2-APQC is an orally active and selective agonist of Sirtuin-3 (SIRT3), with a KD value of 2.756μM[1]. 2-APQC upregulates the expression levels of AMPK/SIRT3 proteins, downregulates the expression levels of cellular aging and inflammation, and prevents ribosomal stress to alleviate kidney inflammation and senescence[2]. 2-APQC ameliorates acid-sensing ion channel 1a (ASIC1a)-mediated mitophagy levels, reduces mitochondrial superoxide release, and decreases the expression of PANoptosis-related proteins[3]. 2-APQC improves the migration ability of mouse dermal fibroblasts under high glucose conditions by increasing the protein levels of SIRT3 and SOD2, and decreasing the expression of acSOD2, COL1, and α-SMA[4]. 2-APQC has been used to mitigate endothelial ferroptosis and microvascular hyperpermeability[5].
In vitro, 2-APQC (10µM) treatment for 24 hours enhanced the thermal stability of SIRT3 in H9c2 cells and reduced the hypertrophy and fibrosis of cardiomyocytes induced by isoproterenol (ISO)[1]. Incubation with 10mM 2-APQC for 24 hours alleviated β-glycerophosphate-induced senescence of C2C12 cells, restored autophagy function, and decreased the expression levels of P53 and P62[6].
In vivo, 2-APQC treatment via a single intraperitoneal injection at a dose of 30mg/kg attenuated Lipopolysaccharide and Norepinephrine-induced cardiomyopathy, improved cardiac remodeling, and was accompanied by elevated heme oxygenase-1 expression and ferrous ion levels in mice 7 days later[7]. Intraperitoneal injection of 2-APQC (42mg/kg/day) for 30 days alleviated intervertebral disc degeneration induced by D-galactose (D-gal) in mice, maintained structural integrity, increased proteoglycan content, and restored mitochondrial homeostasis[8]. A single intraperitoneal injection of 2-APQC (20mg/kg) reduced the cerebral infarction volume in mice with cerebral Ischemia/reperfusion and attenuated neurological dysfunction within 7 days[9].
References:[1] Peng F, Liao M, Jin W, et al. 2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis[J]. Signal Transduction and Targeted Therapy, 2024, 9(1): 133.
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[3] Zai Z, Qian X, Xu Y, et al. ASIC1a induces excessive mitophagy and PANoptosis of chondrocyte by the inhibition of SIRT3 mitochondrial translocation[J]. Theranostics, 2025, 15(18): 9623.
[4] Ge X, Ye Z, Qin H, et al. Thiomyristoyl Promotes Type 2 Diabetic Wound Healing and Inhibits Scarring via the PPARγ/Sirt3/SOD2 Axis[J]. Free Radical Biology and Medicine, 2026.
[5] Gao F, Li Z, Peng T, et al. SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury[J]. Autophagy, 2026, 22(6): 1221-1235.
[6] Xu C, Xiong L, Chen J, et al. Sirtuin 3 modulation by high phosphates: a potential mechanism in muscle aging and sarcopenia[J]. American Journal of Translational Research, 2025, 17(6): 4187.
[7] Ma D, Fang W, Cai L, et al. Norepinephrine exacerbates LPS-induced cardiomyopathy via SIRT3/HO-1 axis-mediated ferroptosis[J]. Critical Care, 2025, 29(1): 354.
[8] Du Y, Lv Y, Liu X, et al. Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration[J]. Experimental Gerontology, 2026: 113228.
[9] Lei W, Dong Y, Zhuang H, et al. Astrocytic SIRT3 alleviates neuroinflammatory responses after cerebral ischemia/reperfusion by inhibiting the cGAS-STING pathway[J]. Inflammation, 2026, 49(1): 32.