PI3K/Akt signaling pathway

Overview

The PI3K/Akt pathway carries signals from cell-surface receptors to the machinery controlling growth, survival, metabolism, motility and angiogenesis, and is among the most frequently dysregulated pathways in human disease. Growth factors and cytokines acting through receptor tyrosine kinases recruit class I phosphoinositide 3-kinase, a lipid kinase built from a regulatory subunit and one of four catalytic subunits — p110α, p110β, p110δ and p110γ, encoded by PIK3CA, PIK3CB, PIK3CD and PIK3CG, whose distinct tissue distributions matter for which isoform a drug should hit. The activated enzyme phosphorylates PIP2 to PIP3, a membrane lipid that recruits Akt through its PH domain; PDK1 and mTORC2 then phosphorylate Akt at two sites to activate it fully. Active Akt phosphorylates mTOR, FOXO transcription factors, GSK-3β and the pro-apoptotic protein BAD, promoting protein synthesis and cell-cycle progression while suppressing the apoptotic program — which is why caspase-3 activation falls when the pathway is on and rises when it is blocked. The tumor suppressor PTEN removes the 3-phosphate from PIP3 and is the pathway's principal brake; its loss leaves Akt constitutively active.

Constitutive activation is accordingly a hallmark of many Cancers, including lung adenocarcinoma, hepatocellular carcinoma, oral squamous cell carcinoma, breast cancer, glioma and multiple myeloma, where it supports epithelial–mesenchymal transition, metastasis, and resistance to agents such as cisplatin, gemcitabine and bortezomib. It intersects with cell-death programs beyond apoptosis, including ferroptosis, and with redox and inflammatory biology through reactive oxygen species handling, Toll-like receptor signaling and NF-κB. It also runs alongside the RAS/MAPK, JAK-STAT and HIF-1α axes, and reciprocal relief of feedback between those cascades is the usual reason single-agent inhibition disappoints — one of several arguments for combination targeting.

Because the same pathway transmits insulin's metabolic signal, inhibiting it produces hyperglycemia as a mechanism-based class effect, which has constrained dosing throughout its development. Clinical progress has come from narrowing the target: isoform-selective PI3K inhibitors matched to a mutation, Akt inhibitors, and mTOR inhibitors such as everolimus, rather than pan-PI3K blockade. Inhibition is not always the goal — in wound healing, stem cell–based nerve repair, and mesenchymal stem cell or exosome-delivered growth factor therapies, PI3K/Akt activation is what is wanted. Upstream receptor tyrosine kinase inhibitors such as gefitinib reduce flux through the pathway indirectly, and natural products reported to modulate it, among them berberine and naringenin, remain a large preclinical literature whose in vivo relevance is mostly unsettled.

Recent Publications Summary

Recent studies have repeatedly implicated PI3K/Akt signaling as a mechanistic node in cancer progression, treatment resistance, and therapeutic response. In lung adenocarcinoma, COX7A2L was reported to promote proliferation, migration, invasion, and radioresistance, with these effects associated with altered reactive oxygen species levels and activation of PI3K/AKT signaling; pharmacological inhibition of the pathway attenuated the malignant and radioresistant phenotypes 42508754Jul. Similarly, OSTC and TUBA1C were described as drivers of LUAD malignancy through modulation of N-glycosylation and PI3K/AKT signaling, and silencing either gene suppressed malignant cell behaviors 42464299Jul. In hepatocellular carcinoma, leonurine inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition by suppressing PI3K/AKT activation, with additional antitumor effects observed in vivo and synergy with the PI3K inhibitor LY294002 42429151Jul. Agomelatine and gefitinib were also reported to reduce HepG2 cell viability and induce apoptosis while inhibiting PI3K/AKT-related gene expression 42461339Jul.

