The peptide, known as MOTS-c, is transcribed from the mitochondrial open-reading-frame of the 12S rRNA-c region. Since its discovery, MOTS-c has attracted intense interest as one of a handful of mitochondrial-derived peptides that can act as signaling molecules, influencing metabolism, stress responses and aging far beyond the organelle where they are made. What the Nanjing-led team has done is to trace its role in the eye with unusual precision. Using retinal tissue, they showed that MOTS-c is predominantly localized in retinal endothelial cells, the thin, tightly connected cells that form the inner lining of blood vessels and constitute the blood-retinal barrier, the critical interface that keeps the light-sensitive tissue protected and properly nourished.

That localization matters because the earliest events in diabetic retinopathy are vascular. Chronically high blood sugar injures endothelial cells, weakens the junctions between them, and allows fluid and blood components to leak into the retina. It also damages mitochondria within the endothelial cells themselves, promoting the accumulation of reactive lipid peroxides that attack cellular membranes. To test whether MOTS-c is a casualty of this process, the researchers exposed human retinal endothelial cells to high glucose concentrations and studied a streptozotocin-induced diabetic mouse model, a standard experimental system in which the drug destroys insulin-producing cells and produces sustained hyperglycemia. In both settings, high glucose reduced the expression of MOTS-c in the retinal vasculature, suggesting that the loss of this mitochondrial signal is part of the injury program that diabetes unleashes on the eye.

The therapeutic logic followed directly. When the team supplied MOTS-c to human retinal endothelial cells suffering high-glucose-induced injury, the peptide protected the endothelial barrier and ameliorated mitochondrial dysfunction. The same benefit appeared in the diabetic mice: MOTS-c treatment rescued vascular endothelial damage in the retina. These genetic and pharmacological approaches, applied both in cell culture and in living animals, established that the peptide’s dysregulation is not merely a byproduct of disease but a mechanistically meaningful contributor to the vascular breakdown that drives diabetic retinopathy.

The deeper question was how a 16-amino-acid peptide could accomplish this. To find out, the researchers turned to unbiased molecular profiling. Transcriptomic analyses, which survey changes in gene expression across the whole genome, and lipidomic analyses, which map the constellation of fats and phospholipids inside the cells, converged on a surprising pathway: MOTS-c increased the activity of phospholipase A2, a family of enzymes that cleave phospholipids, the molecules that form the backbone of every cellular membrane, and thereby regulated phospholipid metabolism. In other words, the mitochondrial peptide appears to reprogram how endothelial cells maintain and remodel their own membranes under diabetic stress.

Among the differentially expressed genes associated with this upregulated phospholipase A2 activity, one stood out. Phospholipase A2 group VI, known as PLA2G6, showed the most significant upregulation following MOTS-c treatment. PLA2G6, an intracellular calcium-independent phospholipase, is best known in other contexts for its role in lipid homeostasis and, when mutated, in neurodegenerative disease. In the diabetic retina, the new work assigns it a protective job: PLA2G6-mediated degradation of lipid peroxides served as a primary mediator of the endothelial barrier protection seen during MOTS-c treatment. Lipid peroxides are the corrosive products of unsaturated fatty acid oxidation, and their accumulation is a hallmark of ferroptosis and related forms of oxidative cell death. By accelerating their breakdown, PLA2G6 effectively detoxifies the membrane environment of stressed endothelial cells.

The causal chain was then tested in the most demanding way, by removing the link. When the researchers knocked down PLA2G6, the protective effect of MOTS-c against vascular endothelial damage collapsed, both in vitro and in vivo. The peptide could no longer defend the endothelial barrier without its enzymatic partner. This loss-of-function result elevates the finding from correlation to mechanism: MOTS-c acts upstream, PLA2G6 acts downstream, and the degradation of lipid peroxides is the functional bridge between them. It also suggests that patients or experimental systems with insufficient PLA2G6 activity might respond poorly to MOTS-c-based interventions, a consideration that could shape future strategies for patient selection.

