bims-matara 2026-10-04 papers

on MTOR

Issue of 2026–10–04
fifteen papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.
Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.
Esketamine Ameliorates Propofol-Induced Long-Term Cognitive Impairments in Juvenile Rats by Suppressing Autophagy via Activating the PI3K/Akt/mTOR Signaling Pathway.
Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention.
SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.
Caenorhabditis Intervention Testing Program: the putative mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans.
CSN3 promotes colorectal cancer cell progression through activation of the PI3K/AKT/mTOR pathway.
mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.
Evaluation of PIK3CA, AKT1, and mTOR Genes Polymorphisms in a Sample of Iranian Women with Breast Cancer Compared with Healthy Women.
Targeting RAB27A Enhances Pembrolizumab Sensitivity and Alleviates Immune Escape via Inactivation of the PI3K/Akt/mTOR Pathway in Triple-Negative Breast Cancer.
TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation.
Salicylic acid engages central metabolic regulators SnRK1 and TOR to govern immunity by differential phosphorylation of NPR1.
A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
Neurobehavioral outcomes following epilepsy surgery in tuberous sclerosis complex: A retrospective study.
ACTB promotes ESCC progression by regulating the AKT-mTOR signaling pathway through an m6A-dependent mechanism.

Nat Commun. 2026 08 31. pii: 10359. [Epub ahead of print]17(1):

Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1.

Krystle C Kalafut, Yann Cormerais, Madi Y Cissé, Samuel C Lapp, Karen E Inouye, Gökhan S Hotamışlıgil, Brendan D Manning.

The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, and aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established regulatory mechanisms influencing mTORC1 activation, but the physiological signals that control mTORC1 at the organismal and tissue levels are less well-defined. mTORC1 is dynamically regulated by fasting and feeding in metabolic tissues, with both nutrients and insulin proposed to activate mTORC1 in response to feeding. Here, studies employing a liver-specific genetic mouse model demonstrate that AKT-mediated TSC2 phosphorylation is the predominant mechanism of hepatic mTORC1 induction by insulin but is dispensable for activation by feeding. Furthermore, postprandial activation of hepatic mTORC1 requires dietary protein, which dictates the insulin-responsiveness of the pathway. Contrary to dogma, hepatic mTORC1 signaling was not elevated in response to diet-induced obesity, despite overt impairments in insulin and glucose homeostasis, and blocking hepatic AKT-TSC-mTORC1 signaling did not affect these metabolic phenotypes. Evidence is also provided supporting a role for glucagon in hepatic mTORC1 suppression during fasting. This study reveals a hierarchy of physiological signals regulating hepatic mTORC1.

DOI: https://doi.org/10.1038/s41467-026-77216-6
Cell Death Differ. 2026 Sep 30.

Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.

Marco Ferniani, Irene Sambri, Tuong Huynh, Rossella Pennella, Gennaro Tufano, Niculin J Herz, Barbara Rossi, Antonella Iannaccone, Francesco Trepiccione, Alessia Calcagnì, Andrea Ballabio.

Birt-Hogg-Dubé (BHD) and Tuberous Sclerosis (TSC) are inherited cancer syndromes associated with kidney cystogenesis and tumorigenesis and caused by mutations of the folliculin (FLCN) and TSC1/2 genes, respectively. We and others previously showed that Transcription Factors EB (TFEB) and E3 (TFE3) are the main drivers of the kidney phenotypes observed in mouse models of these conditions. These transcription factors are also responsible for the feedback hyperactivation of the mechanistic Target of Rapamycin Complex 1 (mTORC1), a known tumorigenic factor. This raises the question of whether TFEB/TFE3 exert their oncogenic activity by inducing mTORC1 or by mTORC1-independent pathways. To address this question, we generated kidney-specific mouse models in which we knocked out factors that differentially control mTORC1 and TFEB/TFE3, thus uncoupling their activities. Specifically, we generated three kidney-specific conditional knockout lines: (1) Depdc5-KO mice in which loss of GATOR1 activity leads to mTORC1 hyperactivation and TFEB/TFE3 inhibition, (2) RagC-KO mice in which TFEB/TFE3 are constitutively active and mTORC1 activity is partially inhibited due to impaired Rag heterodimer formation, and (3) Flcn/RagC double KO mice to test whether mTORC1 inhibition induced by RagC loss ameliorates the aggressive kidney phenotype of FLCN KO mice. Comparison between these models revealed that mTORC1 hyperactivation is a key driver of cystogenesis and tumorigenesis, while TFEB/TFE3 constitutive activation further enhances and accelerates pathology by establishing a transcriptional program that integrates metabolic and stress-response pathways. Together, our findings define an oncogenic mechanism by which both mTORC1 and TFEB/TFE3 hyperactivation cooperate in kidney tumorigenesis.

