The proposed mechanism begins with mitochondria failing to maintain the balance among mitophagy, fusion and fission, mitochondrial biogenesis, and mitochondrial DNA homeostasis. When damaged mitochondria are not removed, their electron transport chains become less efficient, reactive oxygen species accumulate, and mitochondrial DNA can escape into the cytosol. These events can activate the cGAS-STING pathway, the NLRP3 inflammasome, and other innate immune sensors, increasing IL-1β-associated sterile inflammation and contributing to foam-cell formation. The review frames mitochondrial quality-control imbalance as both a consequence of the plaque environment and a possible driver of lesion development, a causal question that current evidence cannot yet fully resolve.

Macrophages are well placed to amplify this process because they are the predominant immune cells in atherosclerotic plaques. Uptake of oxidized low-density lipoprotein imposes substantial metabolic stress, while plaque hypoxia and inflammation disturb mitochondrial function. Under less pathological conditions, macrophages rely heavily on mitochondrial oxidative phosphorylation and fatty-acid oxidation to preserve lipid homeostasis and anti-inflammatory activity. Persistent oxidative stress, impaired fusion, excessive fission, and defective mitophagy can shift their metabolism toward glycolysis. Accumulating succinate and citrate, increased mitochondrial reactive oxygen species, and stabilization of HIF-1α can then promote NLRP3 activation and a more inflammatory macrophage phenotype.

Impaired mitophagy provides one of the clearest experimental links between mitochondrial quality control and plaque disease. Loss of PINK1 or Parkin prevents efficient recognition and clearance of dysfunctional mitochondria, allowing electron leakage, mitochondrial DNA release, and inflammasome activation to increase. In ApoE-deficient mice, genetic loss of these mitophagy mediators accelerates lesion development and produces less stable plaques, whereas restoring macrophage mitophagy limits lesion growth. These findings support a functional role rather than a purely statistical association, but most experiments have used global genetic manipulation or systemic drugs. Macrophage-conditional studies with detailed measurements of necrotic cores, collagen, and defined macrophage populations remain limited.

Mitochondrial dynamics provide a second intervention point. Excessive fragmentation can compromise respiratory-chain activity, elevate mitochondrial reactive oxygen species, and increase susceptibility to inflammatory signaling. In high-fat-diet-fed ApoE-deficient mice, the Drp1 inhibitor Mdivi-1 reduced plaque area, NLRP3 activation, and M1-associated polarization; it also suppressed oxidized-LDL-induced inflammation in THP-1-derived macrophages through the mitochondrial reactive oxygen species–NLRP3 axis. The interpretation is nevertheless context-dependent. Drp1-dependent fission can also protect macrophages from mitochondrial DNA and ZBP1-driven inflammation after myocardial infarction, showing that inhibiting a fission pathway cannot be assumed to have the same effect in every vascular setting.

Mitochondrial DNA abnormalities offer a further possible upstream influence. Atherosclerosis-associated mitochondrial variants may be homoplasmic, present in every copy of the genome, or heteroplasmic, present in only a proportion of copies. Hybrid cell experiments showed that mitochondria carrying a single pro-atherosclerotic mutation produced defective mitophagy and an “intolerant” inflammatory response, in which repeated cytokine challenges failed to decline. Editing out the m.15059G>A mutation restored normal mitophagy and cytokine tolerance. Separately, elevated METTL4 was associated with mitochondrial DNA modification that suppressed MT-ATP6 expression, impaired respiratory-chain function, and promoted mitochondrial DNA release. The METTL4 inhibitor pemetrexed delayed atherosclerosis in an animal model, but the delivery challenge for mitochondrial editing remains substantial.

The inflammatory consequences can form a feedback loop between mitochondrial dysfunction and macrophage polarization. Mitochondrially damaged, highly inflammatory macrophages can produce TNF-α and IL-1β, which further disrupt mitochondrial function and sustain tissue injury. Mitochondrial repair or enhanced mitophagy may favor a less inflammatory, M2-like state in the simplified framework used by the review. That sequence, however, should not be treated as universal. Single-cell analyses of mouse and human plaques identify inflammatory monocyte-derived macrophages, TREM2-high foamy macrophages, and resident-like populations, and often find that non-foamy cells constitute the more inflammatory group. Mitochondrial quality-control measurements for these specific plaque subsets are still scarce.

