According to relevant studies, polarized M2 macrophages have been shown to secrete interleukin-6 (IL-6) and facilitate the phosphorylation of PGK1-threonine (T) 243 in tumor cells through the activation of 3-phosphoinositol-dependent protein kinase 1 (PDPK1). In one study, this phosphorylation event was found to enhance PGK1-catalyzed glycolysis by modulating substrate affinity, thereby promoting tumor cell metabolism and facilitating the proliferation and development of glioblastoma multiforme (Fig. 3B) [41].

In the context of glioblastoma, Yajuan Zhang and colleagues [41] made an interesting discovery regarding the interaction between PTEN (a tumor suppressor phosphatase) and PGK1. They found that PTEN’s protein phosphatase activity has a direct effect on PGK1, specifically at position 324 where it dephosphorylates and autophosphorylates PGK1 (tyrosine). This interaction ultimately leads to the inhibition of glycolysis, ATP production, and proliferation in brain tumor cells. Moreover, when they introduced mutant forms of PGK1 with a specific alteration at position 324 (PGK1Y324F), they observed suppression of the formation of brain tumors. Additionally, their analysis of human glioblastoma samples revealed an interesting correlation: lower levels of phosphorylation at position 324 in PGK1 were associated with higher expression levels of PTEN and better prognosis for glioblastoma patients (Fig. 3C) [42].

In a study conducted by Shao et al. [43], the phosphorylation levels of PGK1 serine (S) 203 were analyzed in 818 different cases of cancer. The results revealed that tumor tissues, across all five types of cancer, exhibited higher levels of PGK1 S203 phosphorylation compared to their corresponding normal tissues. Moreover, an association was found between elevated levels of PGK1 S203 phosphorylation and shorter overall survival rates in breast, liver, lung, stomach, and esophageal cancers. Additionally, increased expression of PGK1 S203 phosphorylation was observed in advanced tumor Node Metastasis (TNM) staging for breast and esophageal cancers. Independent prognostic significance for shorter overall survival was also demonstrated by PGK1 S203 phosphorylation in liver, lung, and gastric cancers [43].

Coincidentally, the researchers investigating PGK1 S203 also took into consideration the findings of Li et al. [26]. It was demonstrated by Xinjian Li and his colleagues [26] that in brain tumor development, hypoxia, EGFR activation, K-Ras G12V, and B-Raf V600E expression can induce the translocation of phosphoglycerate kinase 1 (PGK1) to mitochondria. The primary mechanism involves extracellular signal-regulated kinase (ERK)-dependent phosphorylation of PGK1 S203, followed by Pin1-mediated cis-trans isomerization and subsequent binding of PGK1 to the TOM complex. This facilitates successful translocation of PGK1 to mitochondria. Once inside the mitochondria, PGK1 directly interacts with PDHK1 at T338 and phosphorylates it. This phosphorylation enhances PDHK1 activity and PDHK1-mediated PDH phosphorylation. Consequently, pyruvate utilization through PDH is inhibited while cytoplasmic production of pyruvate and lactic acid increases within the mitochondria. These metabolic changes promote cell proliferation and tumorigenesis. Furthermore, Li et al.’s [26] study revealed a significant correlation between phosphorylation of PGK1 S203 and poor prognosis in patients with glioblastoma (Fig. 3D).

Glutamine deprivation and hypoxia have been recognized as triggers of autophagy in various cancer cells, playing a vital role in maintaining cellular equilibrium, including cell metabolism [48]. Xu et al. [39] demonstrated that when glutamine is scarce and oxygen levels are low, the inhibition of Arrest Defective 1 (ARD1) S228 phosphorylation by mTOR occurs. This leads to the association between ARD1 and PGK1, resulting in the acetylation of PGK1 K388. Acetylated PGK1 can directly interact with Beclin1. Experimental evidence has confirmed that the induction of autophagy that is crucial for brain tumor formation relies on ARD1-dependent PGK1 acetylation caused by glutamine deficiency and hypoxia, along with PGK1-mediated Beclin 1 S30 phosphorylation (Fig. 3E) [39].

