Lipogenesis inhibitors: therapeutic opportunities and challenges

作者：Battsetseg Batchuluun, Stephen L. Pinkosky, Gregory R. Steinberg · 发表于：Nature Reviews Drug Discovery · 年份：2022 · DOI：10.1038/s41573-021-00367-2 · 被引用次数：407 · 研究领域：Cancer, Lipids, and Metabolism、Cancer, Hypoxia, and Metabolism、Peroxisome Proliferator-Activated Receptors

Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved mechanisms to generate fatty acids from alternative carbon sources, through a process known as de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with a wide variety of pathologies. Inhibiting core enzymes of DNL, including citrate/isocitrate carrier (CIC), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), represents an attractive therapeutic strategy. Despite challenges related to efficacy, selectivity and safety, several new classes of synthetic DNL inhibitors have entered clinical-stage development and may become the foundation for a new class of therapeutics. De novo lipogenesis (DNL) is vital for the maintenance of whole-body and cellular homeostasis, but aberrant upregulation of the pathway is associated with a broad range of conditions, including cardiovascular disease, metabolic disorders and cancers. Here, Steinberg and colleagues provide an overview of the physiological and pathological roles of the core DNL enzymes and assess strategies and agents currently in development to therapeutically target them.