AKT serine/threonine kinase 1

Overview

AKT serine/threonine kinase 1 (Akt1) is a serine/threonine protein kinase and a central component of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling axis. It is widely involved in regulating cell survival, proliferation, metabolism, migration, and stress responses. In biomedical research, Akt1 is frequently treated as a key signaling node because changes in its phosphorylation state can reflect activation of upstream receptor pathways such as EGFR, MET, FLT1, and TGFBR-linked signaling, as well as downstream effects on targets including GSK3β, FOXO1, and mTOR.

Because of its broad role in oncogenic and metabolic signaling, Akt1 is a common target in studies of cancer progression, drug resistance, lipid metabolism, and tissue remodeling. It is also used as a pharmacological readout in studies evaluating pathway inhibition by agents such as berberine, sirolimus, ponatinib, deferasirox, nobiletin, and tea polyphenol extracts, as well as in mechanistic work on anti-PD-1 therapy, PD-1/PD-L1 regulation, and disease models involving liver cancer, melanoma, Parkinson's disease, venous malformations, and metabolic dysfunction–associated steatotic liver disease.

Focus of Latest Publications

Recent publications have used Akt1 primarily as a signaling target, pathway marker, or mechanistic node rather than as a standalone therapeutic agent. Across these studies, Akt1 was repeatedly linked to the PI3K/Akt signaling pathway and its downstream mTOR signaling, with phosphorylation of AKT serving as an indicator of pathway activation or suppression.

In a molecular design study using a Transformer-based framework with generative flow network (GFlowNet) methods and QSAR modeling, Akt1 was included alongside Dopamine receptor D2 and CXCR4 as a benchmark target for compound exploration. This indicates its continued use in computational drug discovery workflows, where target-aware molecular generation and scoring are applied to identify candidate ligands.

Several disease-focused studies examined Akt1 in the context of cancer biology. In venous malformations, activation of the PI3K/AKT/mTOR pathway was described as a pathogenic driver, and the study evaluated polymeric rapamycin nanoparticles encapsulating ponatinib as a strategy to induce regression in mice. In liver cancer-related work, TMEM45B was reported to promote MET signaling activation, with increased phosphorylation of downstream effectors AKT and ERK, supporting a role for Akt1 as part of MET-driven oncogenic signaling. Another liver cancer study linked FLT1-centered networks to Akt1, suggesting that Akt1 is embedded in broader endothelial and senescence-associated signaling circuits. In a separate hepatocellular context, cathepsin G was reported to promote hepatic lipid deposition by suppressing Akt, connecting AKT signaling to lipid metabolism and metabolic liver disease.

Akt1 was also implicated in therapeutic response and resistance. berberine enhanced cisplatin efficacy in ehrlich ascites carcinoma and was associated with downregulation of Akt1, Axl, Mertk, and Gas6 gene expression, suggesting that Akt1 suppression may contribute to improved antitumor effects and altered efferocytosis. In melanoma, deferasirox was used to disrupt iron-driven PI3K/AKT signaling and PD-L1 upregulation, linking Akt1 to immune evasion and iron metabolism. In lymphoma, AKT was highlighted as part of core survival networks together with B-cell receptor, JAK/STAT, and BCL2 apoptosis pathways, reinforcing its role in adaptive resistance and malignant cell survival.

Outside oncology, Akt1 appeared in studies of neuroprotection and cardioprotection. In Parkinson's disease research, DPP-4 inhibitors sitagliptin and vildagliptin were analyzed through network pharmacology and docking, with Akt1 emerging as a central node alongside DPP-4 and GSK3β, consistent with a role in autophagy modulation. In myocardial protection induced by vagal nerve stimulation preconditioning, myocardial phosphorylation of Akt and GSK-3β was evaluated, indicating AKT pathway involvement in early and delayed cardioprotective responses.