Several intervention classes have improved outcomes in preclinical systems but differ sharply in their evidence and translational limitations. Rapamycin, metformin, and urolithin A have been used to enhance mitophagy through mTOR- or AMPK-SIRT1-related signaling, although their optimal dosing and long-term effects on human autophagy remain unresolved. Mdivi-1 and the mitochondrial protective peptide SS-31 target fission and membrane stability, but Mdivi-1 has context-dependent effects and potential off-target activity. MitoQ and Mito-TEMPO scavenge mitochondrial reactive oxygen species; MitoQ has improved endothelial function in a small randomized human trial, but broader cardiovascular antioxidant trials have not consistently shown benefit. Colchicine, canakinumab, and MCC950 act downstream through inflammation rather than correcting the mitochondrial defect itself.

Macrophage-selective delivery may be necessary if mitochondrial therapies are to move from experimental models into patients. Nanoparticle systems based on lipids or high-density-lipoprotein-like structures are being investigated to carry proteins, peptides, drugs, small interfering RNAs, and microRNAs to plaque macrophages. In theory, this could concentrate treatment in pathogenic subsets while limiting systemic toxicity from antioxidants, fission inhibitors, or metabolic modulators. Inhibiting glycolysis could also restore oxidative phosphorylation and an anti-inflammatory phenotype, but current approaches lack macrophage selectivity and raise concerns about systemic toxicity. Mitochondrial hydrogen sulfide delivery, lipid-based nanocarriers, and mitochondrial genome editors similarly remain at the in-vitro or preclinical stage.

The review’s most important qualification is that the evidence does not yet establish a universal therapeutic sequence from mitochondrial damage to inflammation, foam cells, and plaque rupture. Much of the literature is cross-sectional, so it remains unclear whether mitochondrial abnormalities precede atherosclerosis or arise from established lesions. RAW264.7 cells and ApoE-deficient mice also reproduce only parts of human plaque biology. Resolving the field will require longitudinal interventions, subset-resolved mitochondrial profiling in human plaques, and direct comparisons of mitochondrial manipulations in macrophages, vascular smooth muscle cells, and endothelial cells within the same animal model. The current evidence nevertheless identifies mitochondrial quality control as a plausible inflammatory and metabolic hub in atherosclerosis, with mitophagy restoration, dynamic-balance correction, antioxidant protection, and targeted delivery offering testable routes for future investigation rather than established clinical treatments.

Subject of Research: Macrophage mitochondrial quality control in atherosclerosis

Article Title: Mechanisms and targeted intervention strategies of macrophage mitochondrial quality control imbalance in the progression of atherosclerosis

Article References: Zhili, G., & Xiaoyu, Z. (2026). Mechanisms and targeted intervention strategies of macrophage mitochondrial quality control imbalance in the progression of atherosclerosis. Frontiers in Physiology, 17, 1975785. https://doi.org/10.3389/fphys.2026.1975785

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1975785

Keywords: atherosclerosis, macrophages, mitochondrial quality control, mitophagy, mitochondrial dynamics, mitochondrial DNA, NLRP3 inflammasome, foam cells, plaque stability, preclinical therapeutics, Mechanisms, targeted

The cells in question are senescent vascular smooth muscle cells, and recent single-cell lineage-tracing studies have pushed a striking reframing of atherosclerosis as a tumor-like disease driven by these very cells. Within plaques, vascular smooth muscle cells undergo clonal expansion, dedifferentiation, and metabolic reprogramming, forming pathological structures that resemble solid tumors. The senescent subset behaves like drug-resistant dormant tumor cells: they persist indefinitely, resist apoptosis, and remodel their surroundings through the senescence-associated secretory phenotype, a cocktail of inflammatory signals that drives necrotic core expansion and thins the fibrous cap that keeps plaques from rupturing. Selectively killing these cells, an approach known as senolysis, has already shown promise for extending lifespan in animal studies, but translating that promise into cardiovascular medicine has been hampered by toxicity concerns with existing drug candidates.

