Activation of the EPO–EPOR axis enhances dopamine agonist sensitivity in prolactinoma through mitochondrial STAT5A–mediated suppression of mtDNA transcription

Background Prolactinomas are among the most common pituitary neuroendocrine tumors (PitNETs). Although dopamine agonists (DAs) serve as the first-line medical treatment for prolactinomas, approximately 10-30% of patients exhibit DA resistance, underscoring the need for novel sensitization strategies. Methods A clinical cohort was analyzed to determine the correlation between serum erythropoietin (EPO) levels and responsiveness to DAs in patients with prolactinomas. To evaluate the DA-sensitizing effect of recombinant EPO, we employed both in vitro and in vivo prolactinoma models. Integrated RNA sequencing and metabolomic profiling were performed to characterize the transcriptional alterations and metabolic reprogramming associated with EPO-mediated DA sensitization. Finally, immunofluorescence staining and subcellular fractionation were used to examine the subcellular localization of STAT5A, while ChIP-qPCR demonstrated its distinct enrichment at regulatory regions of mitochondrial DNA (mtDNA). Results In our clinical cohort, we observed that serum erythropoietin (EPO) levels were positively correlated with DA responsiveness. Consistently, in vitro and in vivo prolactinoma models demonstrated that supplementation with the recombinant EPO epobis significantly enhanced DA efficacy. Mechanistically, epobis activated erythropoietin receptor (EPOR) signaling and exposed a metabolic vulnerability in prolactinomas by promoting the mitochondrial translocation of STAT5A and suppressing mtDNA transcription. This process impaired mitochondrial respiration and amplified mitochondrial reactive oxygen species (mitoROS) accumulation, ultimately exacerbating DA-induced apoptosis. Conclusion Our findings reveal that EPO-EPOR signaling sensitizes prolactinomas to DAs by exploiting a mitochondrial metabolic vulnerability. The clinical association between serum EPO levels and DA responsiveness in patients highlights the clinical relevance of this pathway, while the co-administration of epobis with DAs represents a promising translational strategy for overcoming DA resistance.