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Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex
Open accessAbstract
Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.
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“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
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“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
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“84,105,106 However, it should be noted that metformin’s effect on human cells is dose-dependent: while the supra-phar-macological metformin (500-1,000 m M) concentrations used in many studies inhibit mitochondrial respiration, pharmacological metformin concentration ( 100 m M) improves such…”
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“Howell et al. [141] have shown that metformin activates pro-inflammatory AMPK, which inhibits the mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy.”
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“Activated AMPK inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a major regulator of cell growth and proliferation [89, 90].”
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Polyploidy and mTOR signaling: a possible molecular link
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“The most popular treatment for T2D, which is metformin, controls mTORC1 activity [15].”
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“Another candidate drug is metformin that acts as an mTOR inhibitor [38], a fundamentally important signaling pathway that is impaired in the brain of RTT patients [28].”
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Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease
Sato, Y., Qiu, J., Hirose, T., Miura, T., Sato, Y., Kohzuki, M., & Ito, O. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00120.2020 · Cited by 17
Targeting Hypoxia: Revival of Old Remedies
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Park, J., Joe, Y., Ryter, S. W., Surh, Y., & Chung, H. (2019) · PubMed · doi:10.14348/molcells.2019.0016 · Cited by 16
“Activation of AMPK inhibits the mTOR pathway by phosphorylation of tuberous sclerosis complex (TSC), a tumor suppressor gene (Howell et al., 2017)(Fig.”
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“A previous study showed metformin inhibited mTOR signaling via a dose-dependent mechanism, revealing that low-dose metformin directly inhibited mTOR through AMPK and TSC pathway, while high-dose metformin may work through other ways (41).”
BackgroundMorais, T., Seabra, A. L., Patrício, B. G., Guimarães, M., Nora, M. C., Oliveira, P. F., Alves, M. G., & Monteiro, M. P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115695 · Cited by 16
“Metformin decreases gluconeogenesis by inhibiting glycerophosphate dehydrogenase and activating AMPK, which suppresses mTORC1 on the mTOR pathway, responsible for triggering a selective pattern of IR within the AT with hampered insulin-mediated gluconeogenesis suppression, yet preserved lipogenesis [39,42].”
BackgroundLiu, P., Pan, Y., Song, Y., Zhou, Y., Zhang, W., Li, X., Li, J., Li, Y., & Ma, L. (2023) · European journal of medical research · doi:10.1186/s40001-023-01017-6 · Cited by 16
“The potential mechanisms of metformin mainly include the upregulation of nutrient-sensing pathways by activating AMP-activated kinase (AMPK), inhibiting mTORC1 [28], as well as downregulation of insulin/ insulin-like growth factor-1 (IGF-1) signaling.”
BackgroundLu, Y., Jing-Jie, M. A., Li, P., Liu, B., Wen, X., & Yang, J. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15369 · Cited by 16
“Considering mTOR suppression by AMPK activation in metabolic regulation (Bolster et al., 2002; Howell et al., 2017), we hypothesized that ilexgenin A might regulate cytosolic CRTC2 function to inhibit de novo lipid synthesis via AMPK activation.”
Alfaifi, A., Bahashwan, S., Alsaadi, M., Malhan, H. M., Aqeel, A., Al-Kahiry, W., Almehdar, H. A., & Qadri, I. (2022) · Diagnostics · doi:10.3390/diagnostics12020394 · Cited by 17
“Metformininduced energy deprivation mechanistically blocks mTORC1 activity in the physiological [108] and pathological settings in an AMPK-dependent or independent way [109,110].”
BackgroundMetformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction
Auger, C., Sivayoganathan, T., Abdullahi, A., Parousis, A., Pang, B. W., & Jeschke, M. G. (2018) · Scientific Reports · doi:10.1038/s41598-018-24017-7 · Cited by 16
mTORC1 syndrome (TorS): unified paradigm for diabetes/metabolic syndrome
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Disrupting the Mood and Obesity Cycle: The Potential Role of Metformin
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“AMPK activation by metformin inhibits the mechanistic target of rapamycin (mTOR) in the liver with resultant downstream events including suppression of hepatic neogenesis [101].”
BackgroundWang, D., Yang, L., Ding, W., Chen, Z., Yang, X., Jiang, Y., & Liu, Y. (2023) · Phytotherapy Research · doi:10.1002/ptr.8044 · Cited by 15
“The two signaling events and mitochondria are also the targets of MET for its antidiabetic activity (Howell et al., 2017; Wang et al., 2019).”
