bims-matara 2026-11-08 papers

on MTOR

Issue of 2026–11–08
fifteen papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Adaptive induction of NFS1 links mTOR suppression to stemness-associated plasticity in glioblastoma.
TSC2-Mutant Yucatan Minipig Cardiac Rhabdomyoma Model Reveals mTORC1 Activation and MITF/TFE Expression Signature.
Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.
Protective effect of gossypin against high-fat diet-induced atherosclerosis in rats: Role of the phosphoinositide 3-kinase/AKT/mechanistic target of rapamycin pathway and gut microbiota.
Expression, association with clinicopathological features and prognostic potential of FOXR2, mTOR, HIF-1α and PKM2 in high-grade serous carcinoma of the ovary.
Bcl11a preserves hematopoietic stem cell function in culture by restraining Ncf1-dependent ROS.
Characterization of cancer stem-like cells derived from a single 4T1 murine triple-negative breast cancer cell: Involvement of Akt‒mTOR pathway in the proliferation and sphere formation.
Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.
A homozygous C2ORF78 variant is associated with mTOR hyperactivation and neurodevelopmental defects in focal cortical dysplasia.
Exogenous tryptophan aggravates experimental lung fibrosis through activation of AKT-mTORC1 pathway.
NEDD9 confers ferroptosis resistance in liver cancer by inhibiting autophagy via the AKT‑mTOR signaling pathway.
Aspartate inhibits mTORC1 activity and impairs reactivation of HIV-1 provirus.
Tuberous Sclerosis Complex in an Australian Adult Tertiary Centre: Surveillance Adherence and Outpatient Burden in a Fragmented Model of Care.
RICTOR regulates an interspecies crosstalk that influences longevity through a methionine cycle-mitophagy axis.
AICAR induces S phase cell cycle arrest in ESCC by targeting the AMPK/mTORC1 and mTORC2/AKT pathway.

J Neurooncol. 2026 Nov 03. pii: 37. [Epub ahead of print]180(2):

Adaptive induction of NFS1 links mTOR suppression to stemness-associated plasticity in glioblastoma.

Ayako Morino, Yuna Hayakawa, Kenta Masui, Kumiko Murakami, Atsushi Kurata.

   BACKGROUND: Glioblastoma (GBM) exhibits profound therapeutic resistance that is largely attributed to its remarkable cellular plasticity and capacity to adapt to therapeutic and environmental stress. Although suppression of mechanistic target of rapamycin (mTOR) signaling has been extensively investigated as a therapeutic strategy, the adaptive mechanisms that limit its efficacy remain incompletely understood.
METHODS: Human GBM cells were subjected to sphere-forming conditions or pharmacological inhibition of mTOR signaling to evaluate stress-induced cellular responses. Proteomic profiling following mTORC2 inhibition was performed to identify adaptive metabolic alterations. Functional analyses were conducted using NFS1 cysteine desulfurase (NFS1) knockdown, orthotopic xenograft models, and publicly available datasets.
RESULTS: Sphere-forming conditions and pharmacological inhibition of mTOR signaling induced stemness-associated changes in GBM cells. Unbiased proteomic profiling identified NFS1 as a stress-responsive protein induced by mTOR suppression. NFS1 depletion attenuated selected stemness-associated responses and sensitized GBM cells to mTOR pathway inhibition. Increased NFS1 expression was further confirmed in highly tumorigenic orthotopic xenografts, whereas exploratory analyses suggested a potential modulatory role of iron availability in this adaptive phenotype.
CONCLUSIONS: Our findings identify NFS1 as a stress-induced metabolic dependency that emerges during adaptation to mTOR suppression in GBM. Targeting adaptive vulnerabilities by therapeutic stress, rather than constitutive oncogenic pathways alone, may represent a promising strategy for overcoming treatment resistance in malignant gliomas.

Keywords:  Glioblastoma; Glioma stem cells; Metabolic reprogramming; NFS1; mTOR inhibition

DOI:  https://doi.org/10.1007/s11060-026-05856-1
JCI Insight. 2026 Nov 05. pii: e211025. [Epub ahead of print]

TSC2-Mutant Yucatan Minipig Cardiac Rhabdomyoma Model Reveals mTORC1 Activation and MITF/TFE Expression Signature.