The new study began with a deceptively simple observation. When the researchers modeled senescence in human aortic smooth muscle cells by exposing them to palmitate, a lipid that mimics the lipotoxic stress of atherosclerosis, the cells entered a stable senescent state marked by elevated beta-galactosidase activity and upregulation of the cell-cycle inhibitors p16 and p21. Crucially, the cells also ramped up production of heat shock protein 90 alpha, or HSP90α, a chaperone molecule famous in oncology as a scaffold that supports the survival of tumor cells. Given the parallels between tumorigenesis and atherogenesis, the team hypothesized that senescent smooth muscle cells might exploit the same HSP90α machinery to maintain homeostasis and evade death in the hostile plaque microenvironment.

Proteomic analysis after HSP90α knockdown revealed what that machinery was protecting. Silencing HSP90α specifically activated the PERK/eIF2α/ATF4/CHOP arm of the endoplasmic reticulum stress response, suggesting that high HSP90α levels actively restrain this stress pathway in senescent cells. The team then turned to human tissue, integrating four published single-cell RNA sequencing datasets covering 40 samples of human atherosclerotic lesions from carotid endarterectomy and coronary arteries. In senescent smooth muscle cells identified by co-expression of p21 and p16, HSP90α was highly expressed, but the CHOP stress marker was conspicuously absent. Immunofluorescence of human carotid plaques confirmed the same spatial dissociation, and cultured senescent cells showed suppression of the PERK branch specifically, while the ATF6 and IRE1 branches of the unfolded protein response remained untouched.

The mechanism behind that selective suppression proved to be an elegant piece of molecular scaffolding. Prior work had shown that the kinase AKT can bind to the autophosphorylation site of PERK and block its activation. Using protein-protein docking, co-immunoprecipitation, and domain mapping, the researchers demonstrated that HSP90α holds AKT and PERK together in a ternary complex, with the middle region of HSP90α, amino acids 284 through 620, sufficient to bind both partners. In senescent cells this interaction intensifies, stabilizing AKT and keeping PERK dormant. When HSP90α was removed, AKT degraded rapidly through the proteasome, PERK signaling surged, and the senescent cells began to die. Reactivating the pathway with thapsigargin, a specific inducer of endoplasmic reticulum stress, collapsed mitochondrial membrane potential and pushed the cells into apoptosis while reducing their senescence markers.

The downstream killing mechanism runs through calcium. PERK activation is known to tighten physical contacts between the endoplasmic reticulum and mitochondria, and the team documented exactly that: after HSP90α knockdown or thapsigargin treatment, transmission electron microscopy showed expanded mitochondria-associated ER membranes, fluorescent probes confirmed elevated mitochondrial calcium, and the calcium flux funneled through the mitochondrial calcium uniporter, MCU. Blocking mitochondrial calcium uptake with ruthenium red, or silencing MCU directly, rescued the cells from apoptosis. In other words, the senescent cells survive only as long as PERK stays suppressed; once the brake is released, calcium floods the mitochondria, membrane potential collapses, and the cell self-destructs.

Having defined the target, the team went hunting for a drug. They compiled a dataset of 112 natural products with documented anti-atherosclerotic activity from a literature search spanning 1947 to 2024, then docked each compound against the crystal structure of HSP90α using three independent docking programs and a robust rank aggregation method. The top hit was salvianolic acid A, or SAA, a water-soluble polyphenol from Salvia miltiorrhiza, the red sage root used in traditional Chinese medicine. Its docking score rivaled that of 17-DMAG, a well-characterized synthetic HSP90 inhibitor. Two independent binding assays sealed the case: a cellular thermal shift assay showed that SAA stabilizes HSP90α against heat denaturation, and a biotinylated SAA probe pulled down endogenous HSP90α from cell lysates, confirming direct physical binding.

