From metabolic dysregulation to malignancy: the presence of ZPR1 in gastrointestinal and hepatopancreatobiliary malignancies

Introduction

Zinc finger protein one (ZPR1) is zinc finger protein originally discovered as a protein vital for cellular replication and viability and is known to be ubiquitously expressed; it is known to partake in DNA-binding, neurogenesis, and the cell cycle (1-8). Notably, ZPR1 deficiency is shown to worsen outcomes of spinal muscular atrophy (SMA) by contributing to neuron apoptosis (1,4-6,9). Recently, many studies have shown ZPR1, also referred to as rs964184, to be significantly correlated with metabolic syndrome, hyperlipidemia, type two diabetes (T2DM), coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) (10-16). This trend is statistically significant across South and Central American, South Asian, East Asian, and Caucasian populations, indicating that the rs964184 allele is universal and consistent. ZPR1, the protein itself, was shown to function as a transcription factor for peroxisome proliferator-activated receptor gamma (PPAR-γ) by translocation to the nucleus and binding to the PPAR-γ promoter sequence (6,17,18). Additionally, ZPR1 is also shown to be significantly differently expressed in gastrointestinal and hepatopancreatobiliary malignancies, specifically pancreatic adenocarcinoma (PAAD), esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) (19-24). This review explores ZPR1’s current known role in cell signaling, its significant association with dyslipidemia and metabolic syndrome, and presence in PAAD, ESCC, and HCC.

ZPR1 in cell signaling

ZPR1, the protein and gene locus, also identified as ZNF259, is a highly conserved protein in humans, zebrafish, mice, and yeast (2,3). ZPR1 binds to epidermal growth factor receptor (EGFR) in vivo in its inactive form; the ZPR1 domain A and zinc fingers bind to cytoplasmic tyrosine kinase EGFR domains X and XI (2). Upon mitogen activation by EGF, ZPR1 is translocated to the nucleus (2). Likewise, it binds to platelet-derived growth factor receptor (PDGFR) but not to other tyrosine kinase receptors like insulin receptor or other MAP kinases (2). Galcheva-Gargova et al. demonstrated that the overexpression of ZPR1 caused a reduction in the EGF-stimulated tyrosine phosphorylation of both the EGFR and SHC, indicating that ZPR1 negatively regulates EGFR (2). After EGF stimulation, it triggers the formation of ZPR1, eukaryotic elongation factor 1 alpha (eEF1A), and guanosine diphosphate (GDP) complex and translocates both ZPR1 and eEF1A from the cytoplasm to the nucleus (3,4). The ZPR1 A domain binds to eEF1A in the GDP state (4-7); eEF1A residues Arg-164, Ile-175, Phe-178, and Lys 181 are most crucial for ZPR1 binding (6,9). This complex is also required for cell survival (3,4). More recent studies have shown that ZPR1 functions as a co-chaperone protein and mediates eEF1A folding (7,8). Specifically, Sabbarini et al. demonstrated that ZPR1 depletion causes misfolding of newly synthesized eEF1A leading to proteotoxicity and, with prolonged depletion, translational stress due to eEF1A insufficiency, while biochemical reconstitution demonstrates that ZPR1—via its zinc-finger and α-helical hairpin structures—is required to co-chaperone eEF1A biogenesis and folding (8). McQuown et al. show that ZPR1 is a unique co-chaperone protein in that it does not use ATP (7) but uses GTP-ase dependent co-chaperone mechanism for protein folding (7). ZPR1 binds folding intermediates of eEF1A, while folding and release are driven by eEF1A’s intrinsic GTPase activity rather than chaperone ATP hydrolysis. The co-chaperone Aim29 recognizes GTP-bound eEF1A, regulates its interaction with ZPR1, and promotes efficient release of the folded protein (7). In addition to eEF1a, ZPR1 and the survival motor neuron (SMN) protein complex also translocates to the nucleus. The ZPR1 B domain is required for binding to the SMN complex. SMN protein is important for messenger RNA (mRNA) editing and small nuclear ribonucleoprotein (snRNP) complexes (2,3). Without ZPR1, less SMN protein goes to the nucleus and R-loop accumulates, triggering cell death via JNK pathway and Caspase 3 in SMNs (2,4-6). Specifically, upregulation of ZPR1 helps resolve R-loop structures by recruiting senataxin (SETX), an RNA-DNA helicase, mediates its binding with R-loops (6).

