E2F2/PI3K/AKT signaling pathway

Overview

The E2F2/PI3K/AKT signaling pathway refers to a functional signaling axis linking E2F2, a transcription factor involved in cell-cycle regulation, with the PI3K/AKT pathway, a central mediator of growth, survival, metabolism, and stress responses. In biomedical research, this pathway is typically discussed as a regulatory network rather than a single protein, because changes in E2F2 activity can intersect with PI3K/AKT-dependent control of downstream transcriptional programs and metabolic signaling.

Biologically, the PI3K/AKT arm is widely recognized for promoting cell survival and metabolic homeostasis, while E2F2 is associated with proliferation-related gene expression. Dysregulation of this axis has been implicated in cancer biology, metabolic disorders, and virus-associated metabolic perturbations. Recent studies have examined this pathway in contexts such as hepatitis C virus–associated glycolipid metabolism disorders, Metabolic dysfunction associated steatohepatitis (MASLD/MASH), and cancer cell proliferation, often alongside related signaling nodes including FoxO1, MYC, MAPK1, and the broader mitogen-activated protein kinase (MAPK) pathway.

Focus of Latest Publications

The most direct recent mention of this entity came from a study on hepatitis C virus-associated liver dysfunction. In that work, the authors reported that hepatitis C virus inhibits the E2F2/PI3K/AKT signaling pathway through miR-378b and contributes to glycolipid metabolism disorders in the liver. This places the pathway in a disease mechanism involving viral regulation of host metabolic signaling, with downstream consequences for hepatic glucose and lipid homeostasis.

Although most of the other recent papers focused on PI3K/AKT more broadly rather than E2F2 specifically, they provide important context for the pathway’s biological role. Several studies examined therapeutic activation of PI3K/AKT signaling in metabolic or regenerative settings. For example, nuciferine was reported to activate PI3K/AKT signaling via the insulin receptor (IR), improving insulin resistance and slowing progression of type 2 diabetes–associated cognitive impairment. Similarly, Xiaokeping combined with a low-carbohydrate diet was reported to activate the PI3K/Akt pathway in diabetic rats, and PPAR-γ modulation was described as restoring the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated Alzheimer’s pathology. These studies reinforce the pathway’s role in insulin responsiveness, neuronal protection, and metabolic stress adaptation.

In tissue repair and biomaterials research, PI3K/AKT signaling was repeatedly linked to regeneration. A DNA tetrahedron-mediated vascular targeted delivery system for astragaloside IV was reported to enhance distraction osteogenesis, with PI3K/AKT/FOXO signaling identified as the central downstream axis. Another study on tunable bio-inspired hybrid hydrogels found that stem cell-derived extracellular vesicles increased p-AKT/AKT in HaCaT keratinocytes, supporting wound regeneration. A separate dual-enzyme cascade protein hydrogel membrane was reported to orchestrate metabolism-immunity coupling for diabetic wound repair and to activate EGFR-associated PI3K/AKT/mTOR signaling, again highlighting the pathway’s role in tissue remodeling and repair.

Cancer-focused studies in the provided set also emphasized PI3K/AKT as a therapeutic target. Verbascoside was reported to induce apoptosis in endometrial cancer cells by targeting the LRIG2-PI3K/AKT/mTOR axis. Loureirin A showed anti-tumor effects in colorectal cancer cells via inhibition of AKT phosphorylation. Robinin was reported to attenuate DMH-induced colon cancer in Wistar rats by modulating Ras/PI3K/Akt/mTOR and NF-κB/Bax/caspase-3 signaling. In another colorectal cancer study, SOS1 inhibitors suppressed MAPK and PI3K signaling pathways, while YY-20394, a PI3Kδ inhibitor, reduced Akt phosphorylation in acute myeloid leukemia cells. These findings place PI3K/AKT within a broader oncogenic network involving KRAS, MAPK1, MYC, B-cell lymphoma 2, and caspase-3.

Additional studies linked PI3K/AKT signaling to inflammation, ulcer healing, and immune regulation. Sanhuang xiexin decoction was reported to ameliorate gastric ulcers by activating EGFR/PI3K/AKT signaling. Bie-Jia-Jian Pill was described as inhibiting tumor glycolysis and promoting CD8+ cell-mediated anti-tumor immunity by targeting HIF-1α-PI3K/AKT/mTOR and CCL20 in hepatocellular carcinoma. In breast cancer, downregulation of BASP1 suppressed proliferation and migration through inactivation of AKT and ERK signaling, and in esophageal squamous cell carcinoma, epigallocatechin gallate (EGCG) was studied in relation to EGFR/AKT/P38 signaling. Together, these reports show that PI3K/AKT is frequently positioned at the intersection of growth factor signaling, inflammatory control, and cell survival.