SAA’s effects on senescent cells were strikingly selective. At concentrations of 20 to 100 micromolar, it triggered apoptosis in senescent smooth muscle cells, reduced p16 and p21, and suppressed secretion of the inflammatory SASP factors IL-1α and IL-6, while leaving normal smooth muscle cells unharmed. Mechanistically, SAA disrupted the HSP90α-AKT-PERK ternary complex, shifted AKT ubiquitination from the K63-linked form toward K48-linked chains that mark proteins for proteasomal destruction, and thereby reactivated PERK signaling. Overexpressing HSP90α reversed all of these effects, and knocking down PERK rescued the cells, confirming that the pathway runs through the complex the team had identified. A cross-linking assay even captured the intact 340-kilodalton ternary complex and watched it dissolve after SAA treatment.

The in vivo results were equally compelling. In ApoE-deficient mice fed a high-fat diet for 20 weeks, intraperitoneal SAA from week 9 onward significantly reduced plaque area, shrank necrotic cores, thickened fibrous caps, and cut lipid accumulation in the aorta, while lowering serum IL-6. Using adeno-associated viruses to manipulate HSP90α specifically in vascular smooth muscle cells, the researchers showed that VSMC-specific knockdown increased p21-CHOP colocalization in plaques, whereas overexpression blunted SAA’s effects and caused a rebound of p21-positive cells. Co-immunoprecipitation from mouse aortas confirmed that SAA weakened the HSP90α-AKT-PERK interaction in living tissue, closing the loop between the cell culture mechanism and the animal outcome.

What makes this work resonate beyond the lab bench is SAA’s clinical head start. Unlike geldanamycin-derived HSP90 inhibitors, whose toxicity has blocked every approval attempt in oncology, SAA is already in a phase II trial for diabetic microangiopathy and two phase I trials for angina pectoris and diabetes, suggesting a tolerability profile that could accelerate translation. The authors caution that mouse-to-human translation is complex and that whether SAA can actually reverse plaque progression will require endpoint clinical trials. Still, the study delivers something the senolytics field has lacked: a senolytic strategy grounded in a defined survival mechanism of the target cells, delivered by a natural compound with human safety data, and validated from molecular docking all the way to plaque stabilization. If the findings hold, the humble red sage root may offer a way to evict the zombie cells that make aging arteries fragile.

Subject of Research: Targeting the HSP90α-AKT-PERK complex in senescent vascular smooth muscle cells as a senolytic strategy against atherosclerosis

Article Title: Salvianolic Acid a Disrupts the HSP90α‐AKT‐PERK Ternary Complex to Alleviate Atherosclerosis by Activating Endoplasmic Reticulum Stress of Senescent Vascular Smooth Muscle Cells

Article References: Guan, X., Lu, M., Cui, X., Zhang, D., Zhang, L., Lin, L., Li, Y., Hu, Y., & Li, C. (2026). Salvianolic Acid a Disrupts the HSP90α‐AKT‐PERK Ternary Complex to Alleviate Atherosclerosis by Activating Endoplasmic Reticulum Stress of Senescent Vascular Smooth Muscle Cells. Advanced Science, Article e77891. https://doi.org/10.1002/advs.77891

Image Credits: AI Generated

DOI: 10.1002/advs.77891

Keywords: atherosclerosis, senescence, senolytics, HSP90α, PERK, endoplasmic reticulum stress, vascular smooth muscle cells, salvianolic acid A, SASP, mitochondrial calcium, AKT, plaque stability

The research, led by Mingjing Lu, Zhongjian Xu, and Tang Hanfei, with senior authors Dehai Lang, Guo Daqiao, and Guofu Wang, took a deliberately dual approach. Rather than betting on a single machine learning paradigm, the investigators built and compared two complementary pipelines. The first was a classical radiomics pipeline, in which hand-engineered quantitative features—describing the shape, texture, and intensity distribution of the plaque—are extracted from manually defined regions of interest on CT angiography images. The second was a deep learning pipeline, in which convolutional neural networks learn discriminative image patterns directly from pixel data without explicit feature engineering. Both pipelines were trained to answer the same clinically critical question: is this plaque histologically stable or vulnerable, as confirmed by pathology after carotid endarterectomy?

