Aloe-emodin Antagonizes Cisplatin-induced Ferroptosis and Osteogenic Suppression in Bone Marrow Stromal Cells by Targeting the Hippo-YAP1 Pathway

Background: Cisplatin (CDDP) induces chemotherapy-induced bone loss (CIBL), compromising prognosis via suppressing osteogenesis and reducing bone mass. Aloe-emodin (AE) , with anti-inflammatory and antioxidant properties, protects against chemotherapy-induced tissue injury such as the heart and kidneys by inhibiting ferroptosis. However, AE's role in CDDP-induced osteogenic suppression is unknown. Purpose: To identify whether AE rescues CDDP-impaired osteogenesis via ferroptosis modulation and elucidate the mechanisms. Methods: CDDP's cytotoxicity was determined using the osteosarcoma cell line 143B. Mouse bone marrow stromal cell line ST2 were treated with CDDP to assess ferroptosis markers (lipid peroxidation, Gpx4 / Acsl4 ) and osteogenic capacity ( Alpl / Osx / Col1α1 ). AE's effects on reversing ferroptosis and restoring osteogenesis were evaluated. RNA-seq with bioinformatic analysis identified key pathways. Blocking experiments targeting critical signaling nodes validated the regulatory axis. Results: The CDDP concentration that effectively kills 143B cells can induce ferroptosis in ST2 cells ( elevated lipid peroxidation, downregulated Gpx4 and Ncoa4 , upregulated Acsl4 and Dmt1 ) and inhibited osteogenesis ( downregulated osteogenic markers Alpl , Osx and Col1α1 ). AE co-treatment restored Gpx4 , inhibited Dmt1 and TFR1 , reversed ferroptosis, and recovered osteogenic markers. In 143B cells, AE enhanced CDDP cytotoxicity and synergistically with CDDP reduced 143B cell viability. Hippo signaling pathway disruption was identified by RNA-seq and bioinformatics analysis, with CDDP suppressing YAP1 nuclear translocation - reversed by AE. YAP1 inhibitor verteporfin (VPF) eliminated AE's protective effects on ferroptosis and osteogenesis. Conclusions: CDDP suppresses osteogenesis in ST2 cells through ferroptosis. AE activates Hippo-YAP1 signaling, concurrently protecting bone formation and sensitizing tumors, providing a novel strategy for CIBL.