Once in the nucleus, it is assumed that ZPR1 participates in the synthesis of ribosomal RNA (rRNA), because it aggregates in the nucleolus in proliferating cells (3). Similarly, ZPR1 can also interact with RNA polymerase II (5,6). ZPR1 may directly participate in snRNP complex with SMN protein, but this idea is not well supported by experimental evidence. It is known that ZPR1 indirectly affects snRNP complexes by controlling the amount of SMN protein that enters the nucleus (1,5). Aside from SMN protein, ZPR1 binds to the promoter of peroxisome proliferator-activated receptor-gamma (PPARG or PPAR-γ), acting as a transcription factor (5,6,18). The general structure of the PPAR gene contains the following functional domains: A/B, C, D, and E/F. C domain of PPAR-γ1/2, also called the DNA-binding domain (DBD), codes for a highly conserved region of DNA that binds to two zinc finger proteins (17,18). For PPAR-γ 1/2, this C domain binds to ZPR1 (17,18). In this article, we will elaborate the second isoform of PPAR-γ since it participates mostly in adipogenesis and lipid metabolism (17,18). Figure 1 illustrates how ZPR1 translocates to the nucleus.

Figure 1 Hyperphosphorylation of EGFR translocates more ZPR1 into the nucleus, increasing the transcription of PPAR-γ. EGFR, epidermal growth factor receptor; PPAR-γ, peroxisome proliferator-activated receptor gamma; PPRE, peroxisome proliferator response element; RNAP, RNA polymerase; ZPR1, zinc finger protein 1.

ZPR1, metabolic syndrome, and dyslipidemia

Rs964184 is a specific single-nucleotide polymorphism within the ZPR1 gene locus, depicted in Table 1. ZPR1, or rs964184, has been studied in context with APOA5 or with the APOA4-APOA5-ZNF259-BUD13 group on chromosome band 11q.23.3. Numerous studies with large sample sizes have the presence of rs964184 to be significantly correlated with metabolic syndrome, defined as central obesity, insulin resistance, hypertension, and dyslipidemia, across several different populations, specifically South and Central American, South Asian, East Asian, and Caucasians (10,12-15,25-28). Studies have also shown rs964184 to be significantly linked with dyslipidemia. These studies are composed of prospective, randomized controlled trials, case control cohorts, genome-wide association studies (GWAS), prospective cohorts, and retrospective cohorts (10,12-15,25-28) with sample sizes ranging from 200 to over thousands of subjects. These large sample sizes increased power and various study designs increased validity and credibility regarding ZPR1 association with dyslipidemia, insulin resistance, metabolic syndrome, and cardiovascular disease. Mechanistically, rs964184 is thought to influence T2DM and CAD and through dysregulated triglyceride metabolism, leading to visceral and subcutaneous lipid accumulation.

Multiple studies have linked ZPR1 SNP rs964184, to cardiovascular disease, specifically CAD and myocardial infarction (MI). In patients with genetically confirmed familial hypercholesterolemia and carriers of hypercholesterolemia, those with the SNP rs964184 had significantly elevated risk of MI, even with classical cardiovascular risk factors adjusted for (27). Alcala-Diaz et al. showed in patients with CAD and are carriers of rs964184, a low-fat diet rather than a Mediterranean diet significantly lowered fasting and postprandial triglycerides (25). Many other GWAS studies also supported significant rs964184 association with CAD, even with adjustment of covariates in European, southern Han Chinese, and Indian ancestry for the past decade (10,12-14,26,29). This association likely exists because rs964184 is located in the APOA5-APOA4-APOC3 gene cluster and influences triglyceride metabolism, leading to elevated plasma triglyceride levels, increased remnant lipoproteins, and subsequent promotion of atherosclerosis and CAD risk.

Several recent GWAS, with large sample sizes, and case-control studies have shown ZPR1, or rs964184 to be significantly correlated with MSALD (11,16,28,30). Notably, Esteve-Luque et al. showed that MASLD is significantly associated with ZPR1 rs964184 (11), and Lau et al. confirmed this across various ethnic groups by showing rs96184 is significantly correlated with elevated fatty liver index (FLI) (16). Liu et al. [2024] showed ZPR1 was significantly elevated in HCC and showed that for every 0.1 g/L increase in ApoB levels, HCC risk decreased by about 11%, suggesting ZPR1 may influence APOB levels and thereby modulate HCC risk (30). Given that ZPR1 is a transcription factor for PPAR-γ1/2 (17,18) and its role of negatively inhibiting EGFR (2,3,8), it plays a critical role in lipid metabolism in subcutaneous and visceral adipose tissue. Mechanistically, unstable binding to EGFR tyrosine kinase domain or hyperphosphorylation of EGFR can send more ZPR1 to the nucleus (2,3,5,7,9,17,18), increasing the transcription of lipogenesis genes. Figure 1 displays this concept. These data indicate that ZPR1 activity and expression are indicative of adipose and hepatic lipogenesis and dysregulation.

