Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis

Area of Science:

• Cardiovascular Research
• Cellular Biology
• Pharmacology

Background:

• Necrotic core formation is central to atherosclerosis development.
• Necroptosis, a regulated form of necrosis, presents a therapeutic target for reducing atherosclerotic plaque.
• Understanding triggers and consequences of necrosis and necroptosis is crucial.

Purpose of the Study:

• To review triggers and consequences of necrosis and necroptosis in atherosclerosis.
• To discuss pharmacological strategies for inhibiting necrotic cell death in atherosclerotic plaques.
• To evaluate therapeutic potential of targeting specific necroptosis-regulating proteins.

Main Methods:

• Literature review of necrosis and necroptosis in atherosclerosis.
• Analysis of pharmacological inhibition strategies.
• Evaluation of targeting receptor-interacting serine/threonine-protein kinases (RIPK) and mixed lineage kinase domain-like pseudokinase (MLKL).

Main Results:

• Necrosis and necroptosis contribute significantly to atherogenesis.
• Inhibiting necroptosis is a potential therapeutic strategy for cardiovascular disease.
• RIPK1 inhibitors have shown efficacy in mouse models, but targeting RIPK3 and MLKL may be more effective due to RIPK1's role in apoptosis and RIPK1-independent necroptosis.

Conclusions:

• Inhibiting necroptosis, particularly by targeting RIPK3 and MLKL, is a promising strategy for cardiovascular disease prevention.
• Combination therapy with standard statins and necroptosis inhibitors could be beneficial.
• Further development of RIPK3 and MLKL inhibitors for preclinical and clinical use is necessary.