Effects of genetic ablation and pharmacological inhibition of HuR/ELAVL1 on gene expression, iron metabolism and hormone levels

HuR/ELAV1, a widely expressed RNA-binding protein, is a member of the RNA-binding protein (RBP) family. It is known to stabilize and regulate translation of various mRNA targets, thereby playing a pivotal role in gene expression regulation. Elevated levels of HuR have been observed in a range of disorders, including cancer and neurodegenerative diseases. While small molecules inhibiting HuR have been identified, their comprehensive characterization remains limited. Notably, Eltrombopag, an FDA-approved medication used for immune thrombocytopenic purpura (ITP) and chemotherapy-induced thrombocytopenia (CIP), has been recently identified as a potent inhibitor of HuR. However, the specific molecular pathways co-regulated by HuR and Eltrombopag are yet to be fully elucidated.Our study reveals that the regulatory impact of Eltrombopag on gene expression through HuR primarily occurs at the protein level. We provide evidence demonstrating that both HuR knockout (KO) and Eltrombopag treatment modulate iron metabolism by suppressing the synthesis of ferritin heavy chain (FTH1) and light chain (FTL), while concurrently enhancing the expression of Iron-regulatory protein 2 (IRP2), a key regulator of ferritin translation. Furthermore, our findings indicate that HuR KO and pharmacological inhibition significantly reduce the levels of Glycoprotein Hormones, Alpha Polypeptide (CGA), a marker frequently elevated in hormone-induced cancers, suggesting a potential rationale for repurposing Eltrombopag in cancers exhibiting high CGA expression.Our results unveil novel post-transcriptional mechanisms governed by HuR and its inhibitor, shedding light on molecular pathways involving HuR and molecular therapies targeting this protein.