The evidence base for the radiomics arm came from a retrospective multi-center cohort of 260 consecutive patients who underwent carotid endarterectomy, meaning that every plaque in the dataset had a gold-standard pathological diagnosis of stability or vulnerability. Of these, 200 patients were used for model development and internal validation, while 60 patients were held out entirely for external validation, a design choice that guards against the optimistic performance estimates that plague many machine learning studies in medicine. For the deep learning arm, the team assembled an independently annotated CT angiography dataset comprising 236 cases and a remarkable 7,394 individual regions of interest, providing the volume of labeled image data needed to train and test convolutional architectures meaningfully.

On the technical side, the radiomics workflow followed rigorous feature-selection discipline. Candidate radiomic features were screened using analysis of variance combined with Kruskal–Wallis testing to identify features that discriminated between stable and vulnerable plaques, followed by correlation filtering to remove redundant measures, and finally least absolute shrinkage and selection operator, or LASSO, regularization to compress the feature set to its most predictive and non-redundant core. Five classifier families were then trained on the selected features: Random Forest, Support Vector Machine, k-Nearest Neighbor, Naïve Bayes, and Logistic Regression. Performance was quantified using receiver operating characteristic analysis and the area under the curve, complemented by calibration analysis, which asks not merely whether a model ranks patients correctly but whether its predicted probabilities match observed reality—a property that matters enormously when model outputs are meant to inform surgical decisions.

The radiomics results were strikingly consistent. On the internal test set, the Random Forest model achieved an AUC of 0.858, followed closely by the Support Vector Machine at 0.857, Naïve Bayes at 0.855, k-Nearest Neighbor at 0.843, and Logistic Regression at 0.821, with small gaps between training and test performance that suggest the models were capturing genuine biological signal rather than memorizing noise. Crucially, this discrimination survived the move to entirely external data. In the 60-patient external validation cohort, the Support Vector Machine led with an AUC of 0.839, Logistic Regression reached 0.835, k-Nearest Neighbor 0.830, and both Naïve Bayes and Random Forest achieved 0.817. Calibration curves showed close agreement between predicted and observed probabilities across the model families, indicating that the classifiers were not only separating stable from vulnerable plaques but doing so with probabilities a clinician could reasonably act upon.

The deep learning arm told a complementary story. The authors trained a multilayer perceptron, a from-scratch convolutional neural network, and three ImageNet-pretrained transfer-learning backbones—VGG16, VGG19, and ResNet50—on the annotated regions of interest. Transfer learning, in which networks pre-trained on millions of natural images are fine-tuned on medical data, proved advantageous: VGG16 achieved the best test AUC of 0.767, ResNet50 followed at 0.754, and VGG19 reached 0.718, while the multilayer perceptron and the from-scratch CNN trailed at 0.669 and 0.654 respectively. External validation reproduced this ordering almost exactly, with VGG16 at 0.776, ResNet50 at 0.751, VGG19 at 0.719, and the simpler architectures in the high-0.68 range. Although the deep models did not surpass the radiomics classifiers in raw discrimination, their performance held up across centers, and they brought a distinct advantage: interpretability through attention mapping.

Using Gradient-weighted Class Activation Mapping, or Grad-CAM, the team visualized which parts of each image the networks attended to when making their predictions. The resulting heatmaps localized hyperattenuating regions—denser, brighter areas within the plaque that correspond to features such as calcification or hemorrhage—and these localizations were consistent with the pathological findings, most clearly for VGG16 and ResNet50. This alignment between machine attention and histological ground truth is more than a technical curiosity. It provides a sanity check that the networks are not exploiting scanner-specific artifacts or incidental image features, but are genuinely looking at the plaque biology that pathologists confirm under the microscope. For a field often criticized for black-box opacity, such visual evidence of anatomically plausible reasoning is a meaningful step toward clinical trust.

The clinical implications are considerable. Current decision-making for carotid stenosis leans heavily on the degree of luminal narrowing, yet the literature has long shown that plaque composition and stability, not stenosis alone, determine rupture risk. A patient with moderate narrowing but a vulnerable plaque may face a higher stroke risk than a patient with severe narrowing and a stable lesion. A validated, automated tool that reads a routine CT angiography scan—the same scan already obtained during standard preoperative workup—and reports a calibrated probability of plaque vulnerability could therefore reshape preoperative risk stratification, help prioritize patients for carotid endarterectomy or stenting, and guide the intensity of medical therapy and surveillance for those managed conservatively. Because the radiomics models in this study used conventional machine learning classifiers on compact feature sets, they are also lightweight and deployable, requiring no exotic hardware and lending themselves to integration into existing picture archiving and communication systems.

