PI3K/Akt signaling pathway

Overview

The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is one of the most frequently activated intracellular signaling cascades in human biology, governing fundamental cellular processes including proliferation, survival, metabolism, angiogenesis, and apoptosis. The pathway is initiated when extracellular stimuli — such as growth factors, cytokines, or receptor tyrosine kinase ligands — activate PI3K, a lipid kinase that phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits Akt (also known as PKB) to the plasma membrane, where it is phosphorylated and activated by PDK1. Active Akt then phosphorylates a broad array of downstream substrates, including mTOR, FOXO transcription factors, GSK-3β, and members of the B-cell lymphoma 2 (BCL-2) family, thereby integrating survival signals, suppressing apoptotic markers, and coordinating metabolic reprogramming. The tumor suppressor PTEN antagonizes this pathway by dephosphorylating PIP3, serving as a critical brake on unchecked Akt activation.

Given its central role in cell fate decisions, dysregulation of the PI3K/Akt signaling pathway is implicated in a wide spectrum of diseases — most prominently cancer, metabolic disorders, neurodegeneration, inflammatory conditions, and reproductive pathologies. Its intersection with parallel cascades such as the MAPK/RAS pathway, the JAK-STAT axis, the nuclear factor kappa B (NF-κB) network, and hypoxia-inducible factor-1α (HIF-1α) signaling makes it a nexus point for multi-pathway therapeutic targeting. Accordingly, PI3K/Akt modulators — both activating and inhibitory — represent some of the most intensively pursued targets in modern pharmacology and translational medicine.

Focus of Latest Publications

Recent investigations have extensively explored PI3K/Akt pathway inhibition as a therapeutic strategy to enhance cancer cell death and chemotherapy sensitivity across multiple malignancy types. In multiple myeloma, MYBL2 knockdown promoted ferroptosis and enhanced bortezomib sensitivity through transcriptional regulation of CDKN3 and inactivation of PI3K/Akt signaling. Natural compounds including scutellarein suppressed proliferation and induced apoptosis in oral squamous cell carcinoma and glioma by modulating the PI3K/Akt pathway. In cervical cancer, simvastatin enhanced cisplatin sensitivity in resistant cells by suppressing caveolin-1-mediated PI3K/AKT signaling, with rescue experiments confirming the critical role of this suppression in chemoresistance. Similarly, psoralen inhibited renal cell carcinoma proliferation through downregulation of PI3K/AKT pathway-related genes, while saikosaponin D and urolithins derivatives targeting PI3K/Akt-mediated ferroptosis demonstrated activity in bladder cancer and hepatocellular carcinoma, respectively. These studies establish PI3K/Akt inhibition as a convergent therapeutic mechanism for enhancing anti-tumor efficacy and circumventing chemotherapy resistance.

In contrast, PI3K/Akt pathway activation emerged as beneficial in regenerative and neurodegenerative disease contexts. A multifunctional polysaccharide-based hydrogel activated PI3K/Akt alongside MAPK/ERK and Rho GTPase pathways to promote endothelial proliferation and accelerate infected wound healing through macrophage-to-myofibroblast transition. K777, a cysteine protease inhibitor, promoted functional motor recovery after spinal cord injury by activating the PI3K/AKT pathway in a dose-dependent manner while reducing oxidative stress and suppressing neuronal apoptosis. CD73-positive mesenchymal stem cells improved diabetic pressure ulcer healing through CD73-dependent regulation of PI3K/Akt activation, which enhanced vascular endothelial growth factor A expression and angiogenesis. Ginkgolide B, a component of Ginkgo biloba, alleviated post-stroke cognitive impairment through exosomal miR-299a-3p regulation of the TRIL/PI3K/AKT axis, with increased phosphorylated PI3K/AKT correlating with enhanced cell proliferation, reduced apoptosis, and decreased oxidative stress.

Dysregulation of the PI3K/Akt pathway contributed to disease pathogenesis in non-malignant contexts. In polycystic ovary syndrome, thrombospondin-1-mediated suppression of PI3K/AKT pathway activity represented a critical pathogenic mechanism; restoration of pathway activity through THBS1 knockdown correlated with improved outcomes in cell and animal models. Conversely, in breast cancer, ubiquitin-like protein UBD promoted malignant progression by driving epithelial-mesenchymal transition through PI3K/AKT pathway activation, with pathway inhibitors suppressing UBD-induced increases in migration, invasion, and EMT marker expression.

