The research team worked with human umbilical vein endothelial cells, known as HUVECs, obtained from newborns with CDH and from healthy controls. Because these cells are collected at birth, they offer a rare window into the fetal biology of the disease, largely free of the confounders that complicate postnatal lung tissue studies, such as prolonged mechanical ventilation, oxygen exposure, vasoactive drug treatment, and critical illness. The investigators combined extracellular flux analysis, which measures oxygen consumption and glycolytic activity in living cells, with measurements of reactive oxygen species, mitochondrial membrane potential, mitochondrial DNA copy number, and mitochondrial morphology assessed by confocal microscopy.

The central observation is genuinely counterintuitive. Mitochondrial respiration in the CDH endothelial cells was not suppressed, as one might expect in a diseased tissue, but increased. Basal respiration, maximal respiration, and spare respiratory capacity were all elevated compared with controls. Yet this greater respiratory activity came at a cost: the cells showed increased proton leak across the inner mitochondrial membrane and reduced ATP coupling efficiency, meaning that a larger fraction of the energy stored in nutrients was dissipated as heat rather than captured in the cellular energy currency. Basal glycolytic activity was also increased, alongside elevated mitochondrial superoxide and cellular reactive oxygen species. Rather than the conventional metabolic switch from oxidative phosphorylation toward glycolysis, the CDH cells appeared to ramp up both pathways simultaneously while extracting energy from respiration less efficiently.

This distinction may matter biologically. Much of the conceptual framework for metabolic dysfunction in pulmonary hypertension comes from adult pulmonary arterial hypertension, where enhanced glycolysis and impaired oxidative phosphorylation are prominent features. The phenotype described by Emrick and colleagues is different in kind: oxidative respiratory capacity is preserved and even augmented, but at the price of increased leak, oxidative stress, and impaired coupling. The authors of the accompanying commentary suggest this may reflect the fundamentally different developmental setting of CDH. The pulmonary circulation in these infants does not transition from a previously normal mature state into vascular disease; it develops abnormally in utero, under conditions of compression, altered oxygen tension, and disturbed signaling.

Endothelial dysfunction in CDH is not a new concept, but the current study supplies a new metabolic explanation for it. In fetal sheep with experimental CDH, Acker and colleagues previously demonstrated markedly impaired pulmonary artery endothelial cell proliferation and tube formation, together with reduced populations of highly proliferative endothelial cells and increased superoxide production. More recently, Kool and colleagues identified reduced endothelial expression of the transcription factor KLF4 and disturbed endothelial–perivascular signaling in experimental CDH, reinforcing the idea that abnormal vascular development is established early and involves intrinsic endothelial programs rather than being purely a consequence of mechanical compression. The present human data complement these observations by suggesting that mitochondrial dysfunction and redox imbalance may be part of the cellular machinery underlying this abnormal endothelial phenotype.

The mitochondrial morphology findings are equally intriguing. Despite reduced MitoTracker Green fluorescence, a dye-based indicator of mitochondrial mass, mitochondrial DNA copy number was preserved, while confocal microscopy revealed a more branched and widely distributed mitochondrial network in the CDH cells. This pattern argues against a simple reduction in mitochondrial abundance and instead points to qualitative remodeling. Such remodeling could initially be adaptive: increased mitochondrial connectivity may help cells maintain ATP production and buffer local mitochondrial damage under sustained stress. However, persistent network remodeling in an environment of elevated reactive oxygen species production could eventually become maladaptive, perpetuating oxidative injury and impairing endothelial function over time.

Perhaps the most clinically interesting observation concerns the relationship between mitochondrial function and disease severity. Higher maximal respiration was associated with prolonged hospitalization and/or mortality, and showed a trend toward an association with lower prenatal observed-to-expected total fetal lung volume, a standard imaging-based measure of disease severity. These analyses are necessarily exploratory given the sample size, but they raise the possibility that the biological severity of CDH leaves a measurable metabolic imprint on endothelial cells already at birth. If confirmed in larger cohorts, such findings may eventually prove relevant not only mechanistically but also for phenotyping a disease in which pulmonary hypertension is remarkably heterogeneous and current management strategies acknowledge that one size does not fit all.

The results also fit into a broader shift in CDH research toward understanding intrinsic cellular and molecular defects across different lung compartments. Patient-derived airway basal cells have revealed persistent pro-inflammatory epithelial abnormalities in CDH, while recent analyses of human hypoplastic lungs demonstrated enrichment of pulmonary macrophages both before and after birth. Viewed together, these observations suggest that epithelial, immune, and vascular abnormalities may not represent isolated phenomena. Mitochondrial reactive oxygen species can modify inflammatory and redox-sensitive signaling pathways, while inflammatory mediators can themselves alter mitochondrial function. It is therefore tempting to speculate that metabolic stress, inflammation, and impaired developmental signaling form interconnected rather than independent disease pathways in the hypoplastic CDH lung, with mitochondria potentially serving as a common node linking them.

