3-TYP

3-TYP is an orally active SIRT3 inhibitor (IC₅₀=16nM) and also inhibits SIRT1 (IC₅₀=88nM) and SIRT2 (IC₅₀=92nM). 3-TYP selectively inhibits the deacetylase function of SIRT3, leading to mitochondrial protein hyperacetylation. 3-TYP thereby regulates oxidative phosphorylation and increases reactive oxygen species levels in cancer cells and primary hepatocytes. 3-TYP can be used in research on metabolic diseases, aging and tumor metabolism^[1-4].

In vitro, treatment of MV4-11 cells with 50μM 3-TYP for 48 hours increased SOD2 acetylation levels in the cells^[5]. During 6 hours of reoxygenation after 24 hours of hypoxia, treatment of H9c2 cells with 50μM 3-TYP aggravated hypoxia-reoxygenation-induced decline in mitochondrial respiration capacity and caused abnormal mitophagy^[6]. During 2 hours of reoxygenation after 10 hours of hypoxia, treatment of H9c2 cells with 1μM 3-TYP aggravated cell morphological damage, enhanced hypoxia/reoxygenation-induced inhibition of cell proliferation, increased apoptosis rate, increased caspase-3 and Bax protein expression and decreased Bcl-2 expression, and elevated LDH release in culture medium^[7].

In vivo, intraperitoneal injection of 50mg/kg 3-TYP into ACE2 knockout mice combined with 1g/kg β-aminopropionitrile fumarate in drinking water once every two days for 4 consecutive weeks increased mortality and incidence of thoracic aortic dissection, enlarged the maximum internal diameter of the thoracic aorta, worsened thoracic aortic histological injury and destroyed elastic fibers [8]. A single intraperitoneal injection of 50mg/kg 3-TYP into C57BL/6J mice 2 hours before thioacetamide (300mg/kg) injection aggravated liver tissue necrosis and inflammatory cell infiltration, increased serum ALT and AST levels, reduced 24-hour survival rate, decreased liver GSH content and increased MDA content [9]. Daily intraperitoneal injection of 20mg/kg 3-TYP into APP/PS1 mice combined with intragastric administration of 20mg/kg/day honokiol for 5 consecutive days eliminated the cognitive improvement effect of honokiol, restored prolonged escape latency and platform crossing latency and reduced platform crossing frequency, and abolished the reduction of Aβ1-42 plaque deposition in hippocampus and cortex induced by honokiol [10].

References:

[1] Song S, Yang M, Li J, et al. Z. SIRT3 mediates CPT2 delactylation to enhance mitochondrial function and proliferation in goat granulosa cells. J Anim Sci Biotechnol. 2025 Jul 17;16(1):101.

[2] Huang X, Gou H, Xie J, et al. Sirt3 Rescues Porphyromonas gingivalis-Impaired Cementogenesis via SOD2 Deacetylation. Cell Prolif. 2025 Sep;58(9):e70022.

[3] Zhu Z, Wang Y, Chen J, et al. 3-TYP protects against heart failure with preserved ejection fraction by inhibiting Sirtuin 3. J Mol Histol. 2025 Oct 23;56(6):357.

[4] Zeng Y, Zhang Y, Cui Z, et al. The Selective SIRT3 Inhibitor 3-TYP Represses Primary Myeloma Growth by Reducing c-Myc Stability. Chem Res Toxicol. 2024.

[5] Ma J, Liu B, Yu D, et al. SIRT3 deacetylase activity confers chemoresistance in AML via regulation of mitochondrial oxidative phosphorylation. Br J Haematol. 2019;187(1):49-64.

[6] Kranrod JW, Valencia R, Heidari M, et al. Establishing a direct interaction between the 19,20-EDP analog SA-22 and SIRT3: impact on cardiac mitochondrial homeostasis. Front Pharmacol. 2026 Jun 2;17:1805965.

[7] Wu H, Liu Y, Hao Y, et al. Lycium barbarum polysaccharide protects cardiomyocytes from hypoxia/reoxygenation injury via activation of SIRT3/CypD signaling. Ann Transl Med. 2023 Jan 31;11(2):72.

[8] Jiang L, Lu L, Xue C, et al. ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch. Mol Med. 2024 Sep 19;30(1):154.

[9] Shi C, Jiao F, Wang Y, et al. SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Front Physiol. 2022 Jul 18;13:915193.

[10] Li H, Sun J, Wu Y, et al. Honokiol relieves hippocampal neuronal damage in Alzheimer's disease by activating the SIRT3-mediated mitochondrial autophagy. CNS Neurosci Ther. 2024;30:e14878.