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 (SIRT1), MAPK signaling pathway, and Yes-associated protein 1 (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.

Recent Publications Summary

Recent publications have continued to position the PI3K/AKT/mTOR pathway as a central signaling axis across diverse disease models, with multiple studies linking its modulation to anti-fibrotic, anti-tumor, neuroprotective, and reproductive effects. In idiopathic pulmonary fibrosis, integrated single-cell RNA sequencing and bulk RNA sequencing identified enrichment of PI3K-Akt signaling in IPF-associated epithelial cells, and network pharmacology ranked the PI3K-Akt pathway as the top enriched cascade for the Sanleng-Ezhu herb-pair; in a bleomycin-induced murine model, this treatment improved lung histopathology, reduced inflammatory infiltration, and alleviated fibrotic remodeling, with the abstract indicating mechanistic suppression of the pathway 42362788Jun. In ischemic stroke, Huangqi Guizhi Wuwu Decoction was reported to promote neuroprotection and functional recovery through activation of PI3K/Akt/mTOR signaling and modulation of microglial polarization 41887379Mar. In oligoasthenospermia, ShenRongGuBenHuanShao Pill was likewise described as ameliorating oxidative stress and DNA damage via activation of the PI3K/Akt/mTOR pathway 41747791Feb.

Several cancer-focused studies reported inhibitory effects on PI3K/AKT/mTOR signaling as part of their antitumor mechanisms. In breast cancer MCF-7 cells, combined ivermectin and metformin treatment significantly reduced viability, proliferation, migration, and invasiveness, and transcriptomic analysis showed enrichment of the PI3K/AKT/mTOR signaling pathway; the study specifically states that the combination promoted autophagy by inhibiting phosphorylation of this pathway 42138203May. In ovarian cancer, dimethyl bisphenolate suppressed cell growth, migration, energy metabolism, and induced cell cycle arrest and apoptosis, with mechanistic studies attributing these effects to regulation of PI3K/AKT/mTOR signaling 41864114Mar. In hepatocellular carcinoma, the AP5Z1 small-molecule inhibitor PGG was evaluated for antitumor activity, but the abstract provided does not specify PI3K/AKT/mTOR-related findings beyond the general mechanistic workup 42347921Jun. In pancreatic neuroendocrine neoplasms, EZH2 inhibition by GSK126 induced ferroptosis and suppressed tumor growth, with mechanistic studies showing that GSK126 acts by inhibiting PI3K/AKT/mTOR signaling; the same report also noted that HMGCS1 may activate this pathway and that combining GSK126 with everolimus more effectively inhibited the disease model 42013002Apr.

Other recent studies linked PI3K/AKT/mTOR signaling to metabolic and carcinogenic contexts. In pancreatic ductal adenocarcinoma, high intrapancreatic fat deposition was associated with increased FABP5 and MKI67 expression and upregulation of the JAK/STAT, PI3K/AKT/mTOR, and Ras/Raf/MEK/ERK pathways, alongside accelerated tumor growth and metastasis in mouse models 42251134Jun. In breast cancer progression driven by di-(2-ethylhexyl) terephthalate exposure, molecular docking identified PIK3CA among the high-affinity carcinogenic targets, and experimental validation showed concentration-dependent promotion of tumor cell proliferation with increased PTPN11 and ESR1 protein levels 41780785Mar. In a chemopreventive mammary cancer model, brucine-gold nanoparticles were reported to reduce tumor incidence, burden, and oxidative damage while improving antioxidant defenses, with the study centered on modulation of the PI3K/AKT/mTOR pathway 41824269Mar. Review articles in meningioma and ovarian aging also highlighted PI3K/AKT/mTOR as a therapeutically relevant or longevity-associated pathway, with meningioma reviews discussing targeted agents such as everolimus and ovarian aging reviews describing PI3K/AKT/mTOR dysregulation as a contributor to follicular activation, granulosa cell apoptosis, and oocyte quality decline 42017452Apr41833148Mar.

What Changes, What Holds

1. PI3K/AKT/mTOR signaling remains a broadly implicated disease axis, now extending into fibrotic, neuroprotective, and reproductive models
REINFORCES These studies do not alter the baseline view of the pathway as a central regulator of growth, survival, metabolism, and stress responses; they mainly broaden the range of contexts in which that role is being applied. The anti-fibrotic, neuroprotective, and fertility-related findings are consistent with the pathway’s established importance in disease modulation, but they do not displace any baseline mechanism. The evidence is preclinical and mechanistically suggestive, so it sharpens breadth rather than changing direction 42362788Jun41887379Mar.

2. Recent antitumor studies continue to support PI3K/AKT/mTOR as a therapeutic node, with inhibition often linked to reduced malignancy
REINFORCES These reports fit the established account that dysregulation of the pathway is relevant to cancer and that pathway-directed modulation can be therapeutically useful. The new work adds more examples of tumors in which suppressing PI3K/AKT/mTOR signaling accompanies reduced proliferation, migration, survival, or growth, and one study even pairs this with everolimus as a comparator or combination partner. Nothing here overturns the baseline; it strengthens the pathway’s standing as a common mechanistic target in oncology 42138203May42013002Apr.

3. Metabolic and carcinogenic exposures are increasingly being mapped onto PI3K/AKT/mTOR, but the baseline role is unchanged
REINFORCES These findings extend the pathway’s known integration with metabolic stress and cancer biology rather than revising it. The association with fat deposition, carcinogen-related signaling, and chemopreventive intervention is compatible with the overview’s description of PI3K/AKT/mTOR as a node linking growth, metabolism, and disease. Review-level discussion in meningioma and ovarian aging also stays within the established frame of therapeutic relevance and aging-related decline. The main update is breadth of application, not a new biological direction 42251134Jun41824269Mar.