This study reveals the coupling mechanism between mechanosensing and metabolic reprogramming in endothelial cells during atherosclerosis, offering a novel perspective for developing anti-thrombotic strategies targeting CD38.
Literature Overview
The article, 'LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis,' published in Circulation Research, systematically investigates the critical role of LATS1 and LATS2 in endothelial cells during disturbed flow (d-flow)-induced intraplaque thrombosis. The study finds that loss of LATS1/2 drives endothelial cells into a unique state called 'senescence-associated stemness' (SAS), which exhibits both proliferative and senescent features, and promotes intraplaque thrombosis through CD38-driven metabolic reprogramming. By integrating spatial proteomics, metabolomics, and multi-omics imaging, this work uncovers a complete pathway from mechanical signaling to metabolic dysregulation and ultimately thrombus formation.Background Knowledge
1. Atherosclerosis challenges addressed by this study: Plaque rupture and erosion are major causes of acute coronary syndromes, with intraplaque thrombosis frequently occurring in regions of disturbed blood flow. However, how disturbed flow drives endothelial dysfunction and initiates thrombosis remains unclear. Current models fail to recapitulate the complex coexistence of endothelial senescence and proliferation seen in human plaques, limiting the discovery of therapeutic targets.
2. Current bottlenecks in CD38 research: CD38 is a key enzyme in NAD+ metabolism, traditionally thought to promote cellular senescence when highly expressed. However, its dual role in endothelial cells—participating in both senescence and potentially supporting proliferation—has not been systematically elucidated. Particularly under disturbed flow conditions, how CD38 is regulated and its downstream metabolic effects remain poorly understood.
3. Research entry point: The authors focus on LATS1/2, core kinases of the Hippo pathway, which serve as critical nodes in endothelial mechanotransduction, potentially linking disturbed flow to endothelial phenotypic switching. By generating endothelial-specific LATS1/2 knockout mouse models and analyzing human atherosclerotic samples, the study systematically uncovers a novel signaling axis—LATS1/2–CD38–SUOX–mitochondrial complex V reverse mode—filling a mechanistic gap between mechanosensing and thrombosis.
Research Methods and Experiments
The authors employed inducible endothelial-specific LATS1/2 double-knockout mice (EKO) combined with a partial carotid ligation (PLCL) model to simulate disturbed flow. Temporal-spatial gene deletion was achieved via tamoxifen induction, avoiding lethal phenotypes associated with systemic knockout. A hypercholesterolemia model was established using AAV8-PCSK9 in combination with a high-fat diet to enhance atherosclerotic lesion development. Imaging Mass Cytometry (IMC), COMET™ multiplex fluorescence imaging, and spatial metabolomics were used to achieve multidimensional analysis of the plaque microenvironment at single-cell resolution. These technologies not only revealed endothelial heterogeneity but also precisely mapped the spatial distribution and co-expression patterns of markers such as CD38, SUOX, and Ki67.Key Conclusions and Perspectives
Research Significance and Prospects
This study identifies CD38 as a novel therapeutic target for drug development. Its inhibitors may not only alleviate NAD+ depletion but also correct mitochondrial dysfunction, thereby simultaneously addressing both senescence and thrombosis—two major pathological processes. Compared to conventional antiplatelet drugs, targeting CD38 may more precisely act on diseased endothelium, reducing systemic bleeding risks.
For clinical monitoring, the SAS phenotype in plaque endothelium could serve as a novel biomarker for high-risk plaques. Measuring CD38, SUOX, or sulfite levels may help identify vulnerable plaques, enabling early intervention.
In disease modeling, this study establishes a more human-relevant atherosclerosis model that recapitulates the coexistence of endothelial proliferation and senescence seen in human plaques. This model can be used in the future to test therapies targeting metabolic reprogramming, advancing the therapeutic paradigm from 'anti-proliferation' to 'restoration of metabolic homeostasis'.
Conclusion
This study systematically reveals the central role of the LATS1/2–CD38–SUOX axis in linking disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis. The discovery of the 'senescence-associated stemness' (SAS) phenotype challenges the traditional view that senescence and proliferation are mutually exclusive, providing a novel framework for understanding plaque instability in atherosclerosis. From bench to bedside, this pathway not only offers potential biomarkers for identifying high-risk patients but also opens new avenues for developing non-antiplatelet antithrombotic drugs. Notably, as a druggable target, CD38 inhibitors hold promise for stabilizing plaques without increasing bleeding risk, potentially becoming a key component of future atherosclerosis care systems. This work underscores the potential of metabolic intervention in cardiovascular disease treatment, marking a strategic shift from simple antithrombosis toward 'metabolic homeostasis restoration'.
