AZD-1480

Metabolic dysfunction‐associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease with no available therapies. Currently, the pathogenesis of MASLD remains to be further elucidated. Ferroptosis and ferroptosis‐related genes may play a vital role in the development of MASLD. Thus, this study investigated the role of heme oxygenase‐1 (HMOX1/HO‐1) in ferroptosis associated with MASLD. Here, we applied bioinformatics to identify ferroptosis‐related genes. HMOX1 expression was validated by immunohistochemistry. Mice fed a methionine‐choline‐deficient diet for 8 weeks were treated with hemin, followed by biochemical and histological analyses. HL7702 cells were transfected to overexpress HMOX1, exposed to oleic acid, and treated with erastin or AZD1480. Iron, ROS, lipid peroxidation, and mitochondrial damage were assessed by ELISA, flow cytometry, and electron microscopy. Western blotting explored molecular mechanisms. HMOX1 was identified as a ferroptosis‐related hub gene in MASLD datasets and was decreased in patient liver tissues. MCD‐fed mice developed hepatic steatosis with elevated ALT, AST, TG, LDL, Fe²⁺, MDA, and ROS, along with reduced HMOX1 and GSH. Hemin ameliorated MASLD and inhibited ferroptosis. Cell experiments showed JAK/STAT pathway activation in MASLD. HMOX1 upregulation reduced lipid peroxidation, inhibited ferroptosis, and downregulated JAK/STAT, whereas erastin reversed these effects. AZD1480 reversed the effects of erastin and improved MASLD. Collectively, our results suggest that HMOX1 protects against MASLD by suppressing ferroptosis through JAK/STAT pathway inhibition.

Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1 (DEC1) in promoting BC-related bone metastasis. Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown reversed these effects. Notably, AMD3100, a specific CXCR4 antagonist, partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 bound to the CXCR4 promoter region (-230 to -326) and activated its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.