PI3K/Akt signaling pathway
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.
Recent Publications Focus
Below is a summary of the newest research publications targeting PI3K/Akt signaling pathway (sorted by publication date).
Recent studies have extensively validated PI3K/Akt pathway inhibition as a therapeutic strategy across multiple cancer types. In cervical cancer, simvastatin enhanced cisplatin sensitivity by downregulating caveolin-1-mediated PI3K/Akt signaling, resulting in suppressed tumor growth both in vitro and in vivo [42087353]. Similar mechanisms have been demonstrated in multiple myeloma, where MYBL2 knockdown promoted ferroptosis and bortezomib sensitivity through transcriptional regulation of CDKN3 and inactivation of PI3K/Akt signaling [42345518]. Multiple natural compounds have shown anticancer efficacy through PI3K/Akt suppression: scutellarein induced apoptosis in oral squamous cell carcinoma and inhibited glioma proliferation, invasion, and migration by triggering oxidative stress and suppressing the pathway [42203337, 41966746]; psoralen demonstrated potent antiproliferative effects against renal cell carcinoma with downregulation of PI3K/Akt signaling [41929235]; and urolithins derivatives suppressed hepatocellular carcinoma proliferation through PI3K/Akt and MAPK pathway inhibition [41855633]. Additional studies showed that saikosaponin D enhanced gemcitabine efficacy in bladder cancer through PI3K/Akt-mediated ferroptosis [41935433], and berberine improved cisplatin efficacy in adenocarcinoma by downregulating Akt1 [42049890].
In marked contrast, PI3K/Akt activation has emerged as critical for tissue regeneration and wound healing applications. A CeO2-loaded hydrogel combined with dental pulp stem cells modulated the injury microenvironment by activating PI3K/Akt to promote M2 macrophage polarization, significantly enhancing facial nerve regeneration [42343878]. A ZnO-integrated polysaccharide hydrogel similarly activated PI3K/Akt alongside MAPK/ERK pathways to drive endothelial proliferation and migration, achieving robust angiogenesis and collagen deposition in infected wound models [42103129]. In diabetic wound healing, CD73+ mesenchymal stem cells enhanced tissue repair through PI3K/Akt pathway activation, with CD73 regulating VEGFA expression under hypoxic conditions [41819469]. Matrix chirality from supramolecular hydrogels was shown to preferentially activate the PI3K-Akt pathway to establish coordinated signaling networks and improve diabetic ulcer healing through enhanced macrophage polarization [41933802].
Mechanistic investigations have identified novel regulators and biomarkers of PI3K/Akt signaling across diverse pathophysiologies. Thrombospondin-1 (THBS1) was identified as a key negative regulator in polycystic ovary syndrome; THBS1 knockdown restored PI3K/Akt pathway activity and alleviated PCOS pathology [42165848]. In breast cancer, ubiquitin-like protein UBD enhanced epithelial-mesenchymal transition through PI3K/Akt pathway activation, with pathway inhibition suppressing UBD-driven invasiveness [42043695]. K777, a cathepsin inhibitor, promoted functional recovery in spinal cord injury by activating PI3K/Akt in a dose-dependent manner, reducing oxidative stress and neuronal apoptosis [42061005]. Exosomal microRNA-299a-3p was identified as a regulator of PI3K/Akt in post-stroke cognitive impairment; ginkgolide B elevated miR-299a-3p and promoted PI3K/Akt phosphorylation, thereby reducing neuroinflammation [41819672].
Traditional Chinese medicine formulations have demonstrated therapeutic efficacy through PI3K/Akt pathway modulation in multiple clinical contexts. The Angelica sinensis and Ligusticum chuanxiong herb pair showed antidepressant potential through PI3K/Akt pathway involvement [41780614], while Simo Tang mitigated mitochondria-dependent apoptosis via PI3K/Akt pathway activation in chronic atrophic gastritis [41765119]. Folium Isatidis suppressed porcine circovirus replication and alleviated virus-induced lung injury through PI3K/Akt signaling modulation [41966777], and Safflower Wash Medicine has demonstrated clinical efficacy in acute soft tissue injury treatment via PI3K/Akt pathway mechanisms [41548617].