BackgroundJohnson, S., Abedian, S., Stürmer, T., Huling, J. D., Lewis, C., V, Buse, J. B., Brosnahan, S. B., Mudumbi, P. C., Erlandson, K. M., McComsey, G. A., et al. (2024) · Diabetes Care · doi:10.2337/dca24-0032 · Cited by 14
Surveying the Therapeutic Potentials of Isoliquiritigenin (ISL): A Comprehensive Review
Mustafa, A. M., El‐Shiekh, R. A., Esmail, M. M., Hassan, E., Senna, M. M., Ebid, N., & Elgindy, A. M. (2025) · Chemistry & Biodiversity · doi:10.1002/cbdv.202500456 · Cited by 14
“Themechanismsunderlyingtheseeffectsinvolvetheactivationof AMP-activated protein kinase (AMPK) and the inhibition of the mammalian target of rapamycin complex 1 (mTORC1) [87, 88].”
Cutting edge: Metabolic immune reprogramming, reactive oxygen species, and cancer
Aria, H., Ghaedrahmati, F., & Ganjalıkhani-Hakemi, M. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30303 · Cited by 14
Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical TrialPreprint
Bramante, C. T., Beckman, K. B., Mehta, T., Karger, A. B., Odde, D. J., Tignanelli, C. J., Buse, J. B., Johnson, D. M., Watson, R. H. B., Daniel, J. J., et al. (2023) · medRxiv · doi:10.1101/2023.06.06.23290989 · Cited by 14
“Additionally, continuing metformin could reduce symptom rebound given its effects on T-cell immunity.30,31 Further data is needed to correlate whether decreased viral load and faster viral clearance decreases onward transmission of SARS-CoV-2.”
MethodInfluentialDominiak, A., Gawinek, E., Banaszek, A. A., & Wilkaniec, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178693 · Cited by 14
“Other strategies, such as inducing mild bioenergetic stress with agents like 2-deoxyglucose [176] or mitochondrial uncou-plers [177], or using autophagy enhancers like rapamycin and metformin, have also been shown to activate mitophagy and mitigate neurodegenerative phenotypes [178–180].”
Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib
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“Mechanistically, metformin activates AMP-activated kinase (AMPK), a key sensor of the energetic state of the cell that switches off energyconsuming pathways, including mammalian target of rapamycin (mTOR) signaling [2] via inhibiting the lysosomal proton pump v-ATPase [1,3,4].”
BackgroundMetformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology
Shivaprakash, P., Beeraka, N. M., Madhunapantula, S. V., Nikolenko, V. N., & Basalingappa, K. M. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673289342240213040144 · Cited by 14
Fine-tuning AMPK in physiology and disease using point-mutant mouse models
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“…in RAPTOR alone was not sufficient to completely prevent the regulation of mTORC1 by AMPK, as the additional deletion of the mTORC1 negative regulator TSC2, another critical substrate of AMPK, was required to completely abrogate mTORC1 function (Howell et al., 2017; Van Nostrand et al., 2020) (Fig.”
BackgroundMeng, Y., Xiang, R., Yan, H., Zhou, Y., Hu, Y., Yang, J., Zhou, Y., & Cui, Q. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15472 · Cited by 14
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“Therefore, metformin can inhibit mTORC1 signaling through dose-dependent mechanisms relating to AMPK [23].”
BackgroundGerasymchuk, M., Robinson, G. I., Kovalchuk, O., & Kovalchuk, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158804 · Cited by 13
“Subsequently, this leads to fatty acid synthesis and mTOR signaling network suppression [30], causing reduced cellular energy consumption.”
BackgroundTargeting the Host Mitochondria as a Novel Human Cytomegalovirus Antiviral Strategy
Bachman, L. O., & Zwezdaryk, K. J. (2023) · Viruses · doi:10.3390/v15051083 · Cited by 14
Drugs to Control Diabetes During Pregnancy
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Mechanistic target of rapamycin signaling in mouse models of accelerated aging
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“However, the situation is more complex because both DR and metformin are known to reduce mTOR activity as well (55).”
The Dual Role of Metformin: Repurposing an Antidiabetic Drug for Cancer Therapy
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Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood–Testis Barrier Formation
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Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease
Roberts, C.-T., Raabe, N., Wiegand, L., Shahib, A. K., & Rastegar, M. (2024) · Pharmaceuticals · doi:10.3390/ph17121601 · Cited by 13
“Although metformin Through AMPK activation, metformin also inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling [18].”
Stability of tuberous sclerosis complex 2 is controlled by methylation at R1457 and R1459
Gen, S., Matsumoto, Y., Kobayashi, K., Suzuki, T., Inoue, J., & Yamamoto, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-78274-6 · Cited by 12
Anticancer potential of metformin: focusing on gastrointestinal cancers
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“It can also activate adenosine monophosphate-activated protein kinase (AMPK) to promote the decomposition of lipids, inhibit the synthesis of related proteins, and limit the energy supply of cancer cells, which consequently inhibits cancer cell proliferation and growth (17).”
