A Novel SIRT1 Activator Hydroxygenkwanin Alleviates Osteoporosis by Inhibiting Ferroptosis and Lactylation in Skeletal Stem/Progenitor Cells

Sirtuin 1 (SIRT1) is an important protein for maintaining cellular homeostasis, and targeting SIRT1 represents a promising strategy for alleviating osteoporosis. The discovery of highly potent and safe SIRT1 activators therefore holds significant translational value for clinical anti-osteoporosis therapies. In this study, we performed deep mining of high-throughput RNA-sequencing (RNA-seq) data from 576 young and aged skeletal stem/progenitor cells (SSPCs) and identified SIRT1 downregulation as a critical hallmark of SSPC Ferroptosis during aging-related osteoporosis. In SIRT1 heterozygous deficiency (SIRT1^+/-) mice, we found that SIRT1 deficiency triggered SSPC Ferroptosis and induced premature osteoporosis. Computer-aided drug design (CADD) was employed to screen 9634 compounds targeting the SIRT1 active site, leading to the identification of the natural compound Hydroxygenkwanin (HGK) as a novel SIRT1 Activator. HGK treatment effectively restored SIRT1 activity, suppressed Ferroptosis in SSPCs in vitro, and ameliorated osteoporosis in vivo. Through transcriptomic analysis and lactylation profiling, we further found that HGK can activate SIRT1 and reverse the lactylation-mediated suppression of the enzymatic activities of SOD1 and PRDX1. This mechanism may underlie the ability of HGK to reduce SSPC Ferroptosis and alleviate osteoporosis. Overall, our findings suggest that HGK possesses translational potential for the treatment of osteoporosis through SIRT1 activation.