In humans, clearance of LDL cholesterol, which causes atherosclerotic heart disease, is mediated by the hepatic LDL receptor (LDLR). As a result, therapies that upregulate the LDLR are highly effective treatments for atherosclerosis. Since cardiovascular disease remains the leading cause of death in Western countries, we sought to identify regulators of the LDLR beyond the known genetic causes of familial hypercholesterolemia. Here we show that CSDE1, an RNA-binding protein involved in mRNA stability, enhances LDLR mRNA degradation to modulate LDLR expression and function. Using parallel phenotypic genome-wide screens, based on the CRISPR interference platform, we identified over 100 specific regulators of surface LDLR expression in HepG2 cells, characterized their effects on LDLR function, and leveraged pharmacologic strategies to probe their mechanistic pathways. Among our hits, we found that CSDE1 participates in post-translational control of the LDLR independent from well-established, and clinically exploited, transcriptional and lysosomal regulatory mechanisms. Overall, our results reveal a network of novel LDLR modulators left undiscovered by human genetics, many of which have phenotypic strengths similar to bona fide targets in the clinic, offering hope for new therapeutic strategies against atherosclerosis. We anticipate that our approach of modelling a clinically relevant phenotype in an in vitro experimental system amenable to a forward genetic screen, followed by high throughput validation and mechanistic pharmacologic dissection, will serve as a template for the identification of novel therapeutic targets for other disease states. ### Competing Interest Statement P.N. reports investigator-initiate grant support from Amgen, Apple, and Boston Scientific, and personal fees from Apple, Blackstone Life Sciences, and Novartis, all unrelated to the present work. K.M.S. has consulting agreements for the following companies involving cash and/or stock compensation: Black Diamond Therapeutics, BridGene Bioscences, Denali Therapeutics, Dice Molecules, eFFECTOR Therapeutics, Erasca, Genentech/Roche, Janssen Pharmaceuticals, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Petra Pharma, Revolution Medicines, Type6 Therapeutics, Venthera, Wellspring Biosciences (Araxes Pharma). J.S.C. has received consulting fees from Gilde Healthcare and is an unpaid scientific advisor to Eko, both unrelated to this work.
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