat owing to its multifactorial pathogenesis. Although recent advances, including US Food and Drug Administration (FDA)-approved therapies such as sotatercept, have improved outcomes, no curative treatment is currently available. This study aims to investigate the preventive and therapeutic effects of 20E on PAH and elucidate its underlying molecular mechanisms. Methods A monocrotaline-induced PAH rat model was utilized to evaluate the efficacy of 20E. The Mas receptor antagonist A779 and agonist AVE0991 were used to investigate the role of Mas in PAH progression and 20E-mediated prevention. Molecular docking and pull-down assays were conducted to confirm the interaction between 20E and the Mas receptor. In vitro, the effects of 20E on Ang II-induced proliferation and migration of human pulmonary arterial smooth muscle cells (HPASMCs) were assessed. The PI3K–Akt signaling pathway was analyzed by western blot. Results 20E prevented PAH at 30 mg/kg and 90 mg/kg, while 90 mg/kg rescued preexisting PAH. The protective effects of 20E were attenuated by A779. 20E upregulated Mas receptor expression and directly bound to it. In vitro, 20E inhibited Ang II-induced HPASMC proliferation and migration. It also downregulated p-PI3K, p-Akt, and p-mTOR while restoring P27 and P21 expression. Furthermore, knockdown of the Mas in HPASMCs abolished the effects of 20E on these processes. Conclusions 20E inhibits PASMC proliferation and migration through Mas-dependent mechanisms and modulation of downstream PI3K–Akt signaling, thereby effectively preventing and rescuing PAH. It may be a promising pharmacological candidate for PAH treatment.