Taken together, the study identifies a novel role for MOTS-c dysregulation in mediating vascular endothelial damage in diabetic retinopathy and proposes MOTS-c supplementation as a potential therapeutic approach, one that works by regulating phospholipid homeostasis and protecting the endothelial barrier through PLA2G6. The conceptual appeal is considerable. Rather than blocking a single growth factor after the vasculature has already begun to fail, a MOTS-c-based strategy would aim to reinforce the fundamental resilience of endothelial membranes early in the disease, when intervention could still prevent the cascade of leakage, inflammation and pathological vessel growth that ultimately destroys vision. It also adds to a growing appreciation that mitochondrial-derived peptides are not metabolic footnotes but active hormones with tissue-specific protective functions.

Substantial work remains before this biology reaches the clinic. The findings, published as an open-access article in Cell Death Discovery on 10 October 2026, were obtained in cell culture and in a mouse model of diabetes, and translating a mitochondrial peptide into a safe, durable therapy for human eyes will require solving questions of delivery, dosing, stability and long-term safety that the current study did not address. Human diabetic retinas, exposed to years of metabolic fluctuation, may behave differently from acute experimental hyperglycemia. Yet the study offers something the field has lacked: a defined molecular axis, running from a mitochondrial genome-encoded peptide through phospholipase A2 activity and lipid peroxide clearance to the integrity of the blood-retinal barrier. If that axis holds up in further preclinical and clinical testing, the smallest genome in our cells may turn out to hold one of the larger answers to diabetic blindness.

Subject of Research: The role of the mitochondrial-derived peptide MOTS-c and phospholipase A2 group VI in protecting retinal endothelial cells in diabetic retinopathy

Article Title: Mitochondrial-derived peptide MOTS-c rescues vascular endothelial damage via PLA2G6 in diabetic retinopathy

Article References: Liao, Y., Xiang, J., Xia, Y., Liu, C., He, C., Tong, J., Chen, Y., Yao, G., & Xie, Z. (2026). Mitochondrial-derived peptide MOTS-c rescues vascular endothelial damage via PLA2G6 in diabetic retinopathy. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03384-5

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03384-5

Keywords: MOTS-c, mitochondrial-derived peptide, diabetic retinopathy, retinal endothelial cells, PLA2G6, phospholipase A2, lipid peroxides, endothelial barrier, mitochondrial dysfunction, phospholipid metabolism, blood-retinal barrier, diabetes complications

Vascular endothelial growth factor, or VEGF-A, has a complicated reputation in lung biology. The factor was originally discovered as vascular permeability factor, a molecule secreted by tumor cells that made blood vessels leak fluid at an alarming rate. In the lung, that leakiness is precisely the problem in acute lung injury: when the endothelial lining of pulmonary microvessels becomes permeable, protein-rich fluid floods the airspaces, oxygen exchange collapses, and patients may require mechanical ventilation to survive. Earlier clinical studies had found elevated VEGF in the airspaces of patients with respiratory distress syndrome, and researchers have long debated whether the growth factor is a culprit driving vascular leak or, paradoxically, a repair signal that helps the damaged endothelium recover. The new findings suggest that part of the confusion may have arisen because investigators were measuring a family of molecules with opposite effects as if it were a single entity.

The key to that complexity lies in alternative splicing, the process by which a single gene yields multiple protein versions. In the final stretch of the VEGF-A gene, two different sets of terminal exons can be stitched onto the coding sequence. One choice produces the classical pro-angiogenic isoforms, exemplified by VEGF165a, which bind the receptor VEGFR2 on endothelial cells and trigger the signaling cascades that make vessels grow and leak. The alternative choice produces the so-called b-variants, including VEGF165b, which differ in just six amino acids at the carboxyl terminus. That subtle change, first characterized by researchers studying kidney and cancer biology in the early 2000s, is enough to render the variant weakly angiogenic and poorly permeability-inducing, while still allowing it to occupy the same receptor. The b-isoforms therefore behave as natural antagonists of their pro-angiogenic siblings, competing for receptor binding without delivering the same intracellular message.

The Guangzhou-led team began by asking whether this splice balance is disturbed in human lung injury. Analyzing blood samples from patients, they found that the circulating ratio of VEGF165b to total VEGF-A was significantly reduced in acute lung injury, and that the lower the proportion of the protective variant, the more severe the disease. That inverse correlation, reported alongside ethical approval from the First Affiliated Hospital of Guangzhou Medical University and Zhujiang Hospital of Southern Medical University, provided the first hint that a relative deficiency of VEGF165b might accompany, and possibly contribute to, the vascular catastrophe of respiratory distress syndrome. Correlation alone cannot establish causation, so the investigators turned to experimental models in which the relationship could be tested directly.

In mice, the researchers induced acute lung injury with lipopolysaccharide, the inflammatory toxin derived from bacterial cell walls that mimics Gram-negative sepsis, one of the most common triggers of the human syndrome. When the animals received exogenous VEGF165b, the consequences of the insult were markedly blunted: pulmonary edema diminished, inflammatory infiltration of the lung tissue decreased, and overall measures of injury improved. The converse experiment proved equally telling. When the team neutralized endogenous VEGF165b with antibodies, leaving the pro-inflammatory isoforms to act unopposed, lung damage became worse. Together, these gain-of-function and loss-of-function results established the splice variant as a genuine endogenous protector rather than a passive bystander, and they identified the VEGF165b-to-total-VEGF ratio as a candidate biomarker for tracking disease severity.

The mechanistic core of the study explains how a single splice decision can translate into barrier protection at the molecular level. Using human microvascular endothelial cells, human pulmonary artery endothelial cells, and primary pulmonary microvascular endothelial cells, the researchers showed that VEGF165b acts as a competitive antagonist at VEGFR2, selectively blocking the phosphorylation of the receptor at tyrosine 1175, a docking site whose activation is known to be essential for the permeability response. With that phosphorylation event suppressed, the downstream PI3K/AKT/eNOS pathway, which normally drives nitric oxide production and vessel relaxation during vascular leak, was quieted. The team traced the consequences further downstream to the Src kinase and the adherens junction protein VE-cadherin, the molecular glue that holds endothelial cells together. When Src phosphorylates VE-cadherin, the junctions loosen and fluid escapes; by preventing the upstream signal, VEGF165b reduced VE-cadherin phosphorylation and thereby kept the endothelial barrier intact.

Intriguingly, the protective variant does not stop at junctional reinforcement. Through RNA sequencing and network analysis of the signaling hubs affected by VEGF165b, the investigators found that the variant also suppresses the chemokine CCL2, also known as monocyte chemoattractant protein 1. CCL2 is a potent recruiter of circulating monocytes, and its reduction translated into a second, distinct anti-inflammatory mechanism: fewer monocytes adhered to the endothelial surface, limiting the wave of inflammatory cells that normally amplifies tissue damage in acute lung injury. The authors describe this as a dual mode of action, in which VEGF165b simultaneously strengthens the physical wall of the microvasculature and dampens the cellular inflammatory assault against it. Such a combination is rare among candidate therapies, which typically address either leakiness or inflammation but rarely both.

The findings also reframe a long-running therapeutic debate. Several anti-VEGF strategies, including the monoclonal antibody bevacizumab, have been explored for severe COVID-19 and other causes of pulmonary edema on the logic that blocking VEGF should reduce vascular leak. But blanket VEGF blockade carries well-documented risks, including hypertension, proteinuria, and thromboembolism, precisely because the growth factor performs essential maintenance roles in healthy vessels. The splice-variant view offers a more surgical alternative: rather than eliminating VEGF signaling altogether, one could in principle restore the balance between pro-permeability and anti-permeability isoforms, either by administering recombinant VEGF165b, which has already been tested as an anti-cancer agent in animal models, or by shifting the splicing machinery toward the protective variant. The study’s demonstration that neutralizing VEGF165b worsens injury adds a note of caution for any therapy that removes this natural brake indiscriminately.

As with any preclinical advance, the road from mouse models and cell cultures to the intensive care unit is long. The patient data establish an association between a low VEGF165b fraction and disease severity, but clinical trials will be needed to determine whether replenishing the variant improves outcomes, at what dose, and at what stage of illness. Questions also remain about how the splicing balance is regulated in the acutely inflamed lung, and whether splicing factors such as the SRSF family, which other studies have implicated in acute lung injury, could serve as drug targets. Nevertheless, the conceptual payoff is substantial. The work reveals that vascular homeostasis in the lung depends on the critical equilibrium of VEGF splice variants, positions VEGF165b as both a biomarker and a potential therapeutic agent for acute lung injury and respiratory distress syndrome, and offers a new strategy for treating vascular barrier dysfunction in critical lung disease, one of the most stubborn unsolved problems in modern critical care medicine.

Subject of Research: The role of the VEGF-A splice variant VEGF165b in protecting against acute lung injury by antagonizing VEGF165a/VEGFR2 signaling

Article Title: VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway

Article References: Deng, J., Wang, X., Wu, Z., Bai, Q., Luo, Q., Zhou, L., Yao, Y., Wang, H., Zhong, K., Liu, H., Chen, X., & Wang, T. (2026). VEGF165b attenuates LPS-induced acute lung injury via antagonizing the VEGF165a/VEGFR2 signaling pathway. Angiogenesis, 29(4), Article 75. https://doi.org/10.1007/s10456-026-10090-4

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10090-4

Keywords: acute lung injury, ARDS, VEGF165b, VEGFR2, vascular permeability, endothelial barrier, alternative splicing, VE-cadherin, CCL2, lipopolysaccharide, angiogenesis, pulmonary edema

The research, led by Anna Biedritzky and Michael Koeppen at University Hospital of Tuebingen in Germany, focused on a membrane-bound enzyme called ADAM17, short for A Disintegrin and Metalloproteinase 17. This protease is known to cleave, or shed, the outer portions of a wide range of molecules sitting on the cell surface, including adhesion proteins and cytokine receptors. By snipping these molecules, ADAM17 can fundamentally change how immune cells interact with blood vessels and how inflammatory signals propagate through tissue. What remained poorly understood was how much of the lung damage in ARDS could be attributed specifically to the version of ADAM17 produced by endothelial cells, the thin layer of cells lining the pulmonary microvasculature.

To answer this question, the team engineered mice in which the ADAM17 gene could be selectively deleted in endothelial cells using the Cre/loxP system, crossing mice carrying loxP-flanked ADAM17 alleles with Tie2-Cre driver animals. When these knockout mice and their normal littermates inhaled lipopolysaccharide, a bacterial endotoxin that triggers acute lung inflammation, the difference was striking. Three hours after exposure, total lung ADAM17 messenger RNA in the knockout animals was reduced by 77.5 percent compared with controls, demonstrating that endothelial cells are the dominant source of this protease in the inflamed lung. Flow cytometry confirmed that ADAM17 surface expression dropped on pulmonary endothelial cells while remaining intact on neutrophils and platelets, validating the specificity of the genetic deletion.

The most dramatic consequences appeared at the endothelial barrier itself. In control mice, LPS exposure caused the characteristic hallmarks of ARDS-like injury: thickening of the alveolar septa, gaps between endothelial cells, and protein-rich fluid pouring into the airspaces. In the knockout mice, lung architecture was substantially preserved. The researchers traced this protection to the maintenance of junctional integrity. Surface expression of JAM-A, a junctional adhesion molecule that redistributes during inflammation to permit leukocyte passage, was markedly altered in the absence of endothelial ADAM17. Crucially, the tight junction proteins ZO-1, occludin, and claudin-5, along with the adherens junction protein VE-cadherin, were all preserved at higher levels in the knockout animals, both in vivo and in cultured human endothelial and epithelial cells treated with ADAM17 inhibitors.

Functional measurements confirmed what the microscopy suggested. Using the Evans blue extravasation assay, in which a dye bound to albumin leaks out of vessels only when the barrier fails, the team showed that knockout lungs accumulated significantly less dye six hours after LPS challenge, the known peak of vascular leakage in this model. Total protein in bronchoalveolar lavage fluid, an indirect indicator of alveolar-capillary permeability, was also significantly lower in the knockout group. According to the authors, this represents the first direct demonstration of reduced Evans blue extravasation in this endothelial-specific ADAM17 knockout model, providing functional confirmation of a barrier-protective phenotype that earlier work had inferred mainly from histology and lavage protein measurements.

The study also resolved a long-standing question about where neutrophils get stuck when ADAM17 is missing. Rather than simply counting cells in the whole lung, the researchers used a compartment-specific flow cytometry approach, tagging neutrophils still inside the pulmonary vasculature with an intravenously injected antibody before tissue collection. This allowed them to distinguish intravascular, endothelial-adherent, interstitial, and intra-alveolar neutrophils. The results were revealing: knockout mice had similar numbers of circulating neutrophils as controls, but significantly more neutrophils retained at the endothelial surface and significantly fewer in the interstitium and alveolar space. The retained neutrophils showed elevated surface expression of the adhesion molecules CD162, also known as PSGL-1, and CD49d, an integrin subunit, consistent with a failure to complete the transmigration program.

