Abstract Body (Do not enter title and authors here): Introduction: Phenotype switching, a pathological process involving dedifferentiation, migration, and transdifferentiation into other cell types—particularly fibrochondrocytes—plays a critical role in both aneurysm formation and atherogenesis. However, the molecular mechanisms that distinguish aneurysmal remodeling from atherogenic progression remain poorly understood.

Research Question: What makes thoracic aortic aneurysmal fibrochondrocytes different from atherosclerotic fibrochondrocytes?

Methods: To investigate the molecular distinctions between aneurysmal formation and atherogenesis, we integrated the largest single-cell meta-analysis of thoracic aortic aneurysms to date with well-characterized coronary atherosclerosis data. This combined dataset underwent Level 1 annotation followed by manual Level 2 refinement. Pseudotime analysis was employed to trace trajectories of hypothesized transdifferentiation and VIPER was utilized to assess differentially upregulated and downregulated regulons that drive each pathological process.

Results: Our manual annotation identified distinct fibrochondrocyte-like cell populations that emerged in aneurysmal and atherosclerotic tissues. Pseudotime analysis revealed distinct lineage progression and VIPER analysis identified key transcription factors that were differentially regulated between the two conditions, suggesting distinct molecular drivers underlying aneurysmal remodeling versus atherogenic progression. Notably, aneurysm-specific regulons were enriched for pathways related to extracellular matrix degradation whereas atherosclerosis-specific regulons were associated with fibrosis and lipid metabolism.

Conclusion: In conclusion, this transcriptomic meta-analysis reveals distinct transdifferentiation trajectories and transcriptional regulatory networks that differentiate aneurysmal remodeling from atherogenic progression. The identification of unique fibrochondrocyte-like populations and their divergent pseudotime trajectories highlights fundamental differences in cellular plasticity between these two vascular pathologies, which may inform targeted therapeutic strategies and underscores the need to treat thoracic aortic aneurysms and atherosclerosis as distinct entities at the molecular level.