FGF2-PI3K-Akt1 signaling

Overview

The FGF2-PI3K-Akt1 signaling axis refers to the intracellular cascade initiated by fibroblast growth factor 2 (FGF2) binding to its cognate receptors, leading to the activation of phosphoinositide 3-kinase (PI3K) and its downstream effector serine/threonine kinase Akt1 (also known as protein kinase B alpha). This pathway is a central regulator of cell survival, proliferation, differentiation, and metabolism across a wide range of tissue types. Upon FGF2-mediated receptor engagement, PI3K phosphorylates phosphatidylinositol lipids at the plasma membrane, generating second messengers that recruit and activate Akt1. Once activated, Akt1 phosphorylates numerous substrates involved in cell cycle progression, apoptotic suppression, and anabolic signaling, including components associated with mTOR, FOXO transcription factors, and downstream effectors such as MYC and matrix metalloproteinase-9 (MMP9). The pathway intersects extensively with parallel cascades including MAPK/ERK, JAK-STAT, and Wnt/β-catenin signaling, making it a critical node in both normal physiology and pathological conditions such as cancer, metabolic disease, inflammatory disorders, and tissue aging.

The biological relevance of FGF2-PI3K-Akt1 signaling is underscored by its roles in stem cell maintenance and tissue homeostasis. In bone marrow, for instance, FGF2-PI3K-Akt1 activity supports the function of mesenchymal stromal cells, and its dysregulation has been implicated in age-related changes in bone marrow biology. Dysactivation of this pathway—whether through upstream receptor tyrosine kinase mutations, ligand overexpression, or loss of negative regulators such as PTEN—contributes to oncogenesis and treatment resistance, motivating considerable drug discovery efforts targeting PI3K, Akt1, and associated kinases including FGFR1.

Focus of Latest Publications

Recent publications have examined FGF2-PI3K-Akt1 signaling mainly as part of broader PI3K/Akt-centered oncogenic and disease-related networks, using a mix of network pharmacology, molecular docking, molecular dynamics, transcriptomics, single-cell and spatial profiling, metabolomics, and in vitro/in vivo validation. Across these studies, the pathway was repeatedly linked to cell proliferation, migration, invasion, apoptosis, oxidative stress, and treatment response in cancer and metabolic disease models.

In cervical squamous cell carcinoma progression, multi-omics profiling of premalignant and malignant lesions identified ISG15 as a factor synthesized by inflammatory cancer-associated fibroblasts that stabilizes FGF1 and activates the FGF1/FGFR1/PI3K/AKT/mTOR signaling pathway. In this setting, FGFR1 and PI3K/AKT/mTOR inhibitors suppressed cervical cancer cell proliferation in vitro and tumor growth in vivo, supporting a functional role for FGF-linked PI3K/Akt signaling in malignant progression. Related studies in oral squamous cell carcinoma and glioma also implicated Akt1-associated signaling: hippeastrine was reported to inhibit the HSP90/PI3K/Akt/mTOR axis, while scutellarein and Aucan were both shown to suppress PI3K/AKT signaling and reduce tumor cell growth, migration, invasion, and survival.

Several natural products and herbal formulations were investigated as modulators of Akt1-centered signaling. In silico screening of Scutellaria barbata identified apigenin as a strong Akt1-binding flavonoid with stable molecular dynamics behavior. Comparative metabolomic and network pharmacology analyses of Clerodendrum species also highlighted Akt1 and PIK3CA as core docking targets for candidate bioactive ingredients. Shenling Baizhu Powder was associated with Akt1 among its core targets in ulcerative colitis models, with downstream changes in Akt1, p-Akt1, mTOR, and related inflammatory proteins measured in colon tissue. In hepatocellular carcinoma, a synthesized urolithin derivative inhibited phosphorylation of AKT and ERK1/2, consistent with suppression of PI3K/Akt and MAPK signaling.

Outside oncology, Akt1-related signaling was also connected to metabolic regulation. exercise-induced lactate improved insulin resistance in obese mice and adipocytes through GPR81-dependent activation of the IRS1-AKT-GLUT4 pathway, illustrating a non-cancer context in which AKT signaling contributed to glucose uptake and adipokine balance. In lung adenocarcinoma toxicology analyses, Akt1 emerged as one of several hub targets associated with PFAS exposure, although the study focused on predicted toxicological networks rather than direct pathway validation. Overall, these recent publications position FGF2-PI3K-Akt1 signaling within a broader landscape of FGF/PI3K/Akt pathway regulation, with evidence pointing to roles in cancer progression, natural product pharmacology, and metabolic control.