Akt1 was also used as a mechanistic readout in studies of natural products and pathway inhibitors. Nobiletin was reported to inhibit non-small cell lung cancer and synergize with an HDAC inhibitor by suppressing phosphorylation of the PI3K/AKT/mTOR pathway. Liupao tea polyphenol extract was found to prevent metabolic dysfunction–associated steatotic liver disease by downregulating the EGFR/pEGFR-AKT/pAKT-SREBP-1-ACC1 pathway through EGFR binding. In another study, elevated iron was described as activating PI3K/AKT signaling and upregulating PD-L1, providing a mechanistic rationale for iron chelation. These findings collectively position Akt1 as a convergence point for growth factor signaling, metabolic regulation, and immune modulation.

Key Publications

• NEWJun Targeted activation of PPARG or AKT1 alleviates liver injury in mice with type 2 diabetes and sepsis by modulating inflammatory and metabolic pathways. (Annals of medicine, 2026, PMID 42319089): "Although the activation of peroxisome proliferator-activate receptor gamma (PPARG) and AKT serine/threonine kinase 1 (AKT1) have been shown to confer protection alone in isolated models of sepsis or T2DM."
• May A Transformer for Reaction-Aware Compound Explorations with GFlowNet in QSAR-Guided Molecular Design. (Journal of chemical information and modeling, 2026, PMID 42033344): "In benchmark experiments involving dopamine receptor D2 (DRD2), AKT serine/threonine kinase 1 (AKT1), and C-X-C motif chemokine receptor 4 (CXCR4),"
• May Polymeric rapamycin nanoparticles encapsulating ponatinib cause regression of venous malformations in mice. (Science translational medicine, 2026, PMID 42090479): "Venous malformations (VMs) are caused by activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) and Abelson murine leukemia viral oncogene homolog 1 (c-ABL) pathways."
• May Nobiletin inhibits non-small cell lung cancer through TRKC and exhibits a synergistic effect with the HDAC inhibitor. (Chinese journal of natural medicines, 2026, PMID 42062032): "Eukaryotic transcriptome sequencing revealed that the combination treatment primarily inhibits tumor cell proliferation by modulating TRKC protein expression and suppressing phosphorylation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway."
• May Cathepsin G Promotes Hepatic Lipid Deposition by Regulating Key Genes Related to Lipid Metabolism. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 41996208): "Mechanistically, CTSG upregulated key lipid synthesis genes (ACC, SCD1) and downregulated those involved in lipid oxidation (PPARα, Lcad) and secretion (MTTP) by suppressing Akt."
• May Multi-Omics and Machine Learning-Uncovered FLT1-Mediated Epithelial-Endothelial Crosstalk in Cellular Senescence Driving Clear Cell Renal Cell Carcinoma Malignancy. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 41999263): "Our work reveals a FLT1-centered network of related factors, where FLT1 acts as the core single gene, closely associated with key factors VEGFA and AKT1."
• Apr Berberine enhances cisplatin efficacy in ehrlich ascites carcinoma via modulation of apoptotic pathway and efferocytosis. (Scientific reports, 2026, PMID 42049890): "Berberine ameliorated cisplatin's hepato-renal toxicity and downregulated Akt1, Axl, Mertk, and Gas6 gene expression."
• Apr Elevated TMEM45B expression promotes liver cancer progression and is associated with MET signaling activation. (Scientific reports, 2026, PMID 41998230): "Mechanistically, TMEM45B promoted MET signaling activation, as reflected by increased MET protein levels and enhanced phosphorylation of downstream effectors AKT and ERK."
• Apr Targeted delivery and controlled release of deferasirox for melanoma therapy. (iScience, 2026, PMID 41940349): "Since elevated iron activates phosphoinositide-3-kinase (PI3K)/AKT signaling and upregulates PD-L1, we employed the iron chelator deferasirox (DFX) to disrupt this pathway."
• Apr Hepatocyte-derived LRG1 primes the liver for metastasis and impairs immunotherapy. (Cellular & molecular immunology, 2026, PMID 41963620): "Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs)."