The authors are appropriately measured about what their framework can and cannot yet do. The study is retrospective, and the deep learning models, while externally validated, did not reach the discrimination levels of the best radiomics classifiers, suggesting that hand-crafted quantitative descriptors of plaque texture and morphology still carry information that current convolutional architectures do not fully capture from cropped regions of interest. The natural next steps include prospective validation in consecutive clinical cohorts, testing across scanner vendors and imaging protocols, and exploration of hybrid models that fuse radiomic features with deep-learned representations. Funding for the work came from the Shaoxing City Science and Technology Plan Project 2023, and the study was conducted under the Declaration of Helsinki with institutional ethics approval and informed consent from all participants. Even with those caveats, the convergence of pathology-validated labels, multi-center external testing, strong calibration, and interpretable attention maps makes this one of the more convincing demonstrations that AI-assisted plaque stability assessment is moving from proof of concept toward a genuinely usable instrument in the fight against ischemic stroke.

Subject of Research: AI-based carotid plaque stability assessment on CT angiography for ischemic stroke risk prediction

Article Title: Integrated radiomics and image-based deep learning framework using carotid CT angiography ROI datasets for plaque stability assessment as a predictor of ischemic stroke risk

Article References: Lu, M., Xu, Z., Hanfei, T., Luo, P., Huang, F., Wang, G., Bi, L., Jiang, N., Lang, D., Daqiao, G., & Wang, G. (2026). Integrated radiomics and image-based deep learning framework using carotid CT angiography ROI datasets for plaque stability assessment as a predictor of ischemic stroke risk. BioMedical Engineering OnLine. https://doi.org/10.1186/s12938-026-01621-7

Image Credits: AI Generated

DOI: 10.1186/s12938-026-01621-7

Keywords: carotid CT angiography, radiomics, deep learning, plaque stability, ischemic stroke, stroke risk stratification, carotid endarterectomy, machine learning, VGG16, ResNet50, Grad-CAM, biomedical engineering

The study, titled ‘Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques,’ examines how removing this single kinase alters the metabolic machinery inside macrophages and, as a consequence, changes the inflammatory character of atherosclerotic lesions. The finding is notable because it links three areas that have usually been studied in isolation: kinase signaling, immunometabolism, and the inflammatory form of cell death known as pyroptosis. By connecting them, the work suggests that a pathway long associated with immune activation may instead be a liability in chronic vascular disease.

To understand why this matters, it helps to recall what macrophages do inside an artery wall. These cells are recruited to sites where low-density lipoprotein particles have accumulated beneath the endothelial lining. Once there, they engulf lipids, and in doing so they can become the foam cells that give early plaques their fatty appearance. But macrophages are not passive containers. They are metabolically active, decision-making cells whose internal fuel choices, whether to burn glucose rapidly through glycolysis, whether to rely on mitochondrial oxidative phosphorylation, whether to draw on fatty acid oxidation, shape the inflammatory signals they emit. A plaque dominated by pro-inflammatory macrophages tends to be rich in degradative enzymes and death signals, thinning its protective fibrous cap and raising the risk of rupture.

Pyroptosis is one of the most incendiary of those death signals. Unlike ordinary apoptosis, which quietly packages cellular debris for removal, pyroptosis is a lytic, inflammatory death driven by the activation of inflammasomes, multiprotein complexes that trigger caspase enzymes to cleave gasdermin proteins. Cleaved gasdermins form pores in the cell membrane, causing the cell to swell, burst, and spill its contents, including potent inflammatory messengers such as interleukin-1 family cytokines, into the surrounding tissue. Within a plaque, waves of pyroptotic macrophage death enlarge the necrotic core, weaken the fibrous cap, and promote the thrombus formation that turns a stable lesion into a clinical emergency.

