Inducible degrader of LDLR: A potential novel therapeutic target and emerging treatment for hyperlipidemia

Statins are the most effective lipid-lowering drugs ever developed, and numerous patients with cardiovascular disease (CVD) have obtained remarkable benefits from statin therapy. However, issues with statin resistance and intolerance cannot be ignored in clinical practice. Additionally, adverse effects, such as an increased risk of new-onset diabetes and muscle symptoms, may limit the utilization of statins. Therefore, the development of new lipid-lowering agents is necessary to reduce CVD risk in patients who are unable to receive statin therapy. Among these new lipid-lowering strategies, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is an effective way to enhance clearance of LDL-C from the circulation by impeding the degradation of LDL receptor (LDLR) in hepatocytes. Interestingly, given that upregulation of LDLR is an effective method for lowering lipid levels, the question arises as to whether other LDLR-mediated genes could serve as potential therapeutic targets for CVD. As an E3-ubiquitin ligase, inducible degrader of LDLR (IDOL) can cause ubiquitination and degradation of LDLR in lysosome and is a novel regulator of LDLR expression similar to PCSK9. Although there are no approved drugs for targeting the IDOL-LDLR pathway, recent studies demonstrate that IDOL could serve as a potential therapeutic target for hyperlipidemia. Herein, we have summarized these novel studies to present the pathological role of IDOL in CVD, further assessing its pharmacological effects for lipid-lowering therapy.