Mevalonic acid

Mevalonic acid is a key metabolite for cell growth and participates in the cholesterol and isoprenoid biosynthesis pathways. Mevalonic acid can involve in protein prenylation modifications of small GTPases such as Ras and Rho through downstream isoprene precursors, thereby regulating cell proliferation, differentiation, and inflammatory responses. Mevalonic acid accumulates in mevalonate kinase deficiency and participates in disease progression by activating the IL-1β inflammatory pathway and enhancing FXa procoagulant activity. Mevalonic acid can be used in research on cancer, autoinflammatory diseases, and thrombotic disorders^[1-4].

In vitro, incubation of HepG2 and Caco-2 cells with Mevalonic acid (5-20mM) for 48 hours dose-dependently inhibited acid sphingomyelinase activity, promoted increases in cholesterol, sphingomyelin, and phosphatidylcholine levels, and suppressed cell proliferation^[5]. Incubation of compactin-induced monkey arterial smooth muscle cells and Swiss 3T3 cells with Mevalonic acid (20mM) for 20-96 days reversed the inhibitory effect of compactin on DNA synthesis^[6]. Incubation of B-cell chronic lymphocytic leukemia cells with Mevalonic acid (0.0.5-10mM) for 24-96 hours dose- and time-dependently promoted DNA synthesis and facilitated cell cycle progression from G0 phase to G1, S, and G2-M phases^[7].

In vivo, oral gavage of Mevalonic acid (500mg/kg; twice daily) to fluvastatin-induced pregnant rats from day 15 of gestation through day 21 postpartum blocked or ameliorated fluvastatin-induced maternal death and cardiac myopathy^[8]. Daily topical application of 50μL Mevalonic acid (7.68mM) to a 2.5cm² skin area on the back of hairless mice in an acute barrier disruption model for 5 consecutive days enhanced the resistance of mouse skin to barrier damage, increased HMG-CoA reductase activity, and elevated total cholesterol and free fatty acid content in the epidermis^[9].

References:

[1] Premkumar K, Shankar BS. Identification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds. Life Sci. 2022 Jul 15;301:120643.

[2] Kivrak M, Nalkiran I, Sevim Nalkiran H. Exploring the Therapeutic Potential of the DOT1L Inhibitor EPZ004777 Using Bioinformatics and Molecular Docking Approaches in Acute Myeloid Leukemia. Curr Issues Mol Biol. 2025 Mar 4;47(3):173.

[3] Yu W, Chory EJ, Wernimont AK, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288.

[4] Daigle SR, Olhava EJ, Therkelsen CA, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011 Jul 12;20(1):53-65.

[5] Chen Y, Xu S, Duan R, et al. Mevalonate inhibits acid sphingomyelinase activity, increases sphingomyelin levels and inhibits cell proliferation of HepG2 and Caco-2 cells. Lipids Health Dis. 2015 Oct 22;14:130.

[6] Habenicht AJR, Glomset JA, Ross R. Relation of cholesterol and mevalonic acid to the cell cycle in smooth muscle and Swiss 3T3 cells stimulated to divide by platelet-derived growth factor. J Biol Chem. 1980 Jun 10;255(11):5134-40..

[7] Larson RA, Yachnin S. Mevalonic acid induces DNA synthesis in chronic lymphocytic leukemia cells. Blood. 1984 Jul;64(1):257-62.

[8] Hrab RV, Hartman HA, Cox RH Jr. Prevention of fluvastatin-induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation. Teratology. 1994;50(1):19-26.

[9] Haratake A, Ikenaga K, Katoh N, et al. Topical mevalonic acid stimulates de novo cholesterol synthesis and epidermal permeability barrier homeostasis in aged mice. J Invest Dermatol. 2000 Feb;114(2):247-52.