Elias Bou Farhat, Heng Du, Chrystalle Katte Carreon, Jad Halawi, Sophie Kudler, Magdalena Losko, Zachary T Herbert, Adrienne L Watson, Daniel Carlson, Dennis A Webster, Derek M Korpela, David M Meredith, Elizabeth P Henske, David J Kwiatkowski.

  Tuberous sclerosis complex (TSC) is an inherited tumor predisposition syndrome caused by pathogenic variants in TSC1 or TSC2, yet no animal model faithfully recapitulates the cardiac rhabdomyomas (CR) that are among its earliest manifestations. We generated a heterozygous TSC2-mutant Yucatan minipig carrying the recurrent pathogenic TSC2 p.Arg505* variant and characterized its cardiac phenotype using histopathology, immunohistochemistry, and RNA sequencing. TSC2-mutant minipigs consistently developed multiple CR that closely resembled human lesions, including enlarged glycogen-rich spider cells and activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Comparative transcriptomic analyses demonstrated enrichment of a conserved TSC-associated gene expression program and activation of microphthalmia/transcription factor E (MITF/TFE)-regulated lysosomal pathways in both human and minipig tumors. Although other manifestations of TSC were not observed during the first year of life, this large-animal model faithfully reproduced the principal histopathologic and molecular features of human CR. These findings have established the TSC2-mutant Yucatan minipig as what we believe to be the first large-animal model of TSC-associated CR and provide a physiologically relevant platform for investigating tumor pathogenesis, mechanisms of spontaneous regression, and therapeutic strategies targeting mTORC1- and MITF/TFE-dependent signaling.

Keywords:  Genetics; Oncology; Tumor suppressors

DOI:  https://doi.org/10.1172/jci.insight.211025
Oncogene. 2026 Oct 31.

Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.

Chao Fang, Yuanyuan Yu, Yiping Yin, Zhao Shi, Zhaiyue Xu, Britta Statz, Yina Qiao, Hongzhen Li, Yifeng Sun, Jingxiong Hu, Tamer Abdelaal, Kathleen Schuck, Lei Wang, Thomas Hank, Max Heckler, Martin Loos, Ingrid Herr, Franco Fortunato, Ihsan Ekin Demir, Helmut Friess, Shanshan Shen, Christoph W Michalski, Bo Kong.

Hyperactivation of the mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, is common in pancreatic ductal adenocarcinoma (PDAC). However, clinical use of mTOR inhibitors has shown limited efficacy due to rapid adaptive resistance. Using inducible genetically engineered mouse models and matched organoids, we delineated distinct complex-specific adaptations. Loss of mTORC1 delayed tumor progression but induced compensatory PI3K/Akt signalling hyperactivation, while concurrently suppressing inflammatory cancer-associated fibroblasts and desmoplasia through Il-1ra. In contrast, mTORC2 loss impaired de novo sphingolipid synthesis, shifted lipid composition toward saturation, increased the saturated-to-monounsaturated fatty acid ratio, enriched plasma membrane lipid rafts, and amplified interferon-γ signaling. This lipid reprogramming generated a synthetic-lethal dependency on stearoyl-CoA desaturase 1 (Scd1). Pharmacological co-inhibition of mTORC1/2 and Scd1 prevented adaptive PI3K/Akt signalling rebound, remodelled the tumor stroma, enhanced interferon-γ responses, and synergized with anti-PD-1 therapy. These findings establish dual targeting of mTOR signaling and Scd1 as a rational therapeutic strategy for PDAC.

DOI: https://doi.org/10.1038/s41388-026-04026-x
Indian J Pharmacol. 2026 Nov 01. 58(6): 708-724

Protective effect of gossypin against high-fat diet-induced atherosclerosis in rats: Role of the phosphoinositide 3-kinase/AKT/mechanistic target of rapamycin pathway and gut microbiota.

Yanyan Wang, Ankit Kumar, Fei Lu.

