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Updated: Jun 15, 2025

Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases
Francisco Alejandro Lagunas-Rangel1,2, Edgars Liepinsh2, Robert Fredriksson3
1Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden.
Abstract:
Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.
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