Drug Repurposing Opportunities with Phytoecdysteroids: Emerging Trends and Challenges

Phytoecdysteroids (PEs), such as 20-hydroxyecdysone (20E) and turkesterone, are natural polyhydroxylated steroids first identified as insect molting hormones but now recognized for their anabolic, cytoprotective, and metabolic effects in mammals. Unlike androgenic steroids, PEs act through non-androgenic mechanisms involving estrogen receptor-β, the ACE2/Ang-(1–7)/Mas receptor axis, and mitochondrial biogenesis, showing excellent safety across studies. Clinical data from BIO101 (pharmaceutical-grade 20E) have demonstrated improved muscle performance in older adults with sarcopenia and acceptable safety in respiratory resilience trials. From a drug repurposing perspective, PEs offer broad therapeutic potential, supporting muscle growth in frailty and cachexia, protecting the liver under oxidative stress, and enhancing cardiac and mitochondrial function. Preclinical evidence also suggests roles in pulmonary repair, neuroprotection, and wound healing. However, clinical validation remains limited, and supplement-based claims often exceed evidence. Major translational challenges include low oral bioavailability, inconsistent supplement quality, uncertain receptor dominance (ERβ vs. MasR), and evolving regulatory attention. Future development should focus on pharmaceutical-grade formulations, biomarker-guided trials, and clear pharmacokinetic–pharmacodynamic alignment. Early clinical priorities include Phase 3 studies in sarcopenia and exploratory trials in NAFLD/NASH and cachexia. Overall, PEs represent promising repurposed natural compounds capable of enhancing metabolic and functional resilience with minimal endocrine risk. With rigorous pharmacological validation and controlled clinical evaluation, they may establish a new class of safe, multitarget therapeutics for aging and chronic disease.