Several publications linked PI3K/Akt signaling to chemosensitivity, ferroptosis, and apoptosis. In multiple myeloma, MYBL2 knockdown enhanced ferroptosis and bortezomib sensitivity, and CDKN3 overexpression reversed these effects through interaction with PI3K/Akt signaling 42345518Jun. In bladder cancer, saikosaponin D was reported to inhibit tumor growth and enhance the antitumor effect of gemcitabine by targeting PI3K/AKT-mediated ferroptosis 41935433Apr. In cervical cancer, simvastatin restored cisplatin sensitivity in cisplatin-resistant cells by suppressing caveolin-1-mediated PI3K/AKT signaling 42087353May. berberine likewise enhanced cisplatin efficacy in Ehrlich ascites carcinoma while downregulating Akt1 and efferocytosis-related genes 42049890Apr. Scutellarein was reported to induce apoptosis in SCC-25 oral squamous cell carcinoma cells through suppression of the PI3K/Akt pathway 42203337May, and another study found that scutellarein inhibited glioma malignancy by modulating PI3K/AKT signaling and triggering oxidative stress-associated apoptosis 41966746Apr. In renal cell carcinoma, psoralen showed antiproliferative activity and was linked to PI3K/AKT pathway involvement, with molecular docking suggesting strong binding to PIK3CA 41929235Apr. Urolithin derivatives were also proposed to act through multi-target regulation involving PI3K/Akt and MAPK signaling in hepatocellular carcinoma 41855633Mar.

Beyond oncology, PI3K/Akt signaling was connected to tissue repair, inflammation, and regenerative responses. ADSC-derived exosomes carrying bFGF were reported to promote skin wound healing and correlate with PI3K/AKT activation 42461467Jul. CD73-positive adipose-derived mesenchymal stem cells improved diabetic pressure ulcer healing, with PI3K/Akt activation contributing to accelerated wound closure 41819469Mar. A ZnO-integrated hydrogel promoted infected wound healing and endothelial proliferation/migration through activation of PI3K/Akt among other pathways 42103129May, while a CeO2-loaded hydrogel combined with dental pulp stem cells modulated the oxidative-inflammatory microenvironment and alleviated cellular oxidative damage via PI3K/AKT signaling 42343878Jun. In spinal cord injury, K777 improved neuronal viability, reduced oxidative stress and apoptosis, and promoted axonal growth, with the study identifying PI3K/AKT as part of its mechanism 42061005Apr. In post-stroke cognitive impairment, Ginkgolide B was associated with increased PI3K/AKT phosphorylation through an exosomal miR-299a-3p/TRIL axis 41819672Mar. Additional studies reported PI3K/AKT involvement in inflammatory and immune-related conditions, including THBS1-associated PCOS pathogenesis 42165848May, Huangqin Qingre Chubi Capsule in ankylosing spondylitis via the lncRNA AP005432.1/PI3K/AKT axis 41956229Apr, and Yinhuapinggan granules in Streptococcus pneumoniae-induced lung inflammation 42423763Jul.

What Changes, What Holds

1. PI3K/Akt remains a central driver of malignancy, but these data sharpen its links to ROS and radioresistance in lung adenocarcinoma and to druggable upstream modifiers in hepatocellular carcinoma
REINFORCES The new studies extend the established cancer role of PI3K/Akt rather than revising it: they support its involvement in proliferation, invasion, EMT, and treatment resistance, while adding specific upstream factors that converge on the pathway. The practical implication is that pathway inhibition still looks broadly relevant, with 42508754Jul and 42429151Jul strengthening the case for combination strategies rather than changing the baseline model.

2. PI3K/Akt is now more clearly tied to ferroptosis-linked drug response, but the pathway’s pro-survival role remains intact
REINFORCES These reports do not overturn the baseline view that PI3K/Akt supports resistance to cisplatin, gemcitabine, and bortezomib; instead, they connect that resistance to ferroptosis control and apoptosis suppression in several tumor types. That makes the pathway look like a shared node for sensitization strategies, not a different kind of biology. The most useful addition is mechanistic specificity, especially for 42345518Jun and 41935433Apr.

3. PI3K/Akt is gaining support as a repair and anti-inflammatory axis outside cancer, especially in wound healing and injury recovery
NEW DIRECTION The Overview already noted regenerative uses, and these studies broaden that role into additional tissue-repair settings rather than contradicting it. What changes is the range of contexts in which activation appears beneficial: wound closure, infected wounds, spinal cord injury, and post-stroke cognitive impairment all point to PI3K/Akt as a recovery-associated pathway. The inflammatory disease findings also fit this extension, with 42461467Jul and 42061005Apr adding to the non-oncologic use case.