BackgroundCryoimmunology: Opportunities and challenges in biomedical science and practice
Korpan, N. N., Goltsev, А., Dronov, O. I., & Bondarovych, M. O. (2021) · Cryobiology · doi:10.1016/j.cryobiol.2021.02.005 · Cited by 12
Calorie restriction mimetics against aging and inflammation
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From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin
Campagnoli, L. I. M., Varesi, A., Fahmideh, F., Hakimizad, R., Petkovic, P., Barbieri, A., Marchesi, N., & Pascale, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199748 · Cited by 15
“Furthermore, it may also suppress hepatic gluconeogenesis through AMPK-dependent inhibition of the protein kinase mTORC1 [49].”
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Effect of a High-Fat Diet and Metformin on Placental mTOR Signaling in Mice
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The Potential of a Stratified Approach to Drug Repurposing in Alzheimer’s Disease
Anderson, C., Bucholc, M., McClean, P. L., & Zhang, S. (2023) · Biomolecules · doi:10.3390/biom14010011 · Cited by 13
“It also activates the AMP-activated protein kinase pathway, which ultimately inhibits cell survival [222,223].”
BackgroundThe paradox of autophagy in Tuberous Sclerosis Complex
Reis, L. B., Filippi‐Chiela, E. C., Ashton‐Prolla, P., Visioli, F., & Rosset, C. (2021) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2020-0014 · Cited by 11
“Inhibition of mTORC1 by metformin can occur (a) through the phosphorylation and inhibition of Raptor and (b) through the activation of the TSC1 and TSC2 genes (Howell et al. , 2017) (Figure 2).”
Khalili-Hezarjaribi, H., Bahrami, A. R., Saljooghi, A. S., & Matin, M. M. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124838 · Cited by 11
mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS
Bar‐Tana, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06220-z · Cited by 10
“…by mild uncoupling of mitochondrial oxidative phosphorylation (e.g., DNP, TPP-cations, long-chain fatty acids) [158–162], or mild inhibition of mito complex I (e.g., metformin, phenformin) [163–165], or opening of the mito permeability transition pore (PTP) [166], or mild hypoxia [167, 168] (Fig.”
Amino acid homeostasis is a target of metformin therapy
Forteath, C., Mordi, I. R., Nisr, R. B., Gutierrez-Lara, E. J., Alqurashi, N., Phair, I. R., Cameron, A., Beall, C., Bahr, I., Mohan, M., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101750 · Cited by 11
“Metformin suppresses mTOR signalling in hepatocytes and mouse embryonic fibroblasts (MEFs) Consistent with earlier data from serum-fed MEFs [67] and hepatocytes from fed animals [68], we found that millimolar concentrations of metformin and its more potent analogue phenformin suppressed mTOR signaling in response to a…”
BackgroundResultInfluentialRole of β‐cell autophagy in β‐cell physiology and the development of diabetes
Yasasilka, X. R., & Lee, M. (2024) · Journal of Diabetes Investigation · doi:10.1111/jdi.14184 · Cited by 12
Garcia, I. S., Teixeira, S. A., Costa, K. A., Marques, D. B. D., Rodrigues, G. D. A., Costa, T. C., Guimarães, J. D., Otto, P. I., Saraiva, A., Ibelli, A. M. G., et al. (2020) · Molecular Reproduction and Development · doi:10.1002/mrd.23397 · Cited by 10
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From clock to clock: Therapeutic target discovery for aging and age-related diseases
Chen, J., Leung, G. H. D., Leung, H., Ustiugova, A. S., Shneyderman, A., Korzinkin, M., Gennert, D. G., Pun, F. W., Aliper, A. M., Ren, F., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102871 · Cited by 10
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“Recent work indicates that mTOR is not the sole target of metformin in oncology [13].”
Developmental effects of in utero metformin exposure.
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“Metformin is well known as an AMP-activated protein kinase (AMPK) activator that regulates glucose and lipid metabolism, inflammation regulation, cell proliferation and cell death through interaction with a variety of other factors, such as AKT and mTOR [16,17].”
BackgroundJîtcă, G., Gáll, Z., Jîtcă, C.-M., Buț, M.-G., & Májai, E. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16030403 · Cited by 8
Metformin as a Therapeutic Agent for Obesity-Associated Immune Dysfunction
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Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
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Research Progress on the Use of Metformin in Leukemia Treatment
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ROS, Redox Regulation, and Anticancer Therapy
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“Metformin-activated AMPK directly inhibits mTOR and indirectly inhibits it through the TSC1/2 complex [41,163,164].”
