circOMA1 delivered by exosomes regulates DRD2‑mediated prolactinoma resistance

Among pituitary adenomas, prolactin‑secreting pituitary neuroendocrine tumours (PRL‑PitNETs) are unique in that pharmacotherapy, specifically cabergoline (CAB), can be used as a first‑line treatment, and it is the recommended therapeutic option. However, the mechanisms underlying CAB resistance remain incompletely understood. In the present study, gene microarray analysis and clinical tissue specimens were used to identify circular RNAs (circRNAs) associated with CAB resistance. circOMA1 expression was quantified in PRL‑PitNET tissues and patient plasma using reverse transcription‑quantitative PCR, and its diagnostic potential was evaluated in 219 patients with pituitary adenoma. Gain‑ and loss‑of‑function assays, combined with molecular biology techniques, were used to investigate the biological function of circOMA1 and the underlying molecular mechanism. circOMA1 was identified as a critical circular RNA influencing CAB resistance and prognosis in PRL‑PitNET. Mechanistically, circOMA1 acted as a miR‑145‑5p sponge, leading to upregulation of the E3 ubiquitin ligase Kelch‑repeat and BTB domain‑containing protein 7. This promoted ubiquitination of the CAB‑specific, high‑affinity G‑protein‑coupled receptor dopamine D2 receptor. Consequently, downstream autophagy was attenuated, and AKT pathway inhibition was impaired, which underlied the resistance. Furthermore, in vitro and in vivo studies demonstrated that circOMA1 was transported via exosomes, facilitating the transmission of CAB resistance among PRL‑PitNET cells. Plasma exosomal circOMA1 levels were significantly elevated in PRL‑PitNET patients preoperatively. These findings established circOMA1 as a key mediator of CAB resistance and a potential prognostic indicator in patients with a PRL‑PitNET.