The pathway was also implicated in metabolic disease and liver pathology. In a rat model of metabolic syndrome and MASLD/MASH, hepatic insulin signaling biomarkers IRS-1 and Akt were impaired, with FOXO1 expression increased under monosodium glutamate exposure. Another study on calcitriol and candesartan examined modulation of the GLuR5/Ketohexokinase/FOXO1 axis, again reflecting the close relationship between AKT signaling and metabolic regulation. In a separate study, γ-sitosterol was computationally predicted to interact with AKT, supporting its potential as a multi-target modulator of apoptosis and survival signaling.

Key Publications

• NEWJul DNA tetrahedron-mediated vascular targeted delivery of astragaloside IV enhances distraction osteogenesis via PI3K/AKT/FOXO pathway. (Biomaterials, 2026, PMID 41713052): "Integrated network pharmacology, RNA sequencing, and molecular dynamics simulations identified PI3K/AKT/FOXO signaling as the central downstream axis."
• NEWJul Nuciferine ameliorates cognitive impairment and insulin resistance in T2DM by targeting the insulin receptor and activating PI3K/AKT signaling. (Chinese journal of natural medicines, 2026, PMID 42285687): "Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression."
• NEWJul Tunable bio-inspired hybrid hydrogels reprogram stem cell-derived extracellular vesicles for superior wound regeneration. (Biomaterials science, 2026, PMID 42383565): "Additional in vitro validation showed that 3D-hcEVs enhanced HaCaT migration and more strongly increased p-AKT/AKT than dcEVs at 30 and 60 min."
• NEWJul Epigallocatechin Gallate Attenuates Arecoline-induced Migration and Invasion in Esophageal Squamous Cell Carcinoma Cells Associated With EGFR/AKT/P38 Signaling. (Anticancer research, 2026, PMID 42373249): "Epigallocatechin gallate (EGCG), a major polyphenol in green tea, has exhibited anti-cancer and anti-metastatic activity in multiple tumor models."
• NEWJul Targeting the LRIG2-PI3K/AKT/mTOR Axis to Induce Apoptosis: A Novel Antitumor Mechanism of Verbascoside in Endometrial Cancer Cells. (Anticancer research, 2026, PMID 42373282): "Targeting the LRIG2-PI3K/AKT/mTOR Axis to Induce Apoptosis: A Novel Antitumor Mechanism of Verbascoside in Endometrial Cancer Cells."
• NEWJul Anti-tumor Effects of Loureirin A Treatment in Colorectal Cancer Cells via Inhibition of AKT Phosphorylation. (Anticancer research, 2026, PMID 42373290): "In this study, we aimed to investigate the anti-cancer effects and mechanisms of Loureirin A treatment in CRC."
• NEWJun Dual-enzyme cascade protein hydrogel membrane orchestrates metabolism-immunity coupling for diabetic wound repair. (Acta biomaterialia, 2026, PMID 42289263): "Concurrentl, GM/CEB activated EGFR-associated signaling pathways (PI3K/AKT/mTOR), thereby enhancing tissue regeneration and restoring dermal architecture."
• NEWJul Xiaokeping combined with low-carbohydrate diet slows cognitive decline in diabetic rats through activating TGF-β1/Smad7 signaling. (Biotechnic & histochemistry : official publication of the Biological Stain Commission, 2026, PMID 42324965): "Moreover, LCD and/or XKP treatment activated the PI3K/Akt pathway."
• NEWJul Robinin Attenuates Xenobiotic Enzymes, Inflammation, and Apoptosis on DMH-Induced Colon Cancer via Modulating Ras/PI3K/Akt/mTOR and NF-κB/Bax/Caspase-3 Signalling Pathways in Wistar Rats. (Journal of biochemical and molecular toxicology, 2026, PMID 42365609): "Targeting important signalling pathways, such as NF-κB and PI3K/Akt/mTOR/Ras, facilitated these results."
• NEWJul PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology. (Molecular biology reports, 2026, PMID 42377618): "The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory."