HMGCR Inhibition Impairs Mitochondrial Fatty Acid Oxidation in Clinical and Preclinical Models: Therapeutic Targeting of Long-Chain Acylcarnitines

Background Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) by statins effectively lowers cholesterol levels but has also been suggested to impair mitochondrial metabolism and contribute to statin-associated adverse effects. Debate persists as to whether statin-associated muscle symptoms (SAMS) result primarily from systemic inhibition of the mevalonate pathway or from direct impairment of mitochondrial function by statins. We previously showed that tamoxifen-inducible, whole-body Hmgcr -knockout (Hmgcr-KO) mice develop severe metabolic disturbances and lethal liver injury associated with long-chain acylcarnitine accumulation. Here, we investigated whether a similar metabolic phenotype occurs in statin-treated patients and whether pharmacological lowering of acylcarnitine levels can mitigate the toxicity associated with HMGCR deficiency. Methods Blood plasma and muscle samples were obtained from healthy controls and patients receiving statin therapy. Statin concentrations, acylcarnitine profiles, and mitochondrial respiratory function were analysed in the collected samples. A tamoxifen-inducible, whole-body Hmgcr -KO mouse model was used to assess the effects of pharmacological acylcarnitine lowering. Results In muscle biopsies from statin-treated patients, fatty acid oxidation-linked mitochondrial respiration was reduced, and medium- and long-chain acylcarnitine concentrations were increased, whereas these changes were not evident in plasma. Hmgcr -KO mice similarly exhibited impaired mitochondrial fatty acid β-oxidation and respiration, accompanied by marked hepatic accumulation of long-chain and 3-hydroxy-acylcarnitines. Importantly, treatment with the acylcarnitine-lowering agent methyl-GBB markedly improved survival, prevented hypoglycaemia, reduced liver injury, preserved mitochondrial respiratory function, and normalized hepatic long-chain acylcarnitine profiles. In contrast, mevalonate treatment did not rescue the phenotype and increased the levels of several acylcarnitine species. Conclusions These findings identify a shared fatty acid oxidation–acylcarnitine phenotype associated with pharmacological and genetic HMGCR inhibition and demonstrate that targeting acylcarnitine accumulation can substantially mitigate the severe metabolic consequences of HMGCR deficiency. The findings support long-chain acylcarnitine accumulation as a mechanistically relevant consequence of HMGCR inhibition and suggest that acylcarnitine metabolism may represent a potential therapeutic target for statin-associated adverse effects. Trial registration information: ClinicalTrials.gov registration number NCT07511686.