In liver cancer samples and cell lines, a study conducted by Hu et al. [30] revealed a notable upregulation of PGK1 expression, which showed an inverse correlation with patient survival and overall expression levels. The researchers identified P300/CBP associated factor (PCAF) and Sirtuin 7 (SIRT7) as key regulators responsible for the acetylation of PGK1 at lysine (K)323. PCAF and SIRT7 inhibit PGK1 K323 acetylation resulted in significant inhibition of glycolysis, proliferation, and tumorigenesis in mouse xenotransplantation models used to simulate liver cancer progression (Fig. 3F) [30].

In addition to phosphorylation and acetylation, PGK1 can undergo O-GlcNAc modification, which is a significant type of post-translational modification. Nie et al. [44] demonstrated that the enzyme PGK1, responsible for producing ATP in glycolysis, can be dynamically and reversibly modified at threonine 255 (T255) by O-linked N-acetylglucosamine (O-GlcNAc). This specific modification of PGK1 with O-GlcNAcylation enhances the production of lactate and facilitates its movement into mitochondria. Once inside the mitochondria, PGK1 hinders the pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Moreover, through a xenotransplantation model experiment, it was confirmed that T255 O-GlcNAcylation of PGK1 stimulates proliferation and glycolysis in colon cancer cells, ultimately promoting tumor growth (Fig. 3G) [44].

Ubiquitination of PGK1 has become a prominent area of investigation in the field of tumor research. Recent studies have revealed that the protein kinase activity of PGK1 is intricately linked to the activation of autophagy [39, 49]. Additionally, researchers from Tao Yu’s team reported on the interaction between LINC00963 long coding RNA (lncRNA MetaLnc9) and PGK1by RNA Immunoprecipitation (RIP) technology, which helps mitigate its ubiquitination in non-small cell lung cancer [45]. Moreover, Cai et al. [46] expanded upon this knowledge by demonstrating that an lncRNA called gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) directly interacts with PGK1. This interaction leads to an increase in PGK1 protein levels by inhibiting its ubiquitination process. However, GBCDRlnc1 has also been shown by Cai et al. [46] to promote autophagy in gallbladder cancer cells and ultimately contribute to drug resistance. Therefore, it can be concluded that lncRNA GBCDRlnc1 induces autophagy and confers drug resistance in gallbladder cancer cells through its interaction with PGK1, preventing degradation [46].

Glycolysis represents a pivotal metabolic reprogramming event in pancreatic cancer (PC). In an unprecedented discovery, the research team led by Gang Quan has unveiled that KIF15 actively promotes the glycolytic capacity of PC cells and facilitates the growth of PC tumors. Employing mass spectrometry (MS) and Co-IP assay techniques, it was demonstrated that KIF15 effectively recruits and enhances the interaction between PGK1 and USP10. Furthermore, through ubiquitination assays, it was confirmed that KIF15 plays a crucial role in recruiting USP10 to exert its deubiquitinating effect on PGK1. This groundbreaking study provides compelling evidence for the first time that KIF15 augments PC glycolysis by orchestrating the recruitment of USP10 and PGK1, thereby highlighting the potential therapeutic significance of targeting the KIF15/USP10/PGK1 axis in treating PC [47].

Despite significant progress in early detection and treatment, breast cancer remains a prevalent form of malignancy among women based on the latest data from the American Cancer Society in 2023, with a consistent increase in new cases reported from 2015 to 2019 [50]. Breast cancer cells undergo a transformation that results in weakened cell-to-cell connections, which promotes the spread of cancer and increases its fatality rate [51, 52].

