AUTHOR=Banerjee Priyanka , Rosales Julia Enterría , Chau Khanh , Nguyen Minh T. H. , Kotla Sivareddy , Lin Steven H. , Deswal Anita , Dantzer Robert , Olmsted-Davis Elizabeth A. , Nguyen Hung , Wang Guangyu , Cooke John P. , Abe Jun-ichi , Le Nhat-Tu TITLE=Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=Volume 10 - 2023 YEAR=2023 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1186679 DOI=10.3389/fcvm.2023.1186679 ISSN=2297-055X ABSTRACT=In this review, we highlight the similarities and key distinctions between replicative and stress-evoked senescence. We discuss how cellular senescence acts as a key phenotype in endothelial cells (ECs) in response to disturbed flow (d-flow) and cancer therapy. We identify the link between these two stimuli in the development and progression of atherosclerotic cardiovascular disease (CVD). We highlight the vital role of senescence-associated secretory phenotype (SASP) in the development of atherosclerotic CVD in cancer survivors. We outline the rationale for SASP as a therapeutic target for age-related disorders across a lifespan and discuss the emerging role of posttranslational modification of several molecules in this process. We discuss the mechanisms through which TERF2 interacting protein (TERF2IP), a Shelterin component, is disrupted and subsequently activate cellular senescence. While oxidative stress is a common factor underlying replicative senescence and stress-induced premature senescence (SIPS), we discuss additional factors that give rise to EC senescence under d-flow and cancer therapy. We discuss key pathways that are involved in SIPS progression, such as ribosomal s6 kinase (p90RSK)/TERF2IP, transforming growth factor β receptor1 (TGFβR1)/SMAD, and tetrahydrobiopterin (BH4) signaling. We also highlight distinct roles played by these pathways in senescent ECs. Through this review, the readers will appreciate that cellular senescence is a complex cellular process that often involves multiple cellular mechanisms. Finally, we discuss some of the therapeutic interventions that could be of potential benefit for atherosclerotic CVD patients in different settings particularly focusing on BH4 pathway. This review describes senescence as a complex cellular feature that is not limited to a singular cellular process but has several routes. Our goal is to present a comprehensive review of the data that unites stress, senescence, and CVD in cancer survivors to provide a mechanistic understanding of their interactions and establish rational therapeutic directions.