Two limitations deserve particular emphasis. First, HUVECs are not pulmonary microvascular endothelial cells. They offer an unusually valuable source of primary, patient-specific fetal endothelial cells, but the pulmonary endothelium develops within a highly specific mechanical, oxygen-dependent, and paracrine environment that umbilical vessels do not fully recapitulate. The current results should therefore be interpreted primarily as evidence of a systemic endothelial phenotype associated with CDH, with pulmonary relevance that remains to be demonstrated directly. Validation in human pulmonary vascular tissue, where feasible, and in complementary experimental models will be important next steps. Second, the study establishes an association rather than causality. Increased respiratory capacity may contribute to endothelial dysfunction, but it could equally represent an adaptive response to increased cellular stress or energy demand. The relatively small sample size also limits adjustment for disease severity, maternal comorbidities, and other potential confounders. The most informative next step may therefore be functional intervention: if normalization of mitochondrial reactive oxygen species, respiratory coupling, or mitochondrial dynamics can restore proliferation, migration, or angiogenic capacity in CDH endothelial cells, the argument for a mechanistic role of mitochondrial dysfunction would become considerably stronger.

The translational implications are attractive but should remain appropriately measured. Current treatment of CDH-associated pulmonary hypertension largely targets vascular tone after birth, and clinical responses remain variable. Emrick and colleagues instead identify a cellular metabolic phenotype that may have its origins much earlier in pulmonary development. This does not yet establish mitochondria as a therapeutic target, but it shifts attention toward the developmental biology that precedes postnatal pulmonary hypertension. Ultimately, the importance of this study lies less in proposing mitochondria as the single cause of CDH-associated vascular disease than in adding another layer to an increasingly integrated model of CDH pathogenesis, in which disturbed developmental signaling, abnormal cellular differentiation, inflammation, impaired angiogenesis, and vascular remodeling converge. By demonstrating a metabolically activated yet inefficient endothelial phenotype in primary human cells, the researchers provide a compelling new reason to reconsider the biological origins of vascular dysfunction in CDH, and a promising direction for the studies that must now follow.

Subject of Research: Mitochondrial dysfunction in endothelial cells from newborns with congenital diaphragmatic hernia

Article Title: Endothelial metabolism in CDH: mitochondrial dysfunction as a new piece of the puzzle

Article References: Wagner, R. (2026). Endothelial metabolism in CDH: mitochondrial dysfunction as a new piece of the puzzle. Pediatric Research. https://doi.org/10.1038/s41390-026-05569-1

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05569-1

Keywords: congenital diaphragmatic hernia, endothelial cells, mitochondria, pulmonary hypertension, reactive oxygen species, oxidative phosphorylation, glycolysis, HUVECs, lung development, mitochondrial dynamics, pediatric research, bioenergetics

Dyslipidemia, the medical term for an unhealthy balance of fats circulating in the blood, is one of the most common metabolic disturbances in the modern world. When total cholesterol and low-density lipoprotein cholesterol, often called LDL or the atherogenic form of cholesterol, climb too high, fatty deposits accumulate along arterial walls, stiffening vessels and setting the stage for heart attacks and strokes. Oxidative stress compounds the problem. In metabolically stressed tissue, cells generate an excess of reactive oxygen species, chemically aggressive molecules that attack lipids, proteins, and DNA. In the liver, this oxidative assault drives lipid peroxidation, the chain-reaction degradation of fats that damages hepatic cells and worsens the lipid imbalance. The two processes feed each other, which is why interventions that address both simultaneously are of particular interest to nutritional scientists.

The research team, led by Mei Tong He and Yu Ri Jeong of Gyeongsang National University together with colleagues at the National Institute of Forest Science, set out to test whether honey derived specifically from Hedera rhombea flowers could intervene in this vicious cycle. The researchers chose this honey partly because of its botanical origin: ivy plants are known to contain a rich array of bioactive phenolic compounds, and prior work has shown that chemical constituents isolated from Hedera rhombea fruits exhibit inhibitory activity against enzymes linked to metabolic disease. Because bees concentrate plant-derived phytochemicals in their honey, the team hypothesized that an ivy floral source might yield a product with unusually strong metabolic and antioxidant properties.

To test the hypothesis, the researchers induced dyslipidemia in mice by placing them on a high-fat diet, a well-established model that reliably reproduces the elevated cholesterol, elevated LDL, and elevated atherogenic index seen in human metabolic syndrome. The atherogenic index, a calculated ratio derived from blood lipid measurements, serves as a composite predictor of cardiovascular risk. Mice in the treatment groups received Hedera rhombea honey at doses of 0.5 and 1 gram per kilogram of body weight per day over a four-week period. This dosing regimen allowed the team to evaluate both the efficacy and any dose-dependence of the honey’s effects.

The results on lipid metabolism were striking. Compared with untreated mice on the high-fat diet, the honey-supplemented animals showed significantly lower total cholesterol, significantly lower LDL cholesterol, and a significantly reduced atherogenic index. In practical terms, the honey appeared to blunt the lipid-raising consequences of an obesogenic diet rather than merely shifting numbers at the margins. Because circulating cholesterol is largely managed by the liver, which packages, exports, and clears lipoproteins, the authors turned their attention to hepatic tissue to understand where the intervention was acting.