PGK1 has been linked to the promotion of tumor growth [13, 26, 27]. Previous research has shown that PGK1 can increase lactate production in breast cancer cells and facilitate tumor growth [26]. Studies have revealed that NEAT1 induces breast tumor growth [53, 54] and glycolysis [55, 56, 57] by binding directly with PGK1/PGAM1/ENO1 complexes, thus facilitating efficient substrate pathways for glycolysis [58]. Knockout of PGK expression inhibits the invasion of breast cancer cells and reverses the epithelial mesenchymal transition process while promoting the metastasis of breast cancer [59]. Hypoxia inhibits Long non-coding RNAs (lncRNAs) LINC00926 expression can also promote breast cancer metastasis [60]. Elevated levels of both PGK mRNA and promoter hypomethylation are associated with poor prognosis in breast cancer patients, particularly phosphorylation at S203 on PGK which is significantly correlated with shorter overall survival (OS) and advanced TNM staging [43]. Biogenic analysis shows upregulation of both mRNA and protein expression levels of PGK across various clinicopathological subtypes of breast cancer, highlighting its crucial role in proliferation, migration, and invasion processes within human breast cancer cells [61].

Liver cancer is ranked as the fifth most common malignancy globally and is the third leading cause of cancer-related death [62, 63]. In liver cancer research, significant attention has been paid to PGK1. Overexpression of PGK1 has consistently been observed in clinical samples and cancer cell lines associated with liver cancer cases. Experimental evidence also demonstrates that reducing PGK1 levels decreases both the occurrence and growth of liver cancer cells [30]. Moreover, comprehensive analysis indicates that PGK1 acts as an independent prognostic factor for reduced overall survival in patients with liver cancer [43]. By promoting glycolysis and enhancing metabolic efficiency within human liver tumor tissues, PGK1 facilitates ATP production to support hepatic carcinoma growth. Additionally, increased lactic acid accumulation promotes metastasis and correlates with unfavorable prognosis and overall survival rates among patients diagnosed with this disease [64]. These findings collectively highlight the potential therapeutic significance of targeting PGK1 for the effective management of liver cancer.

In addition to its direct impact on liver cancer, Chen et al. [65] discovered that mcPGK1 (mitochondrial phosphoglycoside kinase 1 translocated circular RNA) has been found to have high expression levels in tumor initiating cells (TICs), apart from its direct impact on liver cancer. It facilitates the movement of PGK1 to the mitochondria through the translocase of outer mitochondria 40 (TOM40). Considering that mitochondrial structure and function can be influenced by various external factors such as hypoxia, starvation, infection, tumorigenesis, and different stages of the cell cycle regulating glycolysis and oxidative phosphorylation (OXPHOS) activity; G1 phase cells tend towards OXPHOS while S phase cells prefer glycolysis. By promoting the localization of PGK1 within mitochondria, mcPGK1 contributes to metabolic reprogramming from OXPHOS to glycolysis. Ultimately, this leads to inhibition of mitochondrial oxidative phosphorylation through reprogramming of the PGK1-PDK1-PDH axis, thereby promoting glycolysis and regulating tumorigenesis and development [65]. Interestingly, N6-methyladenosine (m6A) RNA methylation and its associated enzyme methyltransferase-like 3 (METTL3) can also boost the expression of PGK1 by upregulating m6A modification of nuclear factor of activated T-cells 5 (NFAT5). This ultimately leads to increased proliferation and metastasis [66]. Similarly, miR-450b-3p has an inhibitory effect on hepatocellular carcinoma (HCC) proliferation and cell division by inhibiting PGK1 expression in HCC cell lines [67]. PRAS40 is phosphorylated by PGK1 and mediates the inhibition of autophagy-mediated cell death, thereby promoting cell proliferation and ultimately promoting the occurrence and development of HCC [68]. In order to find highly sensitive and specific biomarkers for predicting HCC recurrence, Liu et al. [69] confirmed in a cohort study that high serum PGK1 levels were closely related to early HCC recurrence and poor prognosis, suggesting that PGK1 may be a new biomarker for the diagnosis of HCC.

Prostate cancer (PCa) has emerged as the primary contributor to mortality among elderly males in both the United States and Europe. In 2013, there were approximately 238,590 reported cases of PCa in the US, resulting in 29,720 fatalities [70], with nearly all deaths attributed to prostate cancer and its spread to the bones [71].

