Metformin Finds Its New Molecular Targets

Abstract

Metformin is a widely used antidiabetic drug. Studies over the past year have identified multiple novel molecular targets and pathways that metformin may act on to exert its beneficial effects in treating diabetes and potentially other disorders involving dysregulated inflammation. These newly found targets include mitochondrial complex I, Nrf2-SIRT3 signaling axis, PEN2, and lysosomal proton pump v-ATPase. (First online: March 1, 2022) REFERENCES Flory J, Lipska K. Metformin in 2019. JAMA 2019; 321(19):1926–7. doi: https://dx.doi.org/10.1001/jama.2019.3805 Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021; 54(7):1463–77 e11. doi: https://dx.doi.org/10.1016/j.immuni.2021.05.004 Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510(7506):542–6. doi: https://dx.doi.org/10.1038/nature13270 Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8):1167–74. doi: https://dx.doi.org/10.1172/JCI13505 Gao P, You M, Li L, Zhang Q, Fang X, Wei X, et al. Salt-Induced hepatic inflammatory memory contributes to cardiovascular damage through epigenetic modulation of SIRT3. Circulation 2022; 145(5):375–91. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.121.055600 Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 2022. doi: https://dx.doi.org/10.1038/s41586-022-04431-8