What they found in the liver pointed to a coordinated rescue of the organ’s antioxidant defense system. Mice receiving the honey exhibited markedly reduced lipid peroxidation, indicating that their fat molecules were undergoing less oxidative degradation. Levels of nitric oxide and reactive oxygen species in hepatic tissue also fell, while the expression of antioxidant-related genes and the activity of antioxidant enzymes rose. Perhaps most tellingly, the treatment increased levels of phosphorylated AMPK, or p-AMPK, in the liver. AMP-activated protein kinase is a master metabolic sensor that, when activated, shifts cellular metabolism away from energy storage and toward energy burning, promoting fatty acid oxidation and suppressing cholesterol synthesis. Upregulation of AMPK signaling is a recognized mechanism through which natural products counteract non-alcoholic fatty liver disease and related disorders, and its activation here suggests that the honey’s benefits operate through a well-characterized regulatory pathway rather than an incidental effect.

Beyond cholesterol, the study probed markers of thrombosis, the formation of blood clots that transforms arterial plaques into life-threatening events. High-fat feeding is known to disturb hemostasis, elevating factors that promote both platelet activation and coagulation. In the treated mice, serum levels of thromboxane B2, a stable metabolite that reflects platelet activation, and coagulation factor VII, a key protein in the clotting cascade, were both significantly reduced. This observation is notable because it extends the honey’s apparent benefits beyond lipid chemistry into the domain of blood rheology, echoing earlier human and animal studies suggesting that natural honey consumption can influence platelet function and coagulation proteins. Lowered thrombogenic potential, combined with improved lipids, paints a broader picture of cardiovascular protection than either measure alone.

To explore whether the honey could also protect blood vessels directly, the team turned to an in vitro model using human umbilical vein endothelial cells, or HUVECs, the workhorse cell type for studying vascular biology. These cells were stimulated with tumor necrosis factor-alpha, an inflammatory signaling molecule abundant in obesity and metabolic disease that provokes endothelial cells to produce intracellular reactive oxygen species and express adhesion molecules that recruit immune cells to the vessel wall. When the researchers pretreated the cells with the ivy honey, the TNF-alpha-induced surge of intracellular ROS was significantly and dose-dependently reduced. Because endothelial dysfunction driven by oxidative stress is considered an initiating event in atherosclerosis, this cellular result complements the animal data and suggests a plausible mechanism by which the honey’s constituents might shield the vascular lining.

The convergence of results across three levels, whole-animal lipid profiles, hepatic molecular signaling, and cultured human vascular cells, strengthens the study’s central claim: that honey from Hedera rhombea acts by regulating lipid metabolism, bolstering antioxidant defenses, and engaging AMPK signaling simultaneously. The authors conclude that the honey may serve as a promising functional food ingredient for improving dyslipidemia and oxidative stress. The work was supported by the National Institute of Forest Science in Korea, reflecting a broader national interest in identifying value-added products from forest-derived resources, and the study builds on earlier research in which the same honey was explored as a sugar substitute in functional cookies designed to slow carbohydrate digestion.

As with any preclinical study, caution is warranted before extrapolating to the breakfast table. The mice received controlled doses over a defined period, and the doses used, translated to human scales, would represent meaningful daily quantities of honey with corresponding caloric load. Human clinical trials with natural honeys have produced mixed but often encouraging results on lipid profiles, and systematic reviews have suggested potential benefits of honey in obesity management, yet floral source, regional composition, and phenolic content vary enormously between honeys, making it hazardous to generalize from one botanical variety to another. Indeed, the fact that this study focused on a single, carefully characterized floral source may be its greatest strength, since honey’s biological activity is increasingly understood to depend on the specific phenolic compounds imparted by its nectar origin. If future studies confirm these effects in humans and identify the responsible compounds, ivy honey could join the growing roster of bee products under serious investigation not as folk remedies but as chemically characterized functional foods with measurable metabolic effects. For now, the study offers an intriguing glimpse of how a traditional food, harvested from an unassuming climbing vine, might one day earn a place in evidence-based strategies against the world’s most burdensome chronic diseases.

Subject of Research: Effects of honey from Hedera rhombea Bean on dyslipidemia and oxidative stress in high-fat diet-induced mice

Article Title: Effects of honey from Hedera rhombea Bean on dyslipidemia and oxidative stress in high-fat diet-induced mice

Article References: He, M. T., Jeong, Y. R., Kim, G. M., Lee, A. Y., Na, S.-J., Kim, H.-J., & Kim, J. H. (2026). Effects of honey from Hedera rhombea Bean on dyslipidemia and oxidative stress in high-fat diet-induced mice. Food Science and Biotechnology. https://doi.org/10.1007/s10068-026-02313-7

Image Credits: AI Generated

DOI: 10.1007/s10068-026-02313-7

Keywords: Hedera rhombea, honey, dyslipidemia, oxidative stress, high-fat diet, AMPK signaling, lipid metabolism, reactive oxygen species, HUVECs, atherogenic index, antioxidant enzymes, functional food