   BACKGROUND: Over the last decade, there has been a global prevalence of high morbidity and mortality associated with atherosclerotic disease. Gossypin exhibits the anti-inflammatory and protective effect against various disease. The current protocol demonstrated the antiatherosclerotic effect of gossypin against high-fat diet (HFD)-induced atherosclerosis (AS) in rats and explored the underlying mechanism.
MATERIALS AND METHODS: HFD and Vitamin D3 (600,000 IU/kg) were used to induce AS in rats, and the rats were treated with different doses of gossypin and rosuvastatin, respectively. Body weight, organ weights, inflammatory, cardiac, and lipid parameters, as well as micro-RNA (mRNA) expression, were estimated. The rat faces were collected for the determination of gut microbiota.
RESULTS: Gossypin treatment markedly reduced body weight and altered organ weights. Gossypin treatment Remarkably modulated the level of cardiac parameters such as creatine kinase (CK), CK myocardial band, lactate dehydrogenase, cardiac troponin I, thromboxane B2, endothelin-1; lipid parameters such as total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), very LDL, TC/HDL, TG/HDL, free fatty acid; hepatic parameters, namely, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase; inflammatory parameters such as cyclooxygenase-2, inducible nitric oxide synthetase, C-reactive protein, prostaglandin E2, nuclear factor kappa-B (NF-κB); inflammatory cytokines include interleukin (IL)-1β, 6, 5, 10, 17, tumor necrosis factor-α (TNF-α), C-X-C Motif chemokine ligand 1 (CXCL1), respectively. Gossypin treatment also altered the mRNA expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, ATP-binding cassette transporter A1 (ABCA-1), liver X receptor-α, peroxisome proliferator-activated receptor-γ, toll-like receptor 4 (TLR4), NOD-like receptor family pyrin domain containing 3, NF-κBp65, myeloid differentiation primary response 88, IL-1 β, IL-6, IL-17, TNF-α, phosphorylated AMP-activated protein kinase, phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT), respectively. Gossypin treatment remarkably modulated the abundance of Firmicutes, Bacteroidetes, F/B ratio, deferribacteraceae and cyanobacteria.
CONCLUSION: Gossypin exhibited the anti-AS effect through alteration of PI3K/AKT/mTOR signaling pathway and gut microbiota.

Keywords:  Atherosclerosis; gossypin; inflammation; nuclear factor kappa-B signaling pathway; phosphoinositide 3-kinase/AKT/mechanistic target of rapamycin

DOI:  https://doi.org/10.4103/ijp.ijp_156_26
Diagn Pathol. 2026 Aug 08. pii: 83. [Epub ahead of print]21(1):

Expression, association with clinicopathological features and prognostic potential of FOXR2, mTOR, HIF-1α and PKM2 in high-grade serous carcinoma of the ovary.

Lianguo Hou, Xinyi Dong, Min Li, Jiaxi Yang, Xueli Guo, Juan Wang, Jun Zhang.

   BACKGROUND: High-grade serous carcinoma (HGSC) of the ovary is the most common and deadly subtype of gynecological malignancy. More and more studies have shown that Forkhead Box R2 (FOXR2) is a carcinogenic driver that can enhance cell growth and tumor formation. However, the role of FOXR2 in the development of HGSC and its underlying molecular mechanisms remain unclear. This study investigated the role of FOXR2 in HGSC progression and its relationship with glycometabolic reprogramming, specifically the mTOR/HIF-1α signaling pathway and its downstream key glycolytic enzyme, PKM2.
METHODS: Immunohistochemistry for FOXR2, mTOR, HIF-1α and PKM2 was performed on formalin-fixed paraffin-embedded HGSC tissue and normal fallopian tube tissue. Kaplan Meier analysis and Cox proportional hazards regression analysis were used to evaluate the overall survival curve and independent prognostic factors.
RESULTS: In the present study, FOXR2, mTOR, HIF-1α and PKM2 proteins are highly expressed in HGSC, and are positively correlated with FIGO stage of ovarian cancer. In addition, these four proteins were positively correlated with each other. Overall survival analysis showed that the expression levels of FOXR2, mTOR, HIF-1α and PKM2 proteins, as well as FIGO stage, were correlated with patient prognosis. In addition, FIGO staging was an independent prognostic factor affecting the poor prognosis of patients.
CONCLUSIONS: Taken together, the present results suggested that FOXR2, mTOR, HIF-1α and PKM2 have crucial roles in the progression and prognosis of HGSC and may be potential therapeutic targets.