Protein kinase C delta has long been recognized as a versatile signaling molecule in immune cells, participating in pathways that regulate activation, migration, and death decisions. The new research asked a direct question: what happens to macrophage behavior, and to atherosclerotic disease, when this kinase is missing? The answer, according to the study, is that deficiency of the kinase reprograms macrophage immunometabolism, shifting the internal metabolic set points of the cells in a direction that suppresses pyroptosis. In other words, without protein kinase C delta, macrophages appear to become less prone to the explosive inflammatory death that destabilizes plaques.

The concept of immunometabolic reprogramming is central to interpreting this result. Macrophages adopt broadly distinguishable metabolic profiles depending on their activation state, and these profiles are not merely byproducts of inflammation; they actively reinforce it. A glycolytic shift, for example, supports the rapid production of inflammatory mediators, while a more oxidative, mitochondrial-oriented metabolism tends to accompany reparative, tissue-tolerant behavior. By showing that removing protein kinase C delta rewrites these metabolic choices, the study positions the kinase as a kind of metabolic gatekeeper whose activity licenses the inflammatory, pyroptosis-prone phenotype in the plaque environment.

The downstream consequence reported in the work is plaque stabilization. In atherosclerosis research, stability is assessed through structural features: the thickness of the fibrous cap that separates the thrombogenic necrotic core from the bloodstream, the size of that necrotic core, the collagen content of the cap, and the burden of dead and dying cells within the lesion. A plaque that retains a thick cap, a modest necrotic core, and abundant collagen is far less likely to rupture than one riddled with pyroptotic debris. The finding that PKC delta deficiency suppresses pyroptosis and stabilizes plaques implies that the kinase contributes to precisely the features that make lesions dangerous, and that its removal tilts lesions toward a safer architecture.

These results arrive amid a broader reassessment of inflammation as a therapeutic target in cardiovascular medicine. Landmark clinical trials have already demonstrated that blunting inflammatory signaling, for instance through interleukin-1 beta blockade or colchicine treatment, reduces cardiovascular events in selected patients, validating the idea that the immune component of atherosclerosis is druggable. Against that backdrop, a kinase that governs whether plaque macrophages die inflammatory deaths is an attractive candidate for intervention, because it acts upstream of the terminal events, inflammasome activation, gasdermin pore formation, cytokine release, and necrotic core expansion, that directly damage plaque integrity.

At the same time, the study invites caution. Protein kinase C delta participates in many physiological processes beyond the plaque, including immune defense against infection, platelet function, and the regulation of cell survival in multiple tissues. Any therapeutic strategy aimed at inhibiting the kinase, or at exploiting the metabolic programs it controls, would need to weigh the benefit of calmer plaque macrophages against the risk of impairing the host responses that depend on this enzyme. Translating a reprogramming effect observed in experimental models into a safe clinical approach will require a detailed map of which downstream metabolic and inflammasome pathways mediate the protection, and whether those pathways can be targeted selectively.

Even so, the conceptual contribution is substantial. The work reframes atherosclerotic plaque stability not simply as a matter of lipid lowering, which remains the foundation of therapy, but as a matter of immune cell fate, decided by intracellular metabolic wiring that can be shifted by manipulating a single signaling node. If the findings hold up across models and, eventually, in human tissue, they suggest that future treatment could combine lipid management with agents that nudge plaque macrophages away from pyroptosis and toward a stable, reparative state. In a disease that kills millions each year largely through plaque rupture, teaching immune cells to keep their composure may prove to be one of the more consequential ideas in modern cardiovascular research.

Subject of Research: The role of protein kinase C delta deficiency in reprogramming macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques

Article Title: Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques

Article References: Lien, C.-F., Chang, H.-Y., Yu, S.-H., Cho, R.-L., Chen, S.-J., Kuo, T.-T., Chong, P. C.-T., Ye, C.-H., Lin, F.-Y., Wu, W.-L., Lin, S.-H., Tsai, C.-S., & Lin, C.-S. (2026). Deficiency of protein kinase Cδ reprograms macrophage immunometabolism to suppress pyroptosis and stabilize atherosclerotic plaques. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01842-9

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01842-9

Keywords: protein kinase C delta, macrophages, immunometabolism, pyroptosis, atherosclerosis, plaque stability, inflammasome, foam cells, cardiovascular disease, inflammation, Deficiency, protein