Ac2-26 ammonium

Ac2-26 ammonium is the ammonium salt form of Ac2‑26 (CAS No.: 151988-33-9). Ac2‑26 is a bioactive polypeptide derived from the N-terminus of annexin A1 (Annexin A1, ANXA1), with significant anti-inflammatory, pyroptosis-inhibitory, and tissue injury-alleviating functions. Unlike traditional peptides that rely solely on membrane receptors, Ac2‑26 can act through the ANXA1/FPR pathway and also has an intracellular mode of action that is independent of membrane receptors. In microglia stimulated with conditioned medium from neurons subjected to oxygen-glucose deprivation / reperfusion, its anti-inflammatory effect is independent of FPR; instead, it directly enters the cytoplasm, interacts with intracellular proteins, and acts as an "intracellular protective peptide".

At the molecular mechanism level, Ac2‑26 can achieve integrated regulation of inflammation, pyroptosis, and apoptosis through multiple key signaling pathways: in microglia, after the polypeptide enters the cytoplasm, it can upregulate the expression of the heat shock protein HSPB1, promote the binding of HSPB1 to IKKβ, and mediate lysosomal degradation of IKKβ via the lysosomal membrane protein LAMP‑2A through the chaperone-mediated autophagy (CMA) pathway, thereby indirectly inhibiting IKKβ/NF‑κB pathway activity and reducing TNF‑α transcription and secretion. In a macrophage system treated with high glucose, high fat, and LPS (Cat. No.: N2894), Ac2‑26 inhibits NLRP3 inflammasome activation through ANXA1-related pathways, downregulates Caspase‑1 cleavage and the generation of the GSDMD N-terminal pore-forming fragment, inhibits macrophage pyroptosis, and reduces intracellular reactive oxygen species levels, indirectly improving osteogenic differentiation of osteoblasts under a high-glucose and high-fat microenvironment. In a cardiopulmonary bypass-related lung injury model, Ac2‑26 can promote phosphorylation of AKT1, GSK3β, and endothelial nitric oxide synthase (eNOS), inhibit phosphorylation of NF‑κB and myosin light chain, downregulate pro-apoptotic molecules such as Bax and cleaved caspase‑3, and upregulate Bcl‑xL expression, thereby improving pulmonary capillary permeability and reducing inflammation and apoptosis.

In experimental applications, existing studies are mainly based on therapeutic administration designs. Animal experiments include an SD rat model of diabetic periodontitis-associated alveolar bone defects established by streptozotocin (Cat. No.: A4457, CAS No.: 18883-66-4)-induced diabetes combined with molar ligation, in which Ac2‑26-loaded hydrogel is locally injected after tooth extraction to evaluate bone repair and inflammation improvement; and a rat model of cardiopulmonary bypass-induced acute lung injury, in which lung protection is observed through intravenous administration. Common concentrations at the cellular level are mostly 10 μM, with a treatment time of approximately 24 h; in hydrogel-loaded macrophage experiments, the peptide loading concentration is approximately 10 μmol/mL. The commonly used dose for intravenous administration in animals is 1 mg/kg, used to evaluate its anti-inflammatory, anti-pyroptotic, and tissue-protective potential under various pathological conditions such as cardiopulmonary bypass, metabolic inflammation, and bone tissue repair.

References:

[1] Liu L, An D, Xu J, Shao B, Li X, Shi J. Ac2-26 Induces IKKβ Degradation Through Chaperone-Mediated Autophagy Via HSPB1 in NCM-Treated Microglia. Front Mol Neurosci. 2018 Mar 15;11:76. doi: 10.3389/fnmol.2018.00076. PMID: 29662435; PMCID: PMC5890123.

[2] Zhang LL, Jia BW, Zhuo ZP, Wang HY, Yang Q, Gao W, Ju YN. Ac2-26 Reduced Lung Injury After Cardiopulmonary Bypass via the AKT1/GSK3β/eNOS Pathway. J Surg Res. 2024 Sep;301:324-335. doi: 10.1016/j.jss.2024.06.009. Epub 2024 Jul 15. PMID: 39013279.

[3] Li R, Li W, Teng Y, Li R, Kong S, Chen X, Luo H, Chen D, Guo Y, Qing Y, Leong HC, Guo B, Chen M, Pan Z, Zheng S, Deng Y, Cao Y, Zhou C, Zou X, Wang W. Ameliorating macrophage pyroptosis via ANXA1/NLRP3/Caspase-1/GSDMD pathway: Ac2-26/OGP-loaded intelligent hydrogel enhances bone healing in diabetic periodontitis. Biofabrication. 2025 Jan 23;17(2). doi: 10.1088/1758-5090/ada737. PMID: 39773706.