Keywords:  FOXR2; Glycometabolic reprogramming; High−grade serous carcinoma of the ovary; MTOR/HIF−1α signaling pathway; PKM2; Prognosis

DOI:  https://doi.org/10.1186/s13000-026-01818-3
J Exp Med. 2027 Jan 04. pii: e20261384. [Epub ahead of print]224(1):

Bcl11a preserves hematopoietic stem cell function in culture by restraining Ncf1-dependent ROS.

Xiang Xu, Linlin Zhang, Yandong An, Jing Wang, Xiaoyan Ding, Jing Xie, Yong Yu.

Ex vivo expansion of hematopoietic stem cells (HSCs) is limited by culture-induced oxidative stress, yet the upstream transcriptional drivers remain poorly defined. Here, we show that the transcription factor Bcl11a is rapidly and persistently downregulated during HSC culture and that this decline drives functional deterioration. Bcl11a was both required and sufficient to maintain quiescence, clonogenic activity, and serially transplantable HSC function. Mechanistically, Bcl11a directly represses a Nox2 NADPH oxidase gene module, including Ncf1, encoding the p47phox organizer subunit; Ncf1 deletion reduced ROS and partially rescued the defects of Bcl11a-deficient HSCs. Rapamycin-but not the ROS scavenger N-acetylcysteine-restored Bcl11a expression, suppressed Ncf1 and ROS, and improved HSC function, identifying Bcl11a as a candidate effector linking mechanistic target of rapamycin complex 1 inhibition to redox control. This axis was conserved in human hematopoietic stem and progenitor cells, revealing a druggable transcriptional vulnerability of cultured HSCs and a framework for improving ex vivo-expanded grafts.

DOI: https://doi.org/10.1084/jem.20261384
Arch Biochem Biophys. 2026 Nov 03. pii: S0003-9861(26)00323-1. [Epub ahead of print]787 111050

Characterization of cancer stem-like cells derived from a single 4T1 murine triple-negative breast cancer cell: Involvement of Akt‒mTOR pathway in the proliferation and sphere formation.

Masato Maruyama, Taketo Yoshitomi, Miho Seguchi, Wataru Hiraoka, Kazutaka Higaki.

  Triple-negative breast cancer (TNBC) is refractory, which could be likely ascribed to cancer stem cells (CSCs) harbored in TNBC. Therefore, to develop a novel therapeutic strategy for TNBC by targeting CSCs, we established and characterized 4T1-derived CSC-like cells. First, cell clones were obtained from a single mouse TNBC 4T1 cell utilizing a sphere-formation method. Then, their CSC-like properties were investigated for several CSC markers and in-vivo tumorigenicity to select 4T1-derived CSC-like cell clones. Among 16 cell clones obtained, the 6A10 and 6A12 clones highly expressed a CSC marker, CD44 variant, and stem-cell marker genes, such as Oct3/4, Sox2, and Nanog. Furthermore, these clones exhibited significantly greater in-vivo tumorigenicity than the parental 4T1 cells did in the mice that received subcutaneous injections of the cell suspension. These results clearly indicated that the two clones should be 4T1-derived CSC-like cells. To identify potential therapeutic targets for TNBC stem cells, the effects of various signaling inhibitors on cell proliferation and sphere formation were subsequently evaluated in the two established CSC-like cell clones. Notably, the mTOR inhibitor, rapamycin, and Akt inhibitor, GSK2110183, significantly suppressed both cell proliferation and sphere formation. Western blot analysis suggested that Akt activation was involved in mTOR phosphorylation in 6A10 cells. In conclusion, 4T1-derived CSC-like cells were successfully established from a single mouse TNBC cell, and it was suggested that the Akt-mTOR pathway was involved in the proliferation and sphere formation. The current results provide a promising therapeutic target for eliminating TNBC stem cells.

Keywords:  CD44 variant isoform; Cancer stem cells; Mammalian target of rapamycin; Sphere formation; Triple-negative breast cancer; Tumorigenicity

DOI:  https://doi.org/10.1016/j.abb.2026.111050
Aging Cell. 2026 Nov;pii: e70805. [Epub ahead of print]25(11):

Constitutive Activation of Skeletal Muscle mTORC1 Drives Pro-Inflammatory Gene Expression in Skeletal Muscle of Aged Mice.

