FASN activity is important for the initial stages of the induction of senescence
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Volume
10
Publisher
DOI
10.1038/s41419-019-1550-0
Journal
Cell Death & Disease
Issue
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Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as
ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of
molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase
during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also
observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in
senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment
prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the
expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small
extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN
inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a
pharmacological inhibitor for reducing the impact of senescent cell accumulation