How does the mTOR pathway work?

Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and the catalytic subunit of two distinct multiprotein complexes, mTORC1 and mTORC2. It is also referred to in the literature as FKBP12-rapamycin-associated protein (FRAP) and rapamycin and FKBP12 target 1 (RAFT1). The EVIDENCE block supplied for this page does not give a sequence, formula or molecular weight for mTOR, so none is stated here.

The work summarised below centres on the PI3K/AKT/mTOR signalling axis and its upstream negative regulator PTEN, together with the PPAR and RhoA pathways that intersect it in the models studied.

Research Studies

LL-37 and SQLE-mediated cholesterol synthesis in osteosarcoma cells

In in vitro work using osteosarcoma (OS) cell lines alongside normal human bone marrow mesenchymal stem cells (hBMSCs), LL-37 was reported to inhibit OS progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway [1]. Assays covered cell viability, clonogenic survival, migration, invasion, cell cycle distribution, cell death and cholesterol metabolism, with transcriptomic profiling and siRNA knockdown used to probe the mechanism [1]. The authors describe LL-37 as a human cathelicidin peptide with context-dependent anti-tumour effects, and note that its role in OS had been largely undefined before this study [1]. These are cell-culture findings; no animal or human outcome data are reported in the evidence supplied.

Intramuscular fat deposition in Yanbian yellow cattle

Sixty 24-month-old Yanbian yellow cattle (n = 30 per group), reared under standardised environmental and dietary conditions, were divided into high-intramuscular-fat (HM) and low-intramuscular-fat (LM) groups [2]. HM beef showed significantly higher intramuscular fat (P < 0.05), increased monounsaturated fatty acids and reduced saturated fatty acids relative to LM [2]. Integrated transcriptomics and non-targeted metabolomics (n = 8 per group) associated intramuscular fat deposition with a dual-layered framework: an upstream signalling layer comprising PPAR, PI3K-Akt and mTOR pathways, and a downstream metabolic execution layer involving lysine degradation [2]. This is a cattle study, not a human study.

Fingolimod and interstitial fibrosis in kidney transplant recipients

A randomised, double-blind, placebo-controlled trial in de novo kidney transplant patients is testing whether adding fingolimod (FTY720) to standard immunosuppression prevents expansion of the interstitial compartment of the transplanted kidney [4]. Interstitial expansion is described as the precursor of interstitial fibrosis and graft loss [4]. The stated hypothesis is that abrogating the fibrogenic effects of both the RhoA and mTOR pathways with fingolimod will reduce structural damage in transplanted kidneys and possible subsequent transplant failure [4]. This is a registered trial protocol; results are not reported in the evidence supplied.

Alpha ketoglutarate and surgical inflammatory response in colorectal cancer

The RISIS-CR trial proposes to identify inflammatory responsiveness in patients before colorectal cancer (CRC) surgery and to administer prophylactic anti-inflammatory treatment only to those showing an excessive pro-inflammatory response [3]. The study team frames this as personalised medicine, treating the appropriate patients while avoiding further suppression of the inflammatory response in those who already have poor immune function [3]. The proposal intends to use alpha ketoglutarate (AKG), described as a geroprotector supplement, on the basis that geroprotectors reduce inflammation and may reduce postoperative systemic inflammatory response and complications after CRC surgery [3]. This is a registered trial protocol; results are not reported in the evidence supplied.

lncRNA DANCR and osteogenic differentiation of bone marrow mesenchymal stem cells

Work on long non-coding RNA DANCR examined its role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanism, in the context of osteoporosis [5]. BMSCs were intervened with sh-DANCR, and the study reports a regulatory role for DANCR acting through the miR-19a-3p/PTEN/AKT/mTOR pathway [5]. This is a cell-based mechanistic study.

Anlotinib and c-MET/AKT/mTOR signalling in glioma cells

Glioma is described as difficult to treat because malignant cells show rapid proliferation, diffuse invasion and frequent recurrence [6]. This study investigated the direct antitumour effects of anlotinib in human glioma cells and examined whether those effects were associated with hepatocyte growth factor receptor (c-MET)/AKT/mTOR signalling and altered autophagy-associated protein expression [6]. The reported outcome was inhibition of glioma cell proliferation, migration and invasion [6]. These are in vitro findings in human glioma cell lines.

Pharmacological mTOR activation in bovine embryos

Blastocyst formation is a highly orchestrated process involving multiple cellular and molecular aspects [7]. In mice, the mTOR pathway influences the Hippo pathway, leading to expression of trophectoderm (TE)-related genes, but these mechanisms are not fully characterised in bovine embryos [7]. The study reports that pharmacological mTOR pathway activation did not enhance trophectoderm differentiation in bovine embryos [7]. This is an embryo model, not a human study.

Mitochondria-enriched BMSC exosomes in Parkinson's disease models

Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD) [8]. While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is described as limited, so mitochondrial-enriched sEVs (Exo-Mito) were engineered [8]. The study reports restoration of microglia-neuron cross-talk via the PINK1/parkin and PI3K/Akt/mTOR pathways [8]. This is preclinical work.

Comparison of study models and reported mTOR-axis involvement

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Sources

• [1] LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway — https://europepmc.org/article/PMC/PMC13321046
• [2] Integrated transcriptomics and metabolomics reveal the molecular mechanisms of intramuscular fat deposition in Yanbian yellow cattle — https://pubmed.ncbi.nlm.nih.gov/42025074/
• [3] Reducing Inflammatory Syndrome in Surgery - Colorectal (RISIS-CR) Trial — https://clinicaltrials.gov/study/NCT06646809
• [4] Fingolimod for the Abrogation of Interstitial Fibrosis and Tubular Atrophy Following Kidney Transplantation — https://clinicaltrials.gov/study/NCT05285878
• [5] Regulatory role of lncRNA DANCR in osteogenic differentiation of bone marrow mesenchymal stem cells through targeting the miR-19a-3p/PTEN/AKT/mTOR pathway — https://pubmed.ncbi.nlm.nih.gov/42686955/
• [6] Anlotinib inhibits glioma cell proliferation, migration, and invasion by suppressing c-MET/AKT/mTOR signaling and altering autophagy-associated protein expression — https://pubmed.ncbi.nlm.nih.gov/42687323/
• [7] Pharmacological mTOR pathway activation does not enhance trophectoderm differentiation in bovine embryos — https://pubmed.ncbi.nlm.nih.gov/42641359/
• [8] Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways — https://pubmed.ncbi.nlm.nih.gov/42556769/