DOI: https://doi.org/10.1038/s41418-026-01881-9
J Integr Neurosci. 2026 Sep 21. 25(9): 50741

Esketamine Ameliorates Propofol-Induced Long-Term Cognitive Impairments in Juvenile Rats by Suppressing Autophagy via Activating the PI3K/Akt/mTOR Signaling Pathway.

Yang Wang, Yin Li, Zhe Chen, Xuexue Zhang, Na Qi, Xueying Chen, Guiping Xu.

   BACKGROUND: Repeated propofol exposure during neurodevelopment induces long-term cognitive deficits in rats, potentially through dysregulated hippocampal neuronal autophagy and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Esketamine has been reported to exert neuroprotective effects; however, the underlying mechanism remains unclear. In the present study, we investigated whether esketamine could ameliorate propofol-induced long-term memory and learning impairments in juvenile rats by suppressing autophagy via activation of the PI3K/Akt/mTOR pathway.
METHODS: Seventy-two Sprague-Dawley rats of both sexes at postnatal day 7 were randomly assigned to one of six groups: Control, Propofol, Esketamine + Propofol, LY294002 (PI3K inhibitor) + Esketamine + Propofol, Rapamycin + Propofol, and Rapamycin + Esketamine + Propofol. All treatments were administered daily for five consecutive days. Cognitive performance was assessed using both the Y-maze test and the Morris water maze test. Hippocampal neuronal pathology was evaluated by histopathological staining and transmission electron microscopy. The concentrations of pro-inflammatory cytokines and expression levels of proteins related to the PI3K/Akt/mTOR pathway and autophagy were measured using Western blotting and immunofluorescence.
RESULTS: Rats exposed to propofol showed significant learning and memory impairments, hippocampal neuronal damage, suppression of the PI3K/Akt/mTOR pathway, excessive autophagy, and elevated levels of pro-inflammatory cytokines (p < 0.01). Esketamine co-treatment significantly alleviated these propofol-induced changes (p < 0.01). However, the neuroprotective effects of esketamine were diminished by pre-treatment with either LY294002 or the autophagy activator rapamycin (p < 0.01).
CONCLUSION: Esketamine ameliorates propofol-induced long-term cognitive impairments in juvenile rats by suppressing excessive autophagy through activation of the PI3K/Akt/mTOR signaling pathway.

Keywords:  autophagy; esketamine; mechanistic target of rapamycin; phosphatidylinositol 3-kinase; propofol; protein kinase B; rats

DOI:  https://doi.org/10.31083/JIN50741
medRxiv. 2026 Sep 11. pii: 2026.09.09.26362677. [Epub ahead of print]

Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention.

Jocelyn Baumel, Michael Lutz, Cynthia Ding, Jamie Capal, David Ritter, Darcy Krueger, Alice Salter, Klaus Werner, Andy J Liu.