Liquid biopsy shows great potential in utilizing circulating tumor cells (CTCs) as important biomarkers for monitoring and predicting cancer outcomes. In relation to prostate cancer (PCa), researchers have identified PGK1 as a possible new marker [72]. A study conducted by Chen et al. [73] revealed that evaluating the metabolic marker (PGK1/G6PD) could provide insights into the functional activity of CTCs when compared to their morphological classification using EMT criteria. These findings indicate that examining the metabolic traits of CTCs, especially those with high metabolism like GM+CTCs, may offer valuable information about prostate cancer metastasis [73]. Additionally, research has indicated the significant impact of tumor-mesenchymal interactions in the tumor microenvironment on the development and progression of cancer. Through laser capture microdissection and cDNA microarray analysis, it was discovered that prostate tumor myofibroblasts or cancer-associated fibroblasts (CAFs) exhibited a notable increase in PGK1 expression. Experimental results demonstrated that overexpression of PGK1 in CAFs led to higher proliferation rates and enhanced ability to promote invasion of prostate tumor cells in vitro, potentially through upregulation of MMP-2 and MMP-3 expression as well as activation of the AKT and ERK pathways. Co-implantation of fibroblasts with elevated levels of pgk1 alongside prostate tumor cells facilitated accelerated growth of the tumor cells when tested in vivo. Overall, these findings suggest that PGK1 plays a supportive role by facilitating interactions between cancer cells and their surrounding microenvironment [74], or by regulating critical factors involved in triggering the angiogenesis required for tumor metastatic growth [75].

Prostate cancer (PCa) is a solid tumor that spreads to the bones. PGK1 in PCa cells stimulates the differentiation of bone marrow stromal cells into bone-forming cells, while the secreted PGK1 inhibits the formation of bone-destroying cells called osteoclasts. Experimental findings indicate that PGK1 released by PCa influences bone development at the metastatic site by promoting bone formation, suppressing osteoclastic activity, and inducing an osteogenic phenotype in PCa cells [76]. However, there is still limited understanding regarding the molecular mechanisms underlying the primary human skeletal characteristics associated with PCa disease. Furthermore, it remains unclear how PGK1 regulates mineralization; therefore, any interpretations made based on available experimental data should be considered speculative. It is plausible that PGK1 may impede osteoclast production through VEGF secretion inhibition. Increased expression of PGK1 has been strongly correlated with unfavorable prognosis among patients diagnosed with PCa [76].

Lung cancer is a highly prevalent form of cancer, accounting for 11.6% of all global cancer cases and being the leading cause of cancer-related deaths worldwide. It is estimated that around 2 million new cases and 1.76 million fatalities occur each year due to this disease, with over 1.7 million reported deaths in 2018 alone [77, 78]. The most common histological subtype of lung cancer is non-small-cell lung cancer (NSCLC), which makes up approximately 85% of all diagnosed cases [79].

lncRNA play a crucial role in the development of lung cancer, specifically in its progression and the formation of tumors. The increased expression of LINC00963 (MetaLnc9) in human NSCLC samples is associated with a negative prognosis, as it promotes the migration and invasion of NSCLC cells both in vitro and in vivo. Research has shown that MetaLnc9 interacts with PGK1, preventing its degradation within NSCLC cells. This interaction activates the AKT/mTOR signaling pathway, which is known to contribute to carcinogenesis [45]. Clinically, high levels of PGK1 protein have been linked to survival outcomes for patients with non-small cell lung cancer, including overall survival and disease-free survival. Additionally, studies have found that PGK1 can induce lung cancer migration by directly binding HIV Tat-specific factor 1 [80]. In Lung Adenocarcinoma (LUAD), PGK1 modulates the immune microenvironment by influencing the crosstalk between tumor metabolism and immune editing within the tumor microenvironment (TME). These findings provide valuable insights into potential combination therapy strategies for Lung Adenocarcinoma (LUAD) that target immunometabolism; however, further experimental and clinical translational studies are needed [81].

Gliomas are most commonly observed in the central nervous system, which includes the brain and spinal cord. At present, the main treatment approaches for glioma involve removing the tumor through surgery, along with additional therapies such as chemoradiotherapy and targeted interventions [82, 83].