Erik D Marchant, Hanna Kalenta, Jacquelyn May, Zhao Lai, Adam B Salmon, Blake B Rasmussen.

  mTORC1 activity is increased in muscle with aging and is implicated as a potential driver of age-related declines in muscle health. While pharmacological inhibition of mTORC1 improves lifespan and healthspan, it remains unclear whether chronic activation of mTORC1 is sufficient to accelerate aging in skeletal muscle. We aimed to address this question using an inducible model of muscle-specific knockout of Depdc5, which encodes the protein DEP domain containing 5 (DEPDC5), a negative regulator of mTORC1. In 27-month-old mice, Depdc5 knockout induced a robust upregulation of inflammatory and immune-related genes, accompanied by alterations in metabolic and angiogenic pathways. Additionally, Depdc5 knockout mice exhibited an increase in TNF-α protein expression. However, these transcriptional and protein changes were not associated with an altered macrophage phenotype or with changes in muscle capillary density. Dietary rapamycin partially reversed mTORC1 signaling and some of the transcriptional changes, including those related to angiogenesis, but did not suppress inflammation-related transcripts or protein expression. These findings demonstrate that constitutive activation of mTORC1 is sufficient to drive pro-inflammatory changes in aged skeletal muscle, adding to the inflammation that already occurs with aging.

Keywords:  aging; geroscience; inflammaging; inflammation; mTOR; nutrient sensing

DOI:  https://doi.org/10.1111/acel.70805
J Hum Genet. 2026 Nov 04.

A homozygous C2ORF78 variant is associated with mTOR hyperactivation and neurodevelopmental defects in focal cortical dysplasia.

S Rehan Ahmad, Md Zeyaullah, Yousef Zahrani, Abdelrhman Ag Altijani, Hytham Hummad, Awad Osman Abdalla Mohamed, Neena Kumar Dhiman.

Focal cortical dysplasia (FCD) is a malformation of cortical brain development, yet its genetic basis remains incompletely understood. Here, we investigate type II FCD in a proband with behavioral disturbances, including aggression, hyperactivity, and sleep dysfunction, but with normal early development and cognition. Magnetic resonance imaging (MRI) of the proband revealed focal cortical thickening, abnormal sulcation, and gray-white matter blurring in the left temporal lobe, consistent with FCD type II. Whole-exome sequencing identified a novel homozygous missense variant in C2ORF78 (c.1264 A > G; p.Ser422Gly), absent in population databases. The S422 residue is evolutionarily conserved, resides within a disordered, solvent-accessible region, and its substitution with glycine caused marked structural destabilization, cytosolic mislocalization, and protein aggregation. Functional studies in proband fibroblasts revealed no significant reduction of C2ORF78 protein, deregulated mTOR signaling, impaired autophagy, ER stress, and G0/G1 cell cycle arrest. Molecular dynamics simulations confirmed significant loss of protein stability and compactness in the S422G mutant. C2ORF78 interacts with RNA-binding and transcriptional regulators, and gene ontology analyses indicated roles in transcription and RNA splicing. We propose that C2ORF78 functions as a transcriptional coregulator of genes negatively regulating mTOR signaling. Mislocalization of the S422G mutant leads to a loss of nuclear function, resulting in hyperactivation of mTOR and disrupted cellular homeostasis. High expression of C2ORF78 in cerebral cortex and hippocampus supports its relevance to brain physiology. Our findings identify C2ORF78 as a novel candidate gene associated with FCD type II and highlight transcriptional dysregulation of mTOR signaling as a potential pathogenic mechanism.

DOI: https://doi.org/10.1038/s10038-026-01524-4
PLoS One. 2026 ;21(11): e0361463

Exogenous tryptophan aggravates experimental lung fibrosis through activation of AKT-mTORC1 pathway.

Jisu Hong, Yunha Nam, Jib Yong Jung, Jun Yeong Baek, Eun Ji Park, Yemin Choi, Shinhee Park, Ae-Rin Baek, Hun-Gyu Hwang, Junehyuk Lee, An-Soo Jang, Do-Jin Kim, Su Sie Chin, Woo Jin Kim, Sung-Woo Park.

