PI3K/AKT/mTOR pathway
PI3K/AKT/mTOR pathway
Overview
The PI3K/AKT/mTOR pathway is a central intracellular signaling cascade that regulates cell growth, survival, metabolism, protein synthesis, autophagy, and stress responses. It is commonly activated by upstream growth factors and other extracellular cues, leading to sequential signaling through phosphoinositide 3-kinase (PI3K), AKT, and mechanistic target of rapamycin (mTOR). Because of its broad control over proliferation and survival, dysregulation of this pathway is implicated in cancer, inflammatory disease, aging-related decline, and other disorders.
In biomedical research, the PI3K/AKT/mTOR pathway is frequently studied as both a mechanistic node and a therapeutic target. Its activity is often interpreted alongside related regulators such as PTEN, Akt1, PRKAA1/AMPK, sirtuin 1, MAPK pathway, and YAP1, reflecting its integration with other growth and stress-response networks. Pharmacologic modulation of this pathway is also relevant to agents such as everolimus and sirolimus, which are used as pathway-directed comparators or interventions in translational studies.
Focus of Latest Publications
Recent studies have used the PI3K/AKT/mTOR pathway as a mechanistic target in a wide range of disease models, often to explain how experimental compounds, natural products, or combination therapies alter cell fate and tissue responses.
In metabolic research, one study on β-hydroxybutyrate in streptozotocin-induced type 1 diabetes reported that its effects on glucose metabolism were GPR109A dependent and linked to inhibition of the PI3K/AKT/mTOR pathway. The work used the mTOR inhibitor rapamycin and siRNA-mediated gene silencing to support this mechanism, and it examined glucose transport in the gut and liver. In a separate epidemiological, computational, and experimental study of per- and polyfluoroalkyl substances (PFAS) and gestational diabetes, network analyses identified PI3K-Akt among several regulatory pathways, alongside PPAR, AMPK, and FoxO signaling, suggesting that this pathway participates in hepatic metabolic network perturbation.
In oncology, the pathway was repeatedly described as a driver of tumor growth, survival, metastasis, and treatment resistance. A study of dimethyl bisphenolate in ovarian cancer found that the compound suppressed cancer cell growth by regulating the PI3K/AKT/mTOR signaling pathway, impairing energy metabolism, and inducing cell cycle arrest and apoptosis. Another study on brucine-gold nanoparticles (BRU-AuNPs) in DMBA-induced mammary cancer reported downregulation of phosphorylated PI3K, AKT, and mTOR, with concurrent upregulation of PTEN and PKD1, consistent with pathway suppression. In hepatocellular carcinoma, the small-molecule inhibitor PGG was reported to act by inhibiting AP5Z1-mediated ubiquitination and degradation of PTEN, thereby blocking downstream PI3K/AKT/mTOR signaling. Similarly, AURKA was linked to radioresistance in pancreatic cancer through GSK3β-mediated PTEN phosphorylation at T366, which impaired PTEN phosphatase activity and sustained activation of the pro-survival pathway.
Additional cancer-focused studies described the pathway as part of broader oncogenic signaling programs. High intrapancreatic fat deposition was associated with pancreatic ductal adenocarcinoma growth and metastasis, with RNA sequencing showing upregulation of PI3K/AKT/mTOR together with JAK/STAT and Ras/Raf/MEK/ERK signaling. In breast cancer, di-(2-ethylhexyl) terephthalate (DOTP) was suggested to promote progression by interfering with carcinogenic signaling pathways, primarily PI3K-Akt-mTOR. In sarcoma, genomic alterations were reported to activate PI3K/Akt/mTOR and MAPK pathways, with relevance to eIF4A-dependent translation. A study of HMGCS1 in pancreatic neuroendocrine neoplasms described resistance to EZH2 inhibition in a context involving ferroptosis mediated by the PI3K/AKT/mTOR pathway, and noted that GSK126 induced ferroptosis by inhibiting this pathway. A review of meningioma therapies also identified everolimus as a targeted agent against PI3K/AKT/mTOR signaling.
The pathway was also implicated in inflammatory, fibrotic, and regenerative contexts. In idiopathic pulmonary fibrosis, Sanleng-Ezhu was reported to exert therapeutic efficacy through suppression of the hyperactivated PI3K-AKT-mTOR signaling pathway. In inflammatory skin disease, a smart hydrogel-based strategy targeting CCR7 and JAK1 downregulated key proteins in the JAK-STAT and PI3K/AKT/mTOR pathways along with pro-inflammatory cytokines. In ischemic stroke, Huangqi Guizhi Wuwu decoction was reported to promote neuroprotection and functional recovery by activating PI3K/Akt/mTOR signaling and modulating microglial polarization. In oligoasthenospermia, ShenRongGuBenHuanShao Pill was described as improving oxidative stress and DNA damage via activation of the PI3K/Akt/mTOR pathway.
Several studies linked the pathway to autophagy and metabolic adaptation. A combination of ivermectin and metformin promoted autophagy in MCF-7 cells by inhibiting phosphorylation of the PI3K/AKT/mTOR pathway, and transcriptomic analysis showed enrichment of this signaling axis with reduced THBS1 expression. A broader review of bioactive natural products noted that many compounds regulate autophagy through AMPK, PI3K/AKT/mTOR, SIRT1, and FOXO pathways. Another review on aging and ovarian function highlighted dysregulation of PI3K/AKT/mTOR as a major longevity-related mechanism. In a related cancer study, CR-1-31B, BMS-309,403, and advanced radiation techniques were among the broader therapeutic contexts in which pathway modulation was considered relevant, especially where survival signaling and treatment response intersect.
Across these studies, the pathway consistently served as a mechanistic node connecting extracellular stimuli to cell survival, metabolism, autophagy, and disease progression. Depending on the disease context, investigators either sought to inhibit the pathway to suppress tumor growth, fibrosis, or pathological metabolism, or to activate it to support tissue repair and functional recovery.