Pituitary adenoma (PA) originates from the adenohypophysis and is one of the common intracranial tumors [1], accounting for about 25 % of all primary intracranial tumors [2]. PA includes functional adenoma (FPA) and non-functional adenoma (NFPA) subtypes [3]. Pituitary adenomas are mostly benign intracranial tumors that do not metastasize and can usually be treated by transsphenoidal surgery. However, because surgical resection of PA is associated with various postoperative complications, such as diabetes insipidus, rhinorrhea, and nasal bleeding, recurrence may occur after surgical resection [4,5]. Prolactinoma is the most common subtype of functional adenomas. In addition to hyperprolactinemia, some prolactinomas also have the characteristics of tumor invasion, drug resistance and high recurrence rate [6]. Therefore, it is very important to explore the pathogenesis of PA and new therapeutic targets for the treatment of PA.

Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer metabolism and plays a key role in the growth of cancer cells [7,8]. The core of aerobic glycolysis is the hypoxia-inducible factor (HIF) 1α-mediated signaling pathway that enables cancer cells to survive under hypoxic stress by altering glucose metabolism into a glycolytic phenotype [9]. Due to aerobic glycolysis, cancer cells show higher glucose uptake, resulting in higher lactic acid levels and accelerated tumor growth and progression [10]. Research has shown that blocking glycolysis effectively inhibited the growth and prolactin (PRL) secretion of pituitary cancer cells [11]. Therefore, understanding the molecular mechanism of aerobic glycolysis in PA is crucial for the development of future diagnostic and therapeutic strategies for PA.

DNA damage binding protein 1 (DDB1), as a substrate receptor in CUL4-DDB1 E3 ligase, is essential for DNA repair [12]. It has been reported that DDB1 usually binds to DDB2 to form UV-damaged DNA-binding proteins and recruits’ proteins from the nucleotide excision pathway to initiate DNA repair [13]. In addition, DDB1 is also a linker protein of Cul4 E3 ubiquitin ligase, regulating nucleotide excision repair, cell cycle, DNA replication and cell growth [14]. It was found that DDB2 mediates LRH-1 degradation through the CUL4-DDB1 ligase complex and affects LRH-1-mediated glucose metabolic activity [15]. DDB1 is also a fully characterized HBx binding partner [16]. Research has found that HBx induces aerobic glycolysis during the development of spontaneous liver cancer [17]. Moreover, a quite recent report revealed that DDB1 was significantly upregulated in PA tissues, with a logCPM value of 9.1490, and was like to play a promoting role in PA progression [18]. However, its exact role and underlying mechanism in the regulation of PA progression is still unclear. We reasonably speculate that DDB1 may affect the aerobic glycolysis of PA.

The aim of this study was to investigate the effect of DDB1 on PA progression by regulating PAK1-mediated aerobic glycolysis using clinical samples, PA cell lines, and a mouse model of PA xenograft tumors, providing potential targets for the diagnosis and treatment of PA.