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function mutations in TSC1 or TSC2 , resulting in chronic hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. TSC patients experience a wide spectrum of cognitive, behavioral, and psychiatric features collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Moreover, these patients develop a clinical trajectory in adulthood with clinical and neuropathological features overlapping those of Alzheimer's disease (AD). Prior neuropathological studies have shown accumulation of AD-type mixed 3R/4R tau isoforms in adults with TSC that is amyloid-independent.
Methods: To further explore the biological convergence of TSC and AD, this study compared plasma levels of phosphorylated tau-217 (ptau-217), a sensitive and specific marker of early AD pathology, in 63 TSC, 25 AD, and 116 cognitively unimpaired (CU) patients.
Results: Findings revealed elevated levels of plasma ptau-217 in individuals with TSC at younger ages with a parallel age-related trajectory between TSC, AD, and CU cohorts. Multivariable linear regression showed that the log 2 ptau-217 concentrations were significantly lower in the CU cohort relative to TSC (β = -0.21, SE = 0.05, p < 0.0001) but were not significantly different between the TSC and AD cohorts (β = 0.17, SE = 0.09, p < 0.071). The comparison of slopes analysis (ANCOVA) supported that the slopes for the regression of log 2 ptau-217 versus age are not significantly different for the TSC and CU cohorts (TSC slope = 0.030, SE = 0.008; CU slope = 0.019, SE = 0.006; p = 0.26), nor for the TSC and AD cohorts (TSC slope = 0.030, SE = 0.01; AD slope = 0.06, SE = 0.03; p = 0.099).
Conclusions: These results suggest a novel link between TSC and AD that substantiates shared downstream neurodegenerative pathways. Furthermore, these results support the potential utility of ptau-217 as a minimally invasive biomarker for TAND severity, neurodegenerative risk, and AD-like prognosis in TSC and as a tool to guide new mTOR-targeted therapeutic strategies.

DOI: https://doi.org/10.64898/2026.09.09.26362677
Nat Commun. 2026 09 11. pii: 10407. [Epub ahead of print]17(1):

SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.

Ke Hu, Yin-Hu Wang, Anthony Y Tao, Maxwell McDermott, Miki Jishage, Li Zhong, Thomas Boehringer, Marcus J Hines, Sergei B Koralov, Ebbe Boedtkjer, Stefan Feske.

Antibody-producing plasmablasts (PB) and plasma cells (PC) are critical for humoral immunity, autoimmunity and vaccine responses. Despite the importance of environmental stressors in regulating humoral immune responses, the influence of pH on PB and PC differentiation remains elusive. Here, we identify SLC4A7/NBCn1, a Na+/HCO3- cotransporter, as a selective regulator of PB differentiation in vitro. SLC4A7 deletion also impairs the formation of antibody secreting cells (ASCs) and antibody responses in mice in vivo following immunization and influenza A virus infection. Mechanistically, SLC4A7 deletion results in intracellular acidification and lysosomal alkalinization, and is associated with impaired function of the mechanistic target of rapamycin complex 1 (mTORC1). Enforcing mTORC1 activation in SLC4A7-deficient B cells or B cells in which intracellular pH is acidified by blocking Na+/H+ exchanger (NHE) function restores PB differentiation in vitro. Moreover, ASC differentiation and antibody responses are impaired under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Altogether, we identify a critical relationship between intracellular pH regulation through SLC4A7 and mTORC1-dependent ASC differentiation and humoral immunity.

DOI: https://doi.org/10.1038/s41467-026-77588-9
MicroPubl Biol. 2026 ;2026

Caenorhabditis Intervention Testing Program: the putative mTOR inhibitors Cinnarizine and Meclizine do not extend lifespan in C. elegans.

Erik Johnson, Christine A Sedore, Anna L Coleman-Hulbert, Brian D Onken, Vijaya Madhuri Achanta, Yuhua Song, Gino Cortopassi, Gordon J Lithgow, Monica Driscoll, Patrick C Phillips.

The mechanistic target of rapamycin (mTOR), a protein kinase and master cell regulator, is one of the most validated longevity drug targets: mTOR inhibition by compounds like rapamycin has been shown to significantly extend lifespan in numerous model organisms. Here, we tested whether the novel putative mTOR-inhibiting compounds cinnarizine and meclizine could likewise increase lifespan in the nematode C. elegans , following standardized protocols from the Caenorhabditis Intervention Testing Program (CITP). Our results indicate that cinnarizine and meclizine have no effect on C. elegans lifespan at lower doses, and that both compounds exert a toxic effect at higher doses, significantly shortening lifespan.

