Fgl-1 has attracted growing attention in cancer biology in recent years, largely because of its dual identity. Originally characterized as a hepatokine, a secreted protein produced mainly by the liver with roles in metabolism and inflammation, it was later recognized as an emerging immune checkpoint ligand. When expressed on the surface of tumor cells, Fgl-1 can bind to lymphocyte activation gene 3, known as LAG-3, on T cells, thereby suppressing the immune response against the tumor. In hepatocellular carcinoma, Fgl-1 has been shown to promote the exhaustion of liver-resident memory T cells, helping the tumor evade immune surveillance. But the protein appears to be more than a decoy for immune cells. Prior work in gastric cancer linked Fgl-1 overexpression to invasion, metastasis and poor prognosis, while studies in metabolic disease connected circulating levels of the protein to insulin resistance and obesity. What remained unclear until now was its clinicopathological significance and oncogenic role in endometrial adenocarcinoma specifically.

To address this gap, the Shandong team first examined Fgl-1 expression in human tissue samples using immunohistochemistry, a staining technique that reveals where and how strongly a protein is produced in tissue sections. The results were unambiguous. Fgl-1 was significantly overexpressed in endometrial adenocarcinoma tissues relative to normal endometrial tissue, a difference that reached high statistical significance, and the level of expression correlated positively with tumor grade, meaning that more aggressive, less differentiated tumors tended to produce more of the protein. This grade association hints that Fgl-1 is not merely a passenger marker of malignant transformation but may actively participate in the biological escalation of the disease.

The investigators then turned to cell lines to probe function. Western blotting, which detects specific proteins in cell lysates, confirmed that Fgl-1 was abundantly produced in endometrial adenocarcinoma cell lines, with particularly high levels in two lines, HEC1B and KLE. These became the workhorses of the study. Using lentiviral vectors, short fragments of genetic material delivered by engineered viruses that silence a target gene, the researchers knocked down Fgl-1 expression by roughly 60 percent. The consequences were dramatic. With Fgl-1 suppressed, the cancer cells lost much of their malignancy in vitro: they became less viable, proliferated more slowly, formed fewer cell clones in colony-formation assays, migrated less effectively across scratched wound-healing cultures, and invaded less aggressively through extracellular-matrix-coated membranes.

To understand how a single secreted protein could exert such broad control over cancer cell behavior, the team examined the molecular circuits downstream of Fgl-1, focusing on two well-known hallmarks of malignant progression: the PI3K/AKT pathway and epithelial-mesenchymal transition. The PI3K/AKT cascade is one of the most frequently dysregulated signaling networks in human cancer, functioning as a central conduit for growth factor signals that promote cell survival, growth, metabolism and motility. When phosphoinositide 3-kinase is activated at the cell membrane, it recruits and activates AKT, a kinase that phosphorylates dozens of downstream targets, tipping the balance toward survival and proliferation while blocking programmed cell death. Western blot analysis in the study showed that silencing Fgl-1 inhibited PI3K/AKT signaling in KLE cells, providing direct evidence that Fgl-1 acts upstream of this pathway in endometrial cancer cells.

The second circuit, epithelial-mesenchymal transition, or EMT, is the process by which epithelial cancer cells shed their adhesive, stationary identity and acquire the motile, invasive characteristics of mesenchymal cells. EMT is orchestrated by transcription factors that repress epithelial markers such as E-cadherin and induce mesenchymal markers such as N-cadherin and vimentin, and it is a critical step in a tumor’s ability to invade surrounding tissue and seed metastases. By assessing EMT-associated proteins with Western blotting, the researchers found that suppressing Fgl-1 dampened EMT, explaining, at least in part, the reduced migration and invasion observed in the functional assays. Together, the data sketch a coherent mechanism: Fgl-1 overexpression activates PI3K/AKT signaling, which in turn drives EMT and the aggressive behaviors that accompany it.

The therapeutic implications are considerable, and they cut across two of the most active frontiers in oncology. First, because Fgl-1 functions as an immune checkpoint ligand through its interaction with LAG-3, it sits at the center of a rapidly expanding drug development effort. LAG-3 has emerged as a promising inhibitory immune checkpoint, and clinical trials of LAG-3 inhibitors, including studies combining agents such as ieramilimab with anti-PD-1 antibodies, are already underway in advanced malignancies. Immunotherapy approaches targeting PD-1 and PD-L1 have shown activity in endometrial cancer, and the field is actively searching for additional checkpoint axes that could extend these benefits to more patients. If Fgl-1 is both an immunosuppressive ligand and an intrinsically oncogenic driver in endometrial adenocarcinoma, blocking it could deliver a double blow: releasing the brakes on antitumor immunity while simultaneously strangling the PI3K/AKT-driven growth program inside the tumor cells themselves.