Key Publications

• NEWJun In silico screening and molecular analyses identify apigenin from Scutellaria barbata as a potent AKT1 inhibitor in breast cancer. (PloS one, 2026, PMID 42348584): "Network analysis identified AKT1, IL6 and TNF as central hub targets, significantly enriched in the PI3K-Akt, MAPK, and TNF signaling pathways."
• NEWJun Multi-omics investigation of per- and polyfluoroalkyl substances in lung adenocarcinoma: comprehensive network toxicology, machine learning and molecular docking experiments. (Molecular diversity, 2026, PMID 42334505): "Consequently, we identified six hub toxicological targets: HSP90AA1, EGFR, AKT1, ALB, SRC, and ESR1, highlighting their potential central roles in PFAS-driven LUAD pathogenesis."
• NEWJun Integrated multi-omics profiling of treatment-naive cervix uteri premalignant lesions and cervical squamous cell carcinoma reveals ecosystem and drivers underlying cervical cancer progression. (Cell death & disease, 2026, PMID 42265073): "Moreover, ISG15, synthesized by inflammatory cancer-associated fibroblasts (CAFs), enhances the stability of FGF1, thereby activating the FGF1/FGFR1/PI3K/AKT/mTOR signaling pathway."
• Jun Comparative metabolomic profiling and potential bioactive marker discovery of three Clerodendrum species and their different plant parts. (Fitoterapia, 2026, PMID 42235855): "molecular docking verification confirmed that these ingredients exhibited favorable binding activities against core targets PIK3CA and AKT1."
• Jun Integrative Database-Driven In Silico and In Vitro Study of Anemarrhena asphodeloides Bunge Highlighting Hippeastrine as a Regulator of the HSP90/PI3K/Akt/mTOR Axis in Oral Squamous Cell Carcinoma. (Advanced biology, 2026, PMID 42216572): "...demonstrated stable binding of key bioactive compounds with HSP90 and AKT1, highlighting hippeastrine as a promising candidate."
• Jun Integrated Serum Pharmacochemistry, Metabolomics, and Network Pharmacology Uncover Potential Active Components and Mechanisms of Shenling Baizhu Powder in Treating Ulcerative Colitis With Spleen Deficiency and Dampness Stagnation. (Biomedical chromatography : BMC, 2026, PMID 42089391): "...six core targets (BCL2, NFKB1, TNF, IL6, AKT1, CASP3) were obtained using serum pharmacochemistry and network pharmacology."
• Jun Exercise ameliorates adipose tissue insulin resistance by activating the lactate/GPR81 signaling pathway in DIO-IR mice. (American journal of physiology. Endocrinology and metabolism, 2026, PMID 41989764): "Mechanistically, lactate/GPR81 signaling potentiated glucose uptake in IR-3T3-L1 adipocytes via the insulin receptor substrate 1 (IRS1)-AKT-glucose transporter 4 (GLUT4) pathway."
• Apr Scutellarein inhibits the malignancy of gliomas by modulating the PI3K/AKT signaling pathway. (Biochemical and biophysical research communications, 2026, PMID 41966746): "Network pharmacology and transcriptomic analyses suggested that scutellarein may target SRC, EGFR, and AKT1; and exerts its effects through the PI3K/AKT signaling pathway, which was subsequently verified by further experiments."
• Jun Integrative network pharmacology and molecular simulation analysis reveals the therapeutic potential of Coscinium fenestratum alkaloids against SARS-CoV-2. (Biochemical and biophysical research communications, 2026, PMID 41967451): "STAT3/AKT1 are the most important hubs (centrality 140, 172) that cause the dysregulation of PI3K-Akt and JAK-STAT, which is a key part of the variant-independent COVID-19 cytokine storm pathophysiology."
• Jun Synthesis and evaluation of Urolithins derivatives as anticancer agents for hepatocellular carcinoma: In vitro, molecular docking, and dynamics simulations. (Bioorganic chemistry, 2026, PMID 41855633): "Moreover, integrated network pharmacology and molecular docking analyses identified several key targets, including EGFR, AKT1, MAPK1, and CASP3, suggesting a multi-target mechanism involving regulation of the PI3K/Akt and MAPK signaling pathways."