ZPR1 and cancer

The relationship between ZPR1 and cancer currently remains largely unexplored. Recent research has shown ZPR1 to be significantly upregulated in gastrointestinal, specifically pancreatic cancer, ESCC, and pancreatic cancer. In ESCC, ZPR1 expression is elevated but significantly decreases following treatment (20,21). Aref et al. demonstrated that ZPR1 is significantly upregulated in pancreatic ductal adenocarcinoma (PDA). The authors developed an 18-protein risk score, including ZPR1, and demonstrated that the risk score was significantly prognostic of overall survival and tumor recurrence (21). Chen et al. also demonstrated ZPR1 to be significantly overexpressed in PAAD, and ZPR1 to have increased interaction with testin, correlating with worse prognosis in PAAD (23). In ESCC, Sun et al. measured expression of ZPR1 protein with immunohistochemistry, having anti-ZPR1 autoantibody bind to ZPR1 protein and demonstrated ZPR1 to be significantly elevated in ESCC; the knockdown of ZPR1 resulted in a reduction of tumor migration and invasion, of which the authors suggest using ZPR1 as an immunodiagnostic biomarker for ESCC (20). Li et al. also demonstrated significantly elevated anti-ZPR1 antibody in ESCC and incorporated this data to develop a machine learning model used to prognosticate for ESCC (22). All these data illustrate the consistent overexpression and prognostic relevance of ZPR1 in gastrointestinal cancers, with functional roles in tumor progression and significant prognostic and diagnostic utility.

In addition to PAAD and ESCC, there are more studies indicating that ZPR1 is significantly in HCC (19,20,24) compared to other types of cancers. Sun et al. studied human proteome microarrays and observed significantly increased mRNA expression of ZPR1 in gastrointestinal cancers, notably PAAD, esophageal SCC, and liver HCC (20). He et al. studied genomes from human HCC tissue and also observed a significant increase in ZPR1 expression in HCC cells and was significantly hypo-methylated status in tumors, of which they suggested that high ZPR1 expression can be an independent risk factor for adverse prognosis of HCC (19). After treatment with immune checkpoint blockade (ICB) immunotherapy, ZPR1 levels were significantly reduced (19). Likewise, Liu et al. also confirmed significant elevation of ZPR1 levels in human HCC tissue (24). Liu et al. [2024] demonstrated that proteomic analysis further supports its role, with ZPR1 (rs964184) identified as the only allele significantly associated with liver cancer in their analysis (30). These data consistently demonstrate consistent and significant overexpression of ZPR1 in human HCC tissue. Given the existing data, further investigation of ZPR1’s role in HCC is warranted, as its elevated expression may likely have prognostic value and potential as a biomarker for risk stratification, early detection, and therapeutic monitoring in individuals at high risk of developing MASLD that can progress to HCC.

Conclusions

ZPR1 integrates growth factor signaling, transcriptional regulation, and translational control with metabolic and oncogenic pathways. Genetic and epidemiologic studies associate the rs964184 variant with dyslipidemia, metabolic syndrome, type 2 diabetes, cardiovascular disease, and MASLD across diverse populations. Mechanistically, ZPR1 regulates EGFR signaling, nuclear transcription of PPAR-γ, and chaperoning of eEF1A, thereby influencing lipid metabolism, protein synthesis, and cell survival. Altered ZPR1 expression has been reported across gastrointestinal and hepatopancreatobiliary malignancies, particularly in PAAD, ESCC, and HCC with evidence supporting context-dependent roles in tumor progression, prognosis, and treatment response. These findings suggest that ZPR1 participates in shared molecular pathways underlying metabolic disease and cancer. Collectively, current evidence supports ZPR1 as a molecular link between metabolic dysfunction and cancer, warranting further mechanistic studies and clinical validation to define its utility as a biomarker for risk stratification, early detection, and therapeutic monitoring in high-risk populations.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0016/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0016/coif). The authors have no conflicts of interest to declare.

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