Idiopathic pulmonary fibrosis (IPF) is marked by aberrant lung remodeling and excessive extracellular matrix (ECM) accumulation. Previously, we observed elevated tryptophan (TRP) levels in the lungs of IPF patients, but its role in fibrogenesis remained unclear. This study examines whether TRP modulate the severity of lung fibrosis by measuring ECM component expression in TRP-treated lung fibroblasts. The activities of key TRP metabolism enzymes, tryptophan hydroxylase (TPH-1) and indoleamine 2,3-dioxygenase (IDO/TDO), were also assessed in IPF lung. Exogenous TRP administration in bleomycin-exposed mice significantly exacerbated lung damage and fibrosis. TPH-1 levels were elevated in lung tissues and primary fibroblasts of IPF patients compared to controls, while IDO/TDO expression showed no significant differences between two groups. TRP treatment increased fibroblast proliferation and upregulated collagen, fibronectin, and α-smooth muscle actin expression, whereas TRP deprivation reduced these ECM component levels. Additionally, TRP upregulated the AKT-mTORC1 and TGF-β1 signaling pathways in IPF fibroblasts. These findings indicate that elevated TRP levels contribute to IPF pathogenesis and suggest that targeting the TRP pathway could offer therapeutic potential for lung fibrosis including IPF.

DOI: https://doi.org/10.1371/journal.pone.0361463
Biol Direct. 2026 Aug 06. pii: 222. [Epub ahead of print]21(1):

NEDD9 confers ferroptosis resistance in liver cancer by inhibiting autophagy via the AKT‑mTOR signaling pathway.

Qisheng He, Yu Bai, Xiaojing Xu, Ya'nan Hu, Jinming Liu, Yixiu Zhang, Yiming Gao, Huanxiang Zhang.

   BACKGROUND: Hepatocellular carcinoma (HCC), the most prevalent primary liver malignancy, is characterized by poor prognosis and limited therapeutic options. Ferroptosis, a recently identified form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising strategy for cancer therapy. Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is a scaffold protein implicated in tumor progression; however, its role in the regulation of ferroptosis remains unclear.
METHODS: NEDD9 was overexpressed or knocked down in liver cancer cells using lentiviral vectors. RNA sequencing was performed to analyze transcriptomic changes. Cell viability and death were assessed using Cell Counting Kit-8 (CCK-8) and propidium iodide (PI) staining assays. C11-BODIPY 581/591, malondialdehyde (MDA), Western blot, dihydroethidium (DHE) and iron assays were used to detect lipid peroxidation, MDA content, protein expression, reactive oxygen species (ROS) and Fe²⁺ levels, respectively. Autophagy was modulated using Torin1 (activator) and chloroquine (inhibitor). For in vivo experiments, NEDD9‑knockdown Hepa1‑6 cells were subcutaneously injected into C57BL/6 mice to assess tumor growth and ferroptosis‑related sensitivity to sorafenib.
RESULTS: RSL3- and sorafenib-induced ferroptosis in HCC cells was accompanied by a significant reduction in NEDD9 expression. NEDD9 overexpression upregulated glutathione peroxidase 4 (GPX4) and conferred resistance to ferroptosis, whereas NEDD9 knockdown decreased GPX4 expression, elevated ROS and MDA levels, and markedly sensitized cells to ferroptosis. Mechanistically, our findings support a model in which NEDD9-associated AKT-mTOR signaling contributes to ferroptosis resistance through the regulation of autophagy-related processes. More specifically, NEDD9 overexpression activated AKT-mTOR signaling and suppressed autophagy, thereby maintaining GPX4 abundance without altering intracellular Fe²⁺ levels, whereas autophagy activation attenuated NEDD9-mediated ferroptosis resistance. In contrast, NEDD9 knockdown attenuated AKT-mTOR signaling and was associated with lysosome-dependent GPX4 loss and intracellular Fe²⁺ accumulation. Pharmacological inhibition of autophagy reversed the ferroptosis-promoting effect caused by NEDD9 knockdown. In vivo, NEDD9 knockdown suppressed tumor growth and potentiated the antitumor efficacy of the ferroptosis‑inducing agent sorafenib.
CONCLUSIONS: Ferroptosis in HCC cells was accompanied by decreased NEDD9 expression. NEDD9 overexpression markedly inhibited ferroptosis, whereas NEDD9 knockdown promoted it. These findings suggest that targeting NEDD9 may represent a potential strategy for enhancing the therapeutic response to ferroptosis-associated treatments in liver cancer.