DOI: https://doi.org/10.17912/micropub.biology.002198
Mol Biol Rep. 2026 Oct 01. pii: 1666. [Epub ahead of print]53(1):

CSN3 promotes colorectal cancer cell progression through activation of the PI3K/AKT/mTOR pathway.

Cheng Chen, Tingting Tu, Haiyan Xu, Gang Wang, Yingzhi Lu, Guanhong Huang.

   BACKGROUND: CSN3 (κ-casein) is essential for casein micelle formation and cellular differentiation, and dysregulated CSN3 has been linked to tumorigenesis. However, its role in colorectal cancer (CRC) remains unclear.
METHODS AND RESULTS: CSN3 expression in CRC was evaluated using GEO and TCGA datasets, immunohistochemistry, and qRT-PCR. Its biological functions were investigated using gain- and loss-of-function approaches combined with CCK-8, apoptosis, wound-healing, and Transwell assays. Transcriptomic analysis of the GEO dataset GSE21510 was used to identify CSN3-associated signaling pathways, which were further investigated by western blotting, RT-qPCR, co-immunoprecipitation (Co-IP), AKT inhibition, and CSN1S1 knockdown rescue experiments. CSN3 was significantly upregulated in CRC tissues and was associated with lymph node metastasis, advanced TNM stage, and poor prognosis. Functionally, CSN3 overexpression promoted CRC cell proliferation, migration, and invasion while suppressing apoptosis, whereas CSN3 knockdown produced the opposite effects. CSN3 also promoted epithelial-mesenchymal transition (EMT). Mechanistically, enrichment analysis and western blotting demonstrated that CSN3 activated the PI3K/AKT/mTOR signaling pathway, accompanied by increased phosphorylation of PI3K, AKT, mTOR, p70S6K, and 4EBP1. MK-2206 attenuated CSN3-induced proliferation, migration, invasion, and EMT, partially restored apoptosis, and reduced AKT phosphorylation. STRING and Co-IP supported an association between CSN3 and CSN1S1. CSN1S1 knockdown attenuated CSN3-induced proliferation, migration, invasion, EMT, and AKT activation.
CONCLUSIONS: CSN3 promotes malignant CRC cell phenotypes partly through AKT signaling, with CSN1S1 contributing to CSN3-mediated AKT activation and tumor-promoting effects, suggesting potential prognostic relevance in CRC.

Keywords:  CSN3; Colorectal cancer; Metastasis; PI3K/AKT/mTOR signaling pathway

DOI:  https://doi.org/10.1007/s11033-026-12825-4
CNS Neurosci Ther. 2026 Oct;32(10): e71174

mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.

Yang Zou, Jun Yang, Yang Li, Guodong Wang, Wen Lu, Xiaoping Chen, Xingxing Ma, Kehan Chen, Peng Liang, Yinghui Wu, Tao Zhuo.

   BACKGROUND: Although depression is a potent risk factor for Alzheimer's disease (AD), the underlying causal mechanisms remain unclear. This study investigated the molecular and circuit-level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting.
METHODS: A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi-scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide-field and two-photon calcium imaging, immunofluorescence, and bulk RNA-sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6.
RESULTS: CRS severely impaired cortical slow-wave oscillations and induced aberrant prefrontal single-neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated Aβ deposition, dystrophic neurite aggravation, and reactive gliosis. Mechanistically, transcriptomic profiling and biochemical validation revealed that chronic stress suppresses autophagic pathways via selective hyperactivation of mTORC1 signaling rather than the AMPK pathway. Time-course analysis showed that mTORC1 activation and autophagy-related abnormalities preceded overt Aβ accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased Aβ42 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy-related abnormalities and was associated with reduced BACE1 abundance and CTFβ generation, together with a diminished global Aβ burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits.
CONCLUSION: Chronic stress-induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro-circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1-autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress-related neurodegenerative conditions.

Keywords:  Alzheimer's disease; autophagy; depression comorbidity; mTOR signaling; neural network

DOI:  https://doi.org/10.1002/cns.71174
Asian Pac J Cancer Prev. 2026 Sep 01. pii: 92365. [Epub ahead of print]27(9): 3245-3251

Evaluation of PIK3CA, AKT1, and mTOR Genes Polymorphisms in a Sample of Iranian Women with Breast Cancer Compared with Healthy Women.