Second, the findings place Fgl-1 within a growing family of proteins that bridge inflammation, metabolism and cancer. Fibrinogen-like protein 1 has been implicated as a biomarker of disease activity in rheumatoid arthritis, as a contributor to T-cell exhaustion in liver cancer, and as a circulating hepatokine altered after bariatric surgery. This pleiotropy raises both opportunities and cautions. A protein that operates across so many physiological contexts may be a valuable drug target precisely because it sits at a hub of disease-relevant signaling, but systemic interference could carry metabolic or inflammatory consequences that will need careful evaluation. The new study does not address those questions directly, and its conclusions rest on correlation in tissue samples and experiments in cell culture rather than animal models or clinical intervention, so translating Fgl-1 blockade into a safe therapy remains a distant goal. Nonetheless, the demonstration that Fgl-1 suppression is sufficient to cripple key malignant behaviors in endometrial cancer cells provides a strong mechanistic rationale for pursuing such strategies.

For patients with endometrial adenocarcinoma, the study’s most immediate significance may lie in biomarker development. Because Fgl-1 expression correlates with tumor grade, it could potentially serve as a pathology-based indicator of aggressiveness, helping clinicians stratify risk and tailor surveillance intensity. The authors suggest that targeting the Fgl-1 pathway represents a promising therapeutic strategy for endometrial adenocarcinoma immunotherapy, and the convergence of their functional data with the broader clinical momentum behind LAG-3 blockade makes that suggestion more than wishful thinking. The research was supported by grants from the Science and Technology Development Program of Jinan, the Shandong Provincial Key Research and Development Program, and the Natural Science Foundation of Shandong Province, and it was conducted with ethics approval and informed consent from all tissue donors. As endometrial cancer incidence continues to rise in many parts of the world, driven in part by rising obesity rates, the discovery that a metabolic, immune-modulating, pro-oncogenic protein sits at the heart of the disease’s progression offers a timely and compelling new target for the next generation of treatments.

Subject of Research: The oncogenic role of fibrinogen-like protein 1 in endometrial adenocarcinoma progression via PI3K/AKT signaling

Article Title: Fgl-1 promotes the progression of endometrial adenocarcinoma through PI3K/AKT signal pathway

Article References: Fgl-1 promotes the progression of endometrial adenocarcinoma through PI3K/AKT signal pathway. (n.d.). https://doi.org/10.1007/s12032-026-03375-7

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03375-7

Keywords: endometrial adenocarcinoma, Fgl-1, fibrinogen-like protein 1, PI3K/AKT signaling, epithelial-mesenchymal transition, immune checkpoint, LAG-3, cancer immunotherapy, tumor progression, oncogenic driver, cell invasion, biomarker

The findings, published in the journal Molecular Genetics and Genomics, began with a bioinformatic sweep of publicly available cancer databases. The research team, led by Yan Liu and co-first authors Xiaolei Lv and Haitao Gao, found that NXPH4 was consistently and significantly overexpressed in clear cell renal cell carcinoma tissues compared with healthy kidney tissue. More ominously, elevated NXPH4 levels correlated with poor prognosis in patients with the disease, suggesting that the protein is not merely a passenger mutation but an active contributor to tumor progression. This pattern echoes previous reports linking NXPH4 to hepatocellular carcinoma, colorectal cancer, colon adenocarcinoma, bladder cancer, prostate cancer and breast cancer, but the new work is among the first to define its role in renal malignancy.

To move beyond correlation, the researchers performed a series of loss- and gain-of-function experiments in clear cell renal cell carcinoma cells grown in the laboratory. When they silenced NXPH4 using knockdown techniques, the cancer cells lost their predatory edge: viability dropped, invasion and migration slowed markedly, and apoptosis, the programmed cell death that cancer cells typically evade, increased. The opposite strategy, forcing NXPH4 overexpression, produced the mirror image of these effects. Cells became more viable, more invasive and more migratory, confirming that the protein functions as an oncogenic driver in this cancer type rather than a byproduct of tumor growth.

Because clear cell renal cell carcinoma is defined by its metabolic reprogramming, the team next turned to glycolysis. Database analysis revealed a positive correlation between NXPH4 expression and the levels of two canonical glycolytic enzymes: lactate dehydrogenase A, or LDHA, which converts pyruvate into lactate, and hexokinase 2, or HK2, which catalyzes the first committed step of glucose metabolism. When NXPH4 was suppressed in kidney cancer cells, protein levels of both LDHA and HK2 fell. When NXPH4 was elevated, glycolysis surged, as measured by glucose uptake, lactate production, ATP levels and the extracellular acidification rate, a standard readout of glycolytic flux. Oxygen consumption rates, which reflect mitochondrial respiration, rose in the knockdown experiments and fell with NXPH4 overexpression, indicating that the protein shifts the cell’s energy strategy away from oxidative phosphorylation and toward fermentative glycolysis.

