The significance of the finding lies in its dual mechanism. Cardiovascular researchers have traditionally treated endothelial dysfunction and macrophage-driven inflammation as related but distinct strands of the atherosclerosis story. The endothelium, a single-cell-thick lining that governs vascular tone, barrier integrity, and leukocyte trafficking, is often the first casualty of cardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes. When endothelial cells malfunction, they express fewer protective molecules such as nitric oxide and more adhesion molecules that invite circulating monocytes to breach the vessel wall. Meanwhile, once inside the intima, monocytes differentiate into macrophages that gorge on oxidized lipids, transform into foam cells, and release a cascade of inflammatory cytokines that amplify lesion growth. The new work suggests that PLCE1 is a single upstream node that helps orchestrate both of these pathological processes at once.

PLCE1 encodes an enzyme belonging to the phospholipase C family, proteins that cleave the membrane phospholipid PIP2 into two potent second messengers, inositol trisphosphate and diacylglycerol. These messengers mobilize intracellular calcium and activate protein kinase C, triggering a wide range of cellular responses. PLCE1 is unusual among phospholipases because it also carries a Ras-associating domain and a Ras-GEF domain, linking it directly to small GTPase signaling pathways that control cell proliferation, migration, and survival. Genetic studies over the past decade and a half have repeatedly flagged variants within the PLCE1 gene locus in genome-wide association studies of coronary artery disease, and even earlier of stroke risk in some populations. What those association studies could not resolve was whether PLCE1 is merely a bystander genetically linked to true disease drivers, or an active participant in the disease process. The new findings argue firmly for the latter.

Using a combination of cellular models, animal experiments, and mechanistic analyses, the research team demonstrated that elevated PLCE1 activity worsens endothelial dysfunction. In endothelial cells, increased PLCE1 expression was associated with impaired endothelial function markers, disturbed barrier behavior, and a shift toward the pro-inflammatory, pro-adhesive state that characterizes early lesion formation. When the investigators suppressed PLCE1 in experimental models of atherosclerosis, the resulting lesions were less severe, and the endothelial lining displayed healthier functional characteristics. This directional evidence, that manipulation of PLCE1 changes disease severity rather than simply tracking with it, is the kind of causal data that genetic association studies alone can never provide.

The second arm of the mechanism concerns macrophages, the immune workhorses whose transformation into lipid-laden foam cells defines the atherosclerotic plaque. The study found that PLCE1 promotes a pro-inflammatory phenotype in macrophages, driving the production and release of inflammatory mediators that recruit further immune cells and destabilize plaques. Macrophage inflammation is now recognized as a central engine of atherosclerotic progression, a view powerfully validated by the landmark CANTOS clinical trial, which showed that directly targeting the inflammatory cytokine IL-1 beta reduces cardiovascular events independently of cholesterol lowering. By implicating PLCE1 upstream of macrophage inflammatory activation, the new research adds a candidate control point that could, in principle, restrain this inflammatory engine at its source.

The most consequential discovery, however, may be the identification of CTNNB1 as the molecular target linking PLCE1 to both pathologies. CTNNB1 encodes beta-catenin, the central transducer of the canonical Wnt signaling pathway and a transcriptional co-regulator with its finger in countless developmental and inflammatory processes. In the study’s experimental framework, PLCE1 was shown to act on beta-catenin signaling, and beta-catenin in turn mediated the downstream effects on endothelial cells and macrophages. When beta-catenin was experimentally depleted, the harmful consequences of PLCE1 overexpression were blunted. This epistatic relationship, in which removing the target abolishes the effect of the driver, is a classic hallmark of a genuine signaling axis, and it suggests a linear pathway: PLCE1 acts upon beta-catenin, and beta-catenin drives the gene expression programs that produce endothelial dysfunction and macrophage inflammation.

This proposed axis is biologically plausible in light of prior literature. Beta-catenin signaling has been repeatedly implicated in vascular inflammation, with Wnt-beta-catenin activity reported to increase endothelial permeability and to promote inflammatory gene expression in both endothelial cells and macrophages under atherosclerotic conditions. What the new study contributes is the placement of PLCE1 upstream of this pathway in the specific context of arterial disease, transforming scattered mechanistic hints into a coherent, testable model. It also offers a potential explanation for longstanding genetic associations between PLCE1 variants and cardiovascular outcomes: those variants may alter the intensity of beta-catenin signaling in the vessel wall, tuning the inflammatory set point of atherosclerotic tissue.

From a therapeutic standpoint, the findings are provocative but must be tempered by important caveats. Both PLCE1 and beta-catenin are pleiotropic molecules, meaning they perform essential functions far beyond the vascular system. Beta-catenin, in particular, is indispensable for stem cell maintenance in the intestine, bone formation, and a host of developmental processes, which is why systemic Wnt-pathway inhibitors have repeatedly stumbled in cancer trials due to toxicity. Any attempt to translate the PLCE1-beta-catenin axis into a cardiovascular therapy would almost certainly require highly targeted delivery, perhaps to vascular endothelium or lesional macrophages, or the identification of downstream effectors that are more vascular-specific. The study does not itself report a candidate drug or clinical intervention, and its conclusions rest on experimental models whose fidelity to human atherosclerosis, while substantial, is never complete.

