The phenomenon at the heart of the study is called intraplaque angiogenesis, the abnormal sprouting of microvessels within the wall of an atherosclerotic plaque. These tiny vessels are not benign plumbing. They leak, they recruit inflammatory cells, and they are widely regarded as a hallmark of plaques that are prone to rupture, the catastrophic event that triggers most heart attacks. What has remained murky is precisely how these vessels are driven to proliferate so aggressively. The Fudan team suspected the answer lay in a poorly explored dialogue between cellular metabolism and the epigenetic machinery that controls gene expression, a dialogue that has become one of the hottest frontiers in cardiovascular biology.

To find the culprit, the researchers combined bioinformatic screening of public gene expression datasets with profiling of actual atherosclerotic plaque specimens from patients and experiments in ApoE-knockout mice, a standard model of human atherosclerosis. Their search converged on TXNIP, a protein already known for its roles in oxidative stress and glucose metabolism, which they found to be significantly downregulated in the endothelial cells of unstable plaques. That pattern was consistent across human datasets and was confirmed by immunohistochemistry in both human plaque tissue and the aortas of mice fed a high-fat diet. In other words, wherever plaques turned dangerous, this protective protein seemed to vanish.

The mechanistic story that followed is where the study becomes genuinely striking. Using co-immunoprecipitation and targeted mutagenesis, the team showed that TXNIP binds directly to LC3, the central engine of autophagy, through a conserved LC3-interacting region known as a LIR motif. This binding allows TXNIP to escort hexokinase 2, or HK2, a glycolytic enzyme that sits on the outer mitochondrial membrane, into the mitophagy pathway, the cellular quality-control system that degrades damaged or surplus mitochondria and their associated proteins. Crucially, this degradation route is ubiquitin-independent, meaning TXNIP provides the targeting signal that conventional degradation pathways would otherwise lack.

When TXNIP is present, HK2 is kept in check. When TXNIP is absent, the brake comes off. HK2 accumulates on mitochondria, aerobic glycolysis accelerates, and the endothelial cells begin churning out lactate in large quantities. The team documented this shift using Seahorse metabolic flux analysis, which measures real-time proton efflux and oxygen consumption in living cells, and confirmed that a TXNIP mutant lacking its LIR motif lost the ability to restrain glycolysis. The result is a metabolic reprogramming of endothelial cells toward the Warburg-like behavior that characterizes rapidly proliferating cells, from tumor tissue to healing wounds.

But lactate, it turns out, is not merely metabolic exhaust. Over the past several years, biologists have recognized that lactate can chemically modify histones, the protein spools around which DNA is wound, through a process called lactylation. The Fudan group used CUT&Tag, a technique for mapping histone modifications across the genome, to show that the lactate flood in TXNIP-deficient cells enriched histone H3 lysine 9 lactylation, or H3K9la, specifically at the promoters of pro-angiogenic genes, including EGR3, PFN1, and MAPK3. This epigenetic mark loosens chromatin at those sites and drives the transcriptional programs that push endothelial cells into excessive proliferation, migration, and tube formation, the three behaviors that define pathological angiogenesis.

The in vivo experiments tied the whole axis together. The researchers knocked down TXNIP in ApoE-knockout mice and watched pathological intraplaque angiogenesis flourish and plaque stability deteriorate. Then came the therapeutic test: the team treated the animals with 2-deoxyglucose, or 2DG, a pharmacological inhibitor of hexokinase activity. Blocking HK2 effectively reversed the pathological vessel growth and improved plaque stability, even in mice lacking functional TXNIP. That result is significant because it demonstrates that HK2 sits downstream of TXNIP in the pathway and can be drugged independently of the upstream protein, offering a realistic pharmacological entry point.

What makes this work resonate beyond the vascular biology community is its framing of a complete chain of causation, from mitochondrial quality control through glycolytic reprogramming to epigenetic regulation of gene expression. The TXNIP-HK2-H3K9 lactylation axis, as the authors describe it, is a rare example of a single pathway connecting three of the most actively studied layers of cell biology. It also provides a mechanistic account of why cholesterol lowering alone cannot fully eliminate cardiovascular risk: plaque vulnerability is not only a lipid problem but a metabolic and epigenetic one, driven by processes that continue operating regardless of circulating LDL levels.

The therapeutic implications are tantalizing but still early. 2DG is a blunt instrument with known toxicity at higher doses, and translating mitophagy modulation or histone lactylation biology into safe human therapies will require years of additional work. Yet the study, funded by the Qingpu Hospital Affiliated to Fudan University and the Natural Science Foundation of Shanghai, points toward a non-cholesterol-dependent strategy for stabilizing vulnerable plaques, a goal that has eluded cardiology for a generation. If subsequent studies confirm the axis in larger cohorts and identify clinically suitable ways to intervene, the humble protein TXNIP, long a supporting character in stories of oxidative stress, may find itself recast as a central player in the battle against the world’s leading cause of death.

Subject of Research: The TXNIP-HK2-H3K9 lactylation axis linking mitophagy, glycolytic reprogramming, and epigenetic regulation in pathological angiogenesis and atherosclerosis.

Article Title: TXNIP restricts angiogenesis and atherosclerosis by targeting HK2 for mitophagic degradation to repress H3K9 lactylation

Article References: Li, L., Li, Y., Gao, H., Li, X., Gao, Y., Wu, W., & Fan, L. (2026). TXNIP restricts angiogenesis and atherosclerosis by targeting HK2 for mitophagic degradation to repress H3K9 lactylation. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08935-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08935-z

Keywords: TXNIP, HK2, mitophagy, H3K9 lactylation, angiogenesis, atherosclerosis, glycolysis, endothelial cells, plaque vulnerability, epigenetics, 2-deoxyglucose, cardiovascular disease

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