Reza Mahdizadeh, Alireza Nakhaee, Mohsen Taheri, Seyed Mehdi Hashemi, Gholamreza Bahari.

   OBJECTIVE: Breast cancer (BC) is the most common cancer among women globally, with Iranian women showing an earlier onset compared to those in Western countries. Genetic variations in the PI3K/AKT/mTOR signaling pathway have been implicated in cancer susceptibility, but limited studies exist on the association of these polymorphisms with BC risk in the Iranian population. This study aimed to investigate the associations of specific polymorphisms in the AKT1, PIK3CA, and mTOR genes with BC susceptibility in an Iranian population.
METHODS: A case-control study was conducted with 222 confirmed BC patients and 230 cancer-free controls. Genotyping of AKT1 rs1130214 and rs1130233, PIK3CA rs6443624, and mTOR rs1883965 polymorphisms was performed using PCR-RFLP methods. Statistical analysis was carried out using logistic regression to evaluate the associations between genotypes and BC risk.
RESULTS: The AKT1 rs1130214 polymorphism was associated with a significantly reduced BC risk (codominant model: OR=0.44, 95% CI=0.30-0.65, p<0.001; allelic model: OR=0.52, 95% CI=0.38-0.72, p<0.001). Conversely, AKT1 rs1130233, PIK3CA rs6443624, and mTOR rs1883965 polymorphisms were linked to an increased BC risk in various inheritance models. For instance, the mTOR rs1883965 G>A variant showed a significantly higher risk (dominant model: OR=2.75, 95% CI=1.84-4.12, p<0.001).
CONCLUSION: This study indicates that polymorphisms in AKT1, PIK3CA, and mTOR genes are associated with altered BC risk among Iranian women. These findings propose that genetic variants in the PI3K/AKT/mTOR pathway could serve as potential biomarkers for BC susceptibility. Further research with larger cohorts and diverse populations is necessary to confirm these associations.

Keywords:  AKT1; breast cancer; cancer susceptibility; genetic polymorphisms; mTOR

DOI:  https://doi.org/10.31557/APJCP.2026.27.9.3245
Clin Exp Pharmacol Physiol. 2026 Oct;53(10): e70159

Targeting RAB27A Enhances Pembrolizumab Sensitivity and Alleviates Immune Escape via Inactivation of the PI3K/Akt/mTOR Pathway in Triple-Negative Breast Cancer.

Tong Sha, Jingjing Fan, Xiaoli Wang, Binlin Ma.

  Ras-related protein Rab-27A (RAB27A) is involved in tumour progression and immune regulation. This study investigated its role in triple-negative breast cancer (TNBC) progression, immune escape and responsiveness to immune checkpoint inhibitors. RAB27A expression was analysed in TNBC tissues and public datasets. Gain- and loss-of-function experiments were performed in TNBC cells. Peripheral blood mononuclear cell (PBMC)-based tumour coculture systems and xenograft mouse models were used to evaluate antitumor immunity and therapeutic responses. RAB27A was upregulated in TNBC and correlated with chemotherapy resistance, advanced T stage, high Ki-67 expression and CD8+ T-cell infiltration. RAB27A overexpression activated PI3K/Akt/mTOR signalling and promoted tumour cell migration and invasion, whereas RAB27A silencing had the opposite effects. Combined RAB27A targeting and PI3K inhibition decreased PD-L1 expression and cell viability while increasing HLA-I expression and apoptosis; these effects were further enhanced by pembrolizumab. In PBMC coculture models, combination treatment promoted T-cell proliferation and CD8+ T-cell expansion while suppressing malignant phenotypes. In vivo, RAB27A knockdown inhibited tumour growth, reduced PI3K/Akt/mTOR activation and PD-L1 expression and increased HLA-I expression. Targeting RAB27A enhances antitumor immunity and pembrolizumab sensitivity by blocking the PI3K/Akt/mTOR axis, representing