BackgroundInduction of Ferroptosis by Shikonin in Gastric Cancer via the DLEU1/mTOR/GPX4 Axis
Wang, Y.-Y., Xu, M.-D., Liu, C., Wang, X., Zhang, X.-Y., Sheng, W.-Q., & Wang, X.-Y. (2025) · Cell Biology International · doi:10.1002/cbin.70018 · Cited by 8
“We also found that mTOR, which plays critical roles in cell growth and metabolism, might be one of the targets by which DLEU1 regulates GPX4. mTOR forms two complexes (mTORC1 and mTORC2), and mTORC1 is involved in amino acid and protein synthesis (Battaglioni et al. 2022; Howell et al. 2017).”
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“Phosphorylated adenosine 5 0 - monophosphate-activated protein kinase (AMPK) can inhibit the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway by activating tuberous sclerosis complex 2 (TSC2) [46, 47], which in turn regulates Lipin1 transcription [48].”
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“39 Thus, the potential exists that the Met-mTORC1-ACAD10 pathway is also responsible for the metabolic benefits of Met.”
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“For example, metformin activates AMPK (Hawley et al., 2010; Howell et al., 2017; Rena et al., 2017); activated AMPK inhibits mTOR (Howell et al., 2017) and phospho-Acetyl-CoA carboxylase (pACC) thus leading to suppression of normal and tumor cell growth (Ibarra-Drendall et al., 2011).”
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“The inhibitory effect of metformin on mTORC1 phosphorylation was incorporated using an indirect effect saturable Emax model, and the parameters were obtained from the literature [28,29].”
Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas
Duchatel, R. J., Savary, C., Germon, Z. P., Riley, M., Ziegler, D. S., Mueller, S., Jackson, E. R., & Dun, M. D. (2025) · Neuro-Oncology · doi:10.1093/neuonc/noaf163 · Cited by 7
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“AMPK inhibits mTOR complex 1 (mTORC1) both directly and indirectly [63], and metformin has been shown to inhibit mTORC1 via AMPK [64].”
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“Formulated metformin at 200 mg/kg, as previously reported [28], was administrated intraperitoneally every day (5D+/2D−) to the mice for three weeks.”
MethodYagasaki, R., Morita, A., Mori, A., Sakamoto, K., & Nakahara, T. (2024) · Current Eye Research · doi:10.1080/02713683.2024.2302865 · Cited by 6
“6,17,18 For immunohistochemistry, in situ hybridization, and western blot analysis, the eyes were collected at P10, P13, and P15.”
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“Recently, it has been discovered that metformin severely reduces hepatic protein synthesis and mTORC1 activity (Howell et al., 2017).”
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“One generally accepted mechanistic action of metformin in the liver involves inhibition of hepatic mTORC1 signaling with subsequent phosphorylation of the mTORC1 downstream target RPS6 [44].”
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Singh, S. S. B., Eligar, S. M., & Patil, K. N. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c07776 · Cited by 4
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“Calorie restriction activates adenosine monophosphate-activated protein kinase (AMPK), which in turn inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) [14].”
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Prospects of Pharmacological Interventions to Organismal Aging
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Insulin Resistance, Secretion and Clearance –Taming the Three Effector Encounter of Type 2 Diabetes
Bar‐Tana, J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.741114 · Cited by 5
“Suppression of hyperactive mTORC1 by mitochondrial complex I inhibitors may be ascribed to redox (NADH/NAD), energy (ATP/AMP), AMPK and/or oxidative (ROS) stress as function of the respective dose (11, 43).”
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“39,40 La Hu et al found that metformin can inhibit tumor development by activating AMPK, which helps regulate cellular energy balance and suppress the mTOR signaling pathway, ultimately reducing cell proliferation.”
Metadata
- Authors
- Howell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D.
- Affiliations
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shaw, Reuben J.
- Manning, Brendan D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 25
- Issue
- 2
- Pages
- 463-471
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5299044
- OpenAlex
- W2572741715
- Cited by
- 408
- References
- 48
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 61 · 2023: 42 · 2022: 47 · 2021: 49 · 2020: 62 · 2019: 42 · 2018: 25 · 2017: 16
- FWCI
- 16.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- NIH (F32-DK095508, F30-DK112604, R01-DK080425, P01-CA120964)
- George E. Hewitt Foundation for Medical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- metformin, mTORC1 signaling, AMPK, tuberous sclerosis complex, liver, hepatocytes, protein synthesis, type 2 diabetes, dose-dependent effects
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Dose-Response Relationship, Drug, Humans, Liver, Metformin, Mice, Inbred C57BL, Organ Specificity, Protein Biosynthesis, Tuberous Sclerosis, Signal Transduction, Mice, Knockout, Hepatocytes, Multiprotein Complexes, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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