Keywords:  AKT-mTOR; Autophagy; Fe2+ ; Ferroptosis; GPX4; NEDD9

DOI:  https://doi.org/10.1186/s13062-026-00927-9
J Virol. 2026 Nov 02. e0142626

Aspartate inhibits mTORC1 activity and impairs reactivation of HIV-1 provirus.

Cindy Lam, Kris Barreto, Wendy Bernhard, Genevieve Morin, Sidong Huang, Ivan Sadowski.

  The mTORC1 complex regulates cell growth in response to various nutrients, including amino acids. We demonstrate that, unlike all other amino acids, aspartate inhibits mTORC1 kinase activity. An shRNA screen revealed that multiple genes related to aspartate metabolism modulate HIV-1 provirus expression. From this observation, we discovered that the cell-permeable aspartate analogs acid dimethyl ester (ADE) and aspartic acid di-tert-butyl ester (ADTB) suppress reactivation of latent HIV-1 expression in T cells and inhibit mTORC1 signaling. mTORC1 was also inhibited by the addition of excess aspartate to Jurkat or HEK293 cells overexpressing the aspartate transporter EAAT1. Aspartate was found to directly inhibit mTORC1 kinase activity in vitro. These observations demonstrate that mTORC1 signaling is inhibited by excess aspartic acid, and we propose that intracellular aspartate levels act as a sensor to regulate anabolic metabolism. Furthermore, these results indicate that therapeutic manipulation of intracellular aspartate concentrations may provide a novel means of modulating HIV-1 provirus expression.
IMPORTANCE: Elevated intracellular concentrations of aspartic acid and cell-permeable aspartate analogs were found to suppress HIV-1 expression in T-cell lines and CD4+ cells from people living with HIV. Accordingly, we show this effect is mediated by inhibition of mTORC1 signaling, and that aspartate inhibits mTORC1 kinase activity in vitro. We propose that intracellular aspartate levels act as a sensor to regulate anabolic metabolism.

Keywords:  HIV-1; T cells; aspartate; latency; mTORC1; protein kinase

DOI:  https://doi.org/10.1128/jvi.01426-26
Nephrology (Carlton). 2026 Nov;pii: e70303. [Epub ahead of print]31(11):

Tuberous Sclerosis Complex in an Australian Adult Tertiary Centre: Surveillance Adherence and Outpatient Burden in a Fragmented Model of Care.

Steven Thien Nguyen, Rory Wallace, Matthew Sypek.

   AIM: The Australian National Strategic Action Plan for Rare Diseases (2020) calls for integrated care, yet the current state for many rare conditions is poorly described. Tuberous Sclerosis Complex (TSC) is a rare genetic disease caused by a loss-of-function mutation in either TSC1 or TSC2, resulting in hamartomas across multiple organs. TSC affects up to 1:5000 live births and requires lifelong multidisciplinary surveillance. The aim of this study was to evaluate TSC care in a single, adult, tertiary service and assess adherence to international best-practice guidelines.
METHODS: We conducted a retrospective audit of adults with TSC cared for between 2021 and 2024. Demographics, genetic testing, clinical manifestations, treatments, and follow up were extracted from electronic medical records. Surveillance was benchmarked against the 2021 Updated International TSC Diagnostic Criteria and Surveillance and Management Guidelines.
RESULTS: 57 patients were included in this study (32 (56%) male). 37.3% had genetic testing documented. Phenotype frequencies were broadly consistent with the published literature. The majority of patients had adequate neurologic and renal surveillance, whereas screening for other comorbidities was infrequent or absent. There were a high number of outpatient clinic attendances, with a mean of 4.6 (IQR: 2.5-5.5) visits per year.
CONCLUSION: Adults with TSC at our centre experience a high care burden yet incomplete surveillance against international recommendations, reflecting fragmented care in the absence of consolidated adult multidisciplinary clinics. Establishing integrated, adult TSC services could improve adherence to surveillance, streamline care, and reduce avoidable mobility. These data provide a baseline for service design and future quality improvement.