The causal nature of this metabolic link was tested with a clever intervention. The researchers treated the cells with 2-deoxyglucose, a glucose analog that blocks glycolysis and is widely used in anti-glycolytic cancer research. Strikingly, 2-deoxyglucose reversed the pro-tumor effects of NXPH4, suppressing the viability, invasion and migration that the protein would otherwise promote. This experiment demonstrates that NXPH4’s oncogenic power in kidney cancer cells depends on the glycolytic engine it revs up; stall that engine, and the tumor-promoting signal loses much of its force.

The question then became how NXPH4 communicates with the glycolytic machinery. The answer, the researchers found, lies in the PI3K/AKT pathway, a signaling cascade whose dysregulation is a hallmark of clear cell renal cell carcinoma and a well-documented accomplice of the Warburg effect across many tumors. In the new study, raising NXPH4 levels activated PI3K/AKT signaling in the cancer cells. When the team pharmacologically blocked this pathway, the effect was dramatic: NXPH4-driven glycolysis, cell viability, invasion and migration were all significantly blunted. The evidence therefore sketches a coherent signaling chain in which NXPH4 acts upstream, AKT serves as the relay, and LDHA- and HK2-fueled glycolysis delivers the metabolic output that sustains malignancy.

These results add NXPH4 to a growing list of metabolic regulators implicated in renal cancer and place it within a broader literature connecting the PI3K/AKT axis to glucose metabolism in cancer. Recent work from other groups has shown that forkhead box protein K1 upregulates NXPH4 to promote proliferation, metastasis and glycolysis in colorectal cancer, and that NXPH4 enhances gemcitabine resistance in bladder cancer by modulating glycolysis through NDUFA4L2. In hepatocellular carcinoma, FOXK1-induced NXPH4 has similarly been linked to poor prognosis via the PI3K/Akt pathway. The consistency of this mechanism across tumor types suggests that NXPH4 may represent a class of secreted protein factors that couple growth signaling to metabolic rewiring, though the precise receptor interactions and upstream transcriptional control of NXPH4 in kidney tissue remain to be defined.

The clinical implications are potentially significant. Clear cell renal cell carcinoma accounts for the majority of kidney cancer deaths, and while immune checkpoint inhibitors and VHL/HIF-targeted therapies have improved outcomes in recent years, many patients eventually develop resistance. A glycolysis-centered dependency offers an alternative vulnerability: even if genetic drivers vary between patients, most clear cell tumors must maintain their glucose-hungry phenotype to survive. The new data indicate that suppressing NXPH4, either directly or by intercepting its activation of PI3K/AKT, could cripple this metabolic supply line. Combining such an approach with existing anti-glycolytic agents like 2-deoxyglucose derivatives, or with pathway inhibitors already approved for other cancers, could open new therapeutic avenues.

Cautious optimism is warranted. The study relies primarily on cell culture experiments and database correlations, and the authors note that all data generated during the work are available from the corresponding author upon request. Confirming the NXPH4-PI3K/AKT-glycolysis axis in animal models and, ultimately, in patient tumor samples will be essential before the protein can be pursued as a drug target or prognostic biomarker. Nevertheless, by tracing a single molecular thread from protein expression through signaling activation to metabolic reprogramming and malignant behavior, the Tangshan team has supplied a detailed mechanistic map of how kidney cancer feeds its own aggression. In a disease defined by metabolic flexibility, blocking the switch that keeps the sugar burning may prove to be a decisive blow.

Subject of Research: The role of neurexophilin 4 in clear cell renal cell carcinoma progression through PI3K/AKT-mediated glycolysis

Article Title: Neurexophilin 4 facilitates the malignant progression of kidney renal clear cell carcinoma by regulating PI3K/AKT-mediated glycolysis

Article References: Lv, X., Gao, H., Cui, D., Li, J., Li, X., & Liu, Y. (2026). Neurexophilin 4 facilitates the malignant progression of kidney renal clear cell carcinoma by regulating PI3K/AKT-mediated glycolysis. Molecular Genetics and Genomics, 301(1), Article 198. https://doi.org/10.1007/s00438-026-02483-3

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02483-3

Keywords: clear cell renal cell carcinoma, NXPH4, glycolysis, PI3K/AKT pathway, LDHA, HK2, metabolic reprogramming, kidney cancer, cell invasion, apoptosis, 2-deoxyglucose, therapeutic target