Across diverse therapeutic contexts, PI3K/Akt signaling frequently integrated with complementary pathways to regulate cellular outcomes. berberine enhanced cisplatin efficacy through concurrent modulation of the PI3K/Akt pathway and efferocytosis mechanisms. Biomaterial-based and pharmaceutical approaches coordinated PI3K/Akt activation with MAPK/ERK, Rho GTPase, and hypoxia-inducible factor-1α signaling to orchestrate tissue regeneration and angiogenesis. The pathway's consistent involvement as a central regulatory hub across diverse cancers and regenerative diseases—coupled with its integration into multi-pathway signaling networks—underscores its fundamental role in controlling cell viability, proliferation, differentiation, and programmed cell death.

Key Publications

• NEWJul MYBL2 Knockdown Enhances Ferroptosis and Bortezomib Sensitivity by Transcriptionally Regulating CDKN3 and Inactivating PI3K/Akt Signaling in Multiple Myeloma. (Journal of biochemical and molecular toxicology, 2026, PMID 42345518): "CDKN3 overexpression prevented the effects of si-MYBL2 on ferroptosis and BTZ sensitivity in MM cells by interacting with the PI3K/Akt signaling pathway."
• Jun Scutellarein Induces Apoptosis in SCC-25 Oral Squamous Cell Carcinoma Cells Through Suppression of the PI3K/Akt Pathway. (Anticancer research, 2026, PMID 42203337): "Scutellarein induces apoptosis in SCC-25 oral squamous cell carcinoma cells through suppression of the PI3K/Akt pathway."
• May THBS1: a biomarker for PCOS and its role in pathogenesis via the PI3K/AKT signaling pathway. (Mammalian genome : official journal of the International Mammalian Genome Society, 2026, PMID 42165848): "THBS1 participates in PCOS pathogenesis by negatively regulating this pathway."
• Jun ZnO-integrated konjac glucomannan/Bletilla striata hydrogel with antibacterial, anti-inflammatory, and pro-angiogenic properties for accelerated infected wound healing. (International journal of biological macromolecules, 2026, PMID 42103129): "the hydrogel's bioactive matrix triggers endothelial proliferation and migration through the integrated activation of PI3K/Akt, MAPK/ERK, and Rho GTPase pathways."
• May Simvastatin Restores Cisplatin Sensitivity by Suppressing the Caveolin-1-Mediated PI3K/AKT Signaling Pathway in Cisplatin-Resistant Cervical Cancer Cells. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42087353): "simvastatin enhanced cisplatin sensitivity by suppressing the CAV1-mediated PI3K/AKT pathway involvement in the development of cisplatin resistance in cervical cancer cells."
• Apr K777 promotes functional recovery after spinal cord injury via the PI3K/AKT signaling pathway. (Biochemical and biophysical research communications, 2026, PMID 42061005): "Mechanistically, K777 activated the PI3K/AKT signaling pathway in a dose-dependent manner."
• Apr Berberine enhances cisplatin efficacy in ehrlich ascites carcinoma via modulation of apoptotic pathway and efferocytosis. (Scientific reports, 2026, PMID 42049890): "In conclusion, berberine showed promising effects on the PI3K/Akt pathway and efferocytosis, reducing cisplatin's side effects and EAC proliferation."
• Apr Exploration of the mechanism by which Ubiquitin-like protein UBD promotes malignant progression of breast cancer. (Medical oncology (Northwood, London, England), 2026, PMID 42043695): "KEGG pathway analysis indicated that differentially expressed genes were significantly enriched in the PI3K/AKT signaling pathway."
• Apr Scutellarein inhibits the malignancy of gliomas by modulating the PI3K/AKT signaling pathway. (Biochemical and biophysical research communications, 2026, PMID 41966746): "...and exerts its effects through the PI3K/AKT signaling pathway, which was subsequently verified by further experiments."
• Jun Folium Isatidis suppresses PCV2 replication and alleviates PCV2-induced lung injury by modulating the PI3K/AKT signaling pathway and TNF-α activity. (International immunopharmacology, 2026, PMID 41966777): "Folium Isatidis suppresses PCV2 replication and alleviates PCV2-induced lung injury by modulating the PI3K/AKT signaling pathway and TNF-α activity."