Complementary experiments in a Transwell system, in which human neutrophils migrate across an endothelial-epithelial barrier along a chemotactic gradient of fMLP, reinforced this interpretation. Pharmacological inhibition of ADAM17 with TAPI-1, or dual inhibition of ADAM17 and ADAM10 with GW280264X, significantly reduced neutrophil transmigration, attenuated myeloperoxidase release, and lowered expression of the transmigration-associated molecules CD11b and JAM-A on the cells that did cross. Together, the in vivo and in vitro data suggest that endothelial ADAM17 does not control the initial adhesion of neutrophils to the vessel wall but rather their passage through it, coordinating shedding events that permit immune cells to squeeze between junctional complexes.

Beyond the physical barrier, the study uncovered a selective signaling role for the endothelial protease. Gene expression analysis three hours after LPS inhalation showed that deletion of endothelial ADAM17 selectively dampened two proinflammatory cascades: the TNF receptor 1 pathway, with reduced downstream NF-kappaB, JNK, TRADD, and CREB transcripts, and the interleukin-6 receptor pathway, with reduced JAK1 and STAT3 expression. In contrast, the TLR4 pathway, the primary sensor for bacterial endotoxin, was activated to the same degree in knockout and control mice, and immunostaining located TLR4 on endothelial cells, epithelial cells, and infiltrating neutrophils in both genotypes. The maturation and trafficking machinery for ADAM17 itself, involving iRhom2, AT1R, and iTAP, was likewise unaffected, indicating that the enzyme’s influence operates through its shedding substrates rather than through its own regulation.

The downstream consequences for the alveolar inflammatory milieu were substantial. Bronchoalveolar lavage fluid from knockout mice contained significantly less TNF-alpha, less soluble CD62L, less myeloperoxidase, and less neutrophil elastase, while levels of the anti-inflammatory cytokine IL-10 were higher, indicating a shift toward a resolving, less tissue-destructive environment. Pharmacological inhibition largely reproduced the genetic phenotype: TAPI-1 reduced interstitial neutrophil accumulation, GW280264X reduced both interstitial and alveolar accumulation, and both inhibitors preserved VE-cadherin expression, reduced chemokine CXCL2/3 release, and limited Evans blue leakage. Dual inhibition even caused neutrophils to pile up at the endothelium, mirroring the genetic knockout and pointing to cooperative roles for ADAM17 and ADAM10 in the transmigration cascade.

The authors are careful to note the translational caveats. In this study, inhibitors were given one hour before the LPS challenge, a standard target-validation design, so whether ADAM17 blockade helps after lung injury has already begun remains to be tested. Because ADAM17 has a broad substrate repertoire with physiological functions throughout the body, the authors suggest that future therapies may need to be temporally restricted, endothelial-targeted, locally delivered, or substrate-selective to minimize systemic side effects. Even with these limitations, the convergence of endothelial-specific genetic deletion and differential pharmacological inhibition makes a compelling case that ADAM17 on the pulmonary endothelium acts as a central inflammatory amplifier in acute lung injury, coordinating neutrophil trafficking, junctional destabilization, vascular leakage, and cytokine signaling. For a syndrome with mortality approaching forty percent and few options beyond supportive care, a druggable molecular chokepoint on the vessel wall is exactly the kind of target the field has been searching for.

Subject of Research: The role of endothelial ADAM17 in neutrophil migration and microvascular permeability during acute lung inflammation

Article Title: Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation

Article References: Biedritzky, A., Kleinmaier, C., Fuhr, A., Herrmann, L. M., Ngamsri, K.-C., Konrad, F., & Koeppen, M. (2026). Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation. Journal of Biomedical Science, 33(1), Article 91. https://doi.org/10.1186/s12929-026-01290-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01290-7

Keywords: ARDS, ADAM17, endothelial barrier, neutrophil migration, acute lung injury, vascular permeability, TNF-alpha, IL-6 signaling, JAM-A, VE-cadherin, LPS, pulmonary inflammation