Keywords:  health services accessibility multidisciplinary; outpatient; surveillance; tuberous sclerosis

DOI:  https://doi.org/10.1111/nep.70303
Nat Commun. 2026 09 14. pii: 11299. [Epub ahead of print]17(1):

RICTOR regulates an interspecies crosstalk that influences longevity through a methionine cycle-mitophagy axis.

Simran Motwani, Somya Bhandari, Shivani Chitkara, Rajat Ujjainiya, Prerona Ghosh, Shantanu Sengupta, Arnab Mukhopadhyay.

Adaptive modulation of physiological traits in response to dietary fluctuations is essential for organismal fitness and is governed by complex gene-diet interactions that remain mechanistically unexplored. Here, we identify the conserved mTORC2 component RICTOR as a critical regulator of dietary plasticity in Caenorhabditis elegans. Loss of rict-1/RICTOR confers enhanced osmotic stress tolerance and longevity on vitamin B12-rich bacterial diets containing optimal methionine. These adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the one-carbon cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism which generates succinyl-CoA, and via the TCA cycle, succinate. Elevated succinate induces mitochondrial fragmentation, activating mitophagy that is indispensable for the stress resilience and longevity of rict-1 mutant worms. This host Met-C-mitophagy axis is tuned by microbial inputs, constituting an interspecies interaction. Early-life fragmentation potentiates sustained mitophagy into late adulthood, preserving tubular mitochondria as the rict-1 mutant worms age, unlike wild-type worms. Thus, RICTOR restrains host sensitivity to microbe-derived metabolite fluctuations through organellar quality control, regulating lifespan.

DOI: https://doi.org/10.1038/s41467-026-77722-7
Front Oncol. 2026 ;16 1975805

AICAR induces S phase cell cycle arrest in ESCC by targeting the AMPK/mTORC1 and mTORC2/AKT pathway.

Muping Zou, Tianrui Zhang, Lingbin He, Jianhong Li, Ze Lin, Chenxi Jia, Kaixuan Ma, Lincui Wang, Shuya Xu, Bozhi Cai, Libiao Wu, Chunhong Ren, Thomas Ming Swi Chang, Pingnan Sun, Xin Zhang.

   Background: 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) agonist, exhibits potent antitumor capacity across various malignancies. However, its efficacy and underlying mechanisms in esophageal squamous cell carcinoma (ESCC) remain largely unexplored.
Methods: We treated HEEC, TE1, and TE13 cells with AICAR and assessed proliferation, cell cycle distribution, and expression of key signaling proteins, followed by SN38 cotreatment to evaluate apoptosis and chemosensitization.
Results: AICAR treatment suppressed proliferation in all three cell lines but induced a distinct S-phase arrest specifically in ESCC cells. Mechanistically, AICAR activated AMPK, which concurrently inhibited the mTORC1 pathway via TSC2 phosphorylation and activated the mTORC2/AKT pathway through FOXO3-mediated transcriptional upregulation of Rictor. A critical difference was observed between cell types: in HEEC cells, AICAR treatment upregulated the tumor suppressor PTEN, which prevented full AKT activation. In contrast, ESCC cells, with unaltered PTEN and dysfunctional p53, sustained AKT hyperactivation. This drove cells into S-phase, where they were subsequently arrested due to the parallel inhibition of mTORC1. Furthermore, synchronizing ESCC cells in the S-phase with AICAR, followed by its withdrawal and subsequent treatment with SN38, significantly enhanced apoptosis.
Conclusion: Our findings reveal that AICAR induces S-phase arrest in ESCC cells by dually modulating the mTORC1 and mTORC2/AKT signaling pathways. This differential effect, stemmed from dysfunctional p53/PTEN axis in ESCC cells, distinguishes ESCC cells from normal epithelial cells. Together, these results suggest that AICAR synchronizes ESCC cells in the S phase, thereby sensitizing them to S-phase-specific agents like SN38 and representing a potential novel strategy for ESCC treatment.

Keywords:  AICAR; AMPK; ESCC; cell cycle arrest; chemo sensitization

DOI:  https://doi.org/10.3389/fonc.2026.1975805