Nevertheless, the work exemplifies a broader and encouraging trend in cardiovascular biology: the convergence of human genetics, molecular signaling, and immunology into unified mechanistic accounts of atherosclerosis. For decades, the field’s therapeutic triumphs came almost exclusively from lipid metabolism, embodied by statins and more recently PCSK9 inhibitors. Yet a large residual risk persists in patients whose cholesterol is well controlled, and that residual burden is increasingly attributed to inflammation and vascular dysfunction. Identifying molecules like PLCE1 that couple inflammatory and endothelial pathologies through a defined signaling route gives researchers exactly the kind of targets needed to address this residual risk. It also enriches the interpretation of existing genetic risk scores, which currently aggregate thousands of variants of unknown function. Each variant that is functionally resolved, as PLCE1 variants now partly are, converts statistical prediction into biological insight.

For now, the immediate value of the study lies in its demonstration of a principle: that a single enzyme can coordinate two of the most destructive processes in atherosclerosis through a well-defined molecular partner. Future work will need to confirm the PLCE1-beta-catenin axis in human tissue, map precisely how PLCE1 activity modifies beta-catenin at the molecular level, and determine whether existing or novel pharmacological tools can safely modulate this pathway in patients at risk. If those steps succeed, a gene discovered through population association studies may finally graduate from statistical curiosity to therapeutic target, offering a new angle of attack on the world’s leading cause of death. In a disease as complex and multifactorial as atherosclerosis, every newly charted junction in the signaling map is a potential checkpoint at which progression might be halted, and PLCE1 has just been added to that map in bold.

Subject of Research: The role of PLCE1 in driving atherosclerosis through endothelial dysfunction and macrophage inflammation via CTNNB1

Article Title: PLCE1 exacerbates the development of atherosclerosis by driving endothelial dysfunction and macrophage inflammation via targeting CTNNB1

Article References: Cheng, W.-L., Shi, Y., Zhang, Q., Cai, Z., Jiang, F.-X., Kong, X., Cao, J.-L., Peng, L., Chen, M., He, T., & Wang, H. (2026). PLCE1 exacerbates the development of atherosclerosis by driving endothelial dysfunction and macrophage inflammation via targeting CTNNB1. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03309-2

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03309-2

Keywords: PLCE1, atherosclerosis, CTNNB1, beta-catenin, endothelial dysfunction, macrophage inflammation, cardiovascular disease, Cell Death Discovery, Wnt signaling, foam cells, heart disease, molecular mechanism

The research, led by Xiaoge Xu, Cuijie Liu, and colleagues under the senior authorship of Huihui Wang and Jingbo Pi, zeroes in on NRF2, a transcription factor formally known as nuclear factor erythroid 2-related factor 2. For decades, NRF2 has been viewed as a molecular guardian: when cells are stressed by oxidants or toxins, NRF2 escapes its cytoplasmic holding protein, migrates into the nucleus, binds to antioxidant response elements in DNA, and switches on a coordinated battery of genes that detoxify electrophiles and neutralize reactive oxygen species. Drug companies have pursued NRF2 activators for everything from neurodegeneration to kidney disease. But the new findings suggest that in macrophages — the immune cells that populate atherosclerotic plaques — keeping NRF2 switched on may be a double-edged sword, and that pharmacologically silencing it in these cells could actually shrink plaques.

The logic of the study begins with a paradox that has nagged the field for years. Global knockout of Nrf2 in atherosclerosis-prone ApoE-deficient mice had been shown to reduce atherosclerotic burden, which seems counterintuitive for a so-called antioxidant factor. Yet when researchers selectively deleted Nrf2 in vascular endothelial cells, or transplanted Nrf2-deficient bone marrow into recipient mice, atherosclerosis got worse, not better. The obvious interpretation was that NRF2 acts in a cell-type-specific fashion — protective in some compartments of the plaque, harmful in others. What remained elusive was the role of NRF2 in macrophages specifically, the cells that constitute the bulk of the lesion and that orchestrate much of its inflammatory chemistry.

To answer that question, the team first combed through single-cell RNA-sequencing datasets from human carotid artery plaques obtained during endarterectomy surgery and from mouse aortas. Across both species, they found that NRF2 and its canonical downstream target genes were upregulated in lesional macrophages, suggesting the pathway is not a bystander but an active participant in plaque biology. They then generated mice lacking Nrf2 specifically in myeloid cells — the lineage that gives rise to monocytes and macrophages — and crossed them onto atherosclerosis-prone backgrounds. The result was unambiguous: loss of Nrf2 in macrophages accelerated plaque development, producing larger lesions with more necrotic cores and a heavier inflammatory fingerprint.