In the case of glioma, cancer cells increase their glycolysis activity to store energy. PGK1 plays a crucial role in promoting tumor cell glycolysis and enhancing the proliferation of glioma cells [84]. Interestingly, high expression levels of PGK1 have been observed in radiation-resistant astrocytoma [33, 35], suggesting its potential involvement as a biomarker for the radiation-resistant phenotype. Further investigations have shown that poor prognosis in glioblastoma patients is positively associated with phosphorylation levels of PGK1 at Y324 and S203 [26, 42]. However, within the tumor microenvironment, polarized M2 macrophages secrete interleukin-6 (IL-6) to facilitate tumor cell phosphorylation of PGK1 at T243. This ultimately leads to enhanced proliferation and formation of glioblastoma multiforme [41]. In terms of the autophagy mechanism, acetylation of PGK1 at K388 directly interacts with Beclin1 to initiate autophagy and further promote brain tumor development [39]. Additionally, secreted PGK1 contributes to the bystander effect observed during MicroRNA-10b (miR-10b) gene editing in gliomas [85]. Furthermore, NEAT1 specifically stabilizes PGK1 through interaction and promotes the progression of glioma [86]. Conversely, miR-6869-5p can inhibit the growth and invasion of glioma cells by binding to PGK1 and down regulating its expression [87]. Similarly, LHX9 and P7C3 bind to PGK1 resulting in down regulation at protein level and through total intracellular kinase activity; thereby inhibiting the malignant growth of glioma both in vitro and in vivo [88, 89].

Colorectal carcinoma (CRC) stands out globally as one of the most commonly diagnosed malignant diseases and represents a major contributor to cancer-related fatalities with around 1.4 million fresh instances reported in 2012 alone resulting in almost 700,000 deaths. Projections indicate an alarming rise in CRC incidence with an estimated surge to about 2.5 million new cases anticipated by the year 2035 [90, 91]. Within colon carcinomas there exists a notable escalation in PGK1 expression throughout the transition from adenomas to carcinomas [92], thus actively promoting tumor development while potentially facilitating metastasis [29]. PTMs of PGK1-t255 enhances lactic acid production, thereby amplifying the proliferation rate of colon cancer cells and ultimately driving tumor progression [44]. Additionally, miR-548c-5p may exert its role as a suppressor of CRC by targeting PGK1 [93], while Islam Khan et al. [94] have also demonstrated that PGK1 holds promise as a biomarker for radiation therapy response in colon cancer tumors.

The potential impact of PGK1 on various types of cancer is underscored by its significant role in glycolysis, and in addition to specific malignancies, PGK1 exerts influence on other forms of cancer.

Deletion of SMAD4 induces upregulation of PGK1 in pancreatic ductal adenocarcinoma (PDAC), which enhances glycolysis and invasiveness, and the unique localization pattern of PGK1 combined with PDAC progression can predict overall survival and disease-free survival [95]. Specific upregulation of PGK1 has been confirmed in renal clear cell carcinoma (KIRC), where increased expression in tumor tissue and serum indicates poor prognosis for patients [96]. In high-risk human papillomavirus (HPV) positive cervical epithelial squamous cell carcinoma (CESC) tissues, PGK1 expression is significantly higher compared to normal cervix tissues, resulting in shorter disease-specific survival (DSS) and progression-free survival (PFS) [97]. The overexpression of PGK1 is associated with the promotion of neuroblastoma bone marrow metastasis and exhibits a negative correlation with patient prognosis [98]. A hypoxic environment promotes glycolysis by inducing PGK1 expression in oral squamous cell cancer cells (OSCs), promoting tumor spread [99]. YTHDF3 enhances the stability of PGK1 mRNA through an M6A-dependent mechanism while HCG18 enhances its expression; both promote osteosarcoma proliferation [17, 100].

The Warburg effect is a distinctive trait observed in cancer and offers significant potential as a focus for both diagnostic and therapeutic approaches. Due to its crucial involvement in the development and advancement of multiple tumors, PGK1 emerges as an essential glycolytic kinase, making it a promising candidate for diverse anti-cancer interventions.