International immunopharmacology · 2025
The upregulation of TNKS1 drives the phenotypic switching of vascular smooth muscle cells in aortic dissection through the activation of ferroptosis.
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Xu Xinyang, Lin Wenfeng, Liu Tianyu, Yuan Chunze, Yan Yuhan, Diao Yifei, Xiong Jiaqi, Shao Yongfeng, Ni Buqing
Аннотация
OBJECTIVE: Aortic dissection (AD) is a life-threatening disease. Tankyrase1 (TNKS1), a PARylating ADP-ribosyl transferase, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration.This study explores the impact of TNKS1 on the transformation of human aortic smooth muscle cells (HASMCs) in AD.
METHODS AND RESULTS: Single-cell RNA sequencing was performed and clusters were used for between-disease differential gene expression analyses. In the AD aorta, WB, immunofluorescence and RT-q-PCR revealed that TNKS1 expression was elevated, accompanied by a disorganized cell phenotype. Further examination like WB，immunofluorescence,Scratch-Wound Assay confirmed the upregulation of TNKS1 triggers phenotypic switching.Subsequent studies revealed that ferroptosis played a key role in TNKS1-induced phenotypic switching. Increased ferroptosis markers, such as elevated iron content,ROS and lipid peroxidation, were observed in HASMCs overexpressing TNKS1, while inhibition of ferroptosis restored the contractile phenotype.Co-IP assay demonstrated a direct protein-protein interaction between TNKS1 and SLC7A11 at the molecular level. In vivo, the upregulation of TNKS1 not only activated ferroptosis but also triggered phenotypic transformation.
CONCLUSION: This study demonstrates that TNKS1 is a key regulator of AD pathogenesis, driving HASMC phenotypic switching through ferroptosis activation, ultimately leading to aortic wall destabilization and dissection. Targeting TNKS1 or the ferroptosis pathway may offer novel therapeutic strategies for AD prevention and treatment.
METHODS AND RESULTS: Single-cell RNA sequencing was performed and clusters were used for between-disease differential gene expression analyses. In the AD aorta, WB, immunofluorescence and RT-q-PCR revealed that TNKS1 expression was elevated, accompanied by a disorganized cell phenotype. Further examination like WB，immunofluorescence,Scratch-Wound Assay confirmed the upregulation of TNKS1 triggers phenotypic switching.Subsequent studies revealed that ferroptosis played a key role in TNKS1-induced phenotypic switching. Increased ferroptosis markers, such as elevated iron content,ROS and lipid peroxidation, were observed in HASMCs overexpressing TNKS1, while inhibition of ferroptosis restored the contractile phenotype.Co-IP assay demonstrated a direct protein-protein interaction between TNKS1 and SLC7A11 at the molecular level. In vivo, the upregulation of TNKS1 not only activated ferroptosis but also triggered phenotypic transformation.
CONCLUSION: This study demonstrates that TNKS1 is a key regulator of AD pathogenesis, driving HASMC phenotypic switching through ferroptosis activation, ultimately leading to aortic wall destabilization and dissection. Targeting TNKS1 or the ferroptosis pathway may offer novel therapeutic strategies for AD prevention and treatment.