But the mechanism turned out to be something few would have predicted. The dominant hypothesis going in might have centered on oxidative stress: without NRF2, macrophages would accumulate reactive oxygen species, become more inflammatory, and thereby aggravate the lesion. Oxidative stress certainly played a role, but the more striking defect lay elsewhere — in a process called efferocytosis, the specialized phagocytosis by which macrophages recognize, engulf, and digest apoptotic cells. In a healthy artery wall, macrophages are continuously clearing out the cellular debris generated by lipid overload and inflammatory injury. When that clearance fails, apoptotic cells accumulate, rupture into necrotic cores, and spill their contents, amplifying inflammation and destabilizing the plaque. Efferocytosis, in other words, is the plaque’s sanitation department, and its failure is one of the most reliable predictors of dangerous lesion progression.

Efferocytosis is mechanically demanding. To engulf a dying cell, a macrophage must reorganize its actin cytoskeleton, extending membrane ruffles around the corpse and internalizing it in a process that depends on the small GTPases RAC1 and CDC42 and the dynamic remodeling of filamentous actin. When the researchers measured efferocytosis in Nrf2-deficient macrophages, they found it was substantially impaired — the cells could find and bind apoptotic targets, but they fumbled the internalization step. Correspondingly, phosphorylation and activation of RAC1/CDC42 were reduced, and the actin architecture of the cells was disorganized.

The molecular culprit linking NRF2 to this machinery emerged from an integrated analysis combining RNA sequencing, quantitative proteomics, and chromatin immunoprecipitation. That culprit was Myh9, the gene encoding non-muscle myosin heavy chain IIA — the motor protein that, together with actin, generates the contractile force required for a macrophage to physically swallow another cell. The data revealed that NRF2 directly binds to and transcriptionally represses the Myh9 promoter, keeping myosin IIA levels in check. When Nrf2 was deleted, the brakes came off Myh9, myosin IIA accumulated, and — counterintuitively — efferocytosis improved. Restoring the Nrf2–Myh9 axis, or manipulating myosin IIA levels directly, rescued or reproduced the efferocytosis defect, establishing a clear causal chain: NRF2 represses Myh9, myosin IIA enables actin-driven internalization, and internalization capacity determines how efficiently macrophages clear apoptotic debris.

In other words, the famous antioxidant factor was behaving as a brake on a mechanical process, not a chemical one. Macrophages burdened with excess NRF2 were simultaneously more inflammatory and less capable of taking out the cellular trash, a combination that proved particularly toxic inside the plaque microenvironment.

The therapeutic implications crystallized around 4-octyl itaconate, a cell-permeable derivative of itaconate, the metabolite made in large quantities by activated macrophages and known to covalently modify proteins and influence inflammatory signaling. In the study, treatment with 4-octyl itaconate activated NRF2 signaling in macrophages — and consistent with the newly described axis, this activated the Nrf2–Myh9 pathway in a way the authors frame as harnessable therapeutically. The team’s reanalysis of bulk RNA-sequencing data from itaconate-treated macrophages further supported the idea that itaconate derivatives reprogram macrophage dynamics relevant to clearance and inflammation. Positioning macrophage NRF2 activation via 4-octyl itaconate as a candidate strategy, the authors argue that the Nrf2–Myh9–efferocytosis axis represents both a previously unrecognized mechanism of atherogenesis and a druggable node for intervention.

The nuance here matters, and the authors are careful about it. NRF2’s role in atherosclerosis is not simply good or bad; it is compartmentalized. In endothelial cells, where Nrf2 deficiency enhances inflammation and lipid peroxidation, NRF2 is clearly protective. In myeloid cells, the picture the new study paints is of a factor whose activation reshapes macrophage mechanics in ways that can impair efferocytosis, even as the same factor suppresses classical oxidative damage. Any attempt to drug the pathway with systemic NRF2 activators would therefore need to reckon with these divergent, cell-type-specific effects — a caution that echoes a growing theme in precision medicine, where the same transcription factor can be friend in one tissue and foe in another.

What makes the study technically notable is its methodology. The team triangulated across human and murine single-cell transcriptomics, bulk datasets deposited in public repositories, proteomics, and chromatin-binding assays to move from correlation to mechanism. The identification of NRF2’s direct binding at the Myh9 locus, confirmed by ChIP-PCR, and the demonstration that myosin IIA abundance tracks with efferocytosis efficiency, provide the kind of mechanistic granularity that can guide medicinal chemistry. The internalization stage of efferocytosis — long considered the most tractable therapeutic target, since interventions at the earlier “find-me” and “eat-me” stages have been dogged by side effects such as broad inflammation suppression and inappropriate red blood cell engulfment — now has a defined molecular handle.

For the broader field, the work reframes efferocytosis as not merely an immunological phenomenon but a biomechanical one, dependent on the cytoskeletal engine that NRF2, unexpectedly, helps govern. It also adds to mounting evidence that metabolic and antioxidant pathways are deeply entangled with the physical mechanics of immune cells — from actin remodeling to phagocytic capacity — in ways that classical antioxidant-versus-oxidant framing fails to capture. Whether 4-octyl itaconate or related NRF2-modulating compounds can be delivered selectively to plaque macrophages, at doses that tilt the Nrf2–Myh9 balance toward improved clearance without compromising NRF2’s protective roles elsewhere, is the question that will determine whether this axis moves from mouse models to the cardiology clinic. For now, the study offers something the atherosclerosis field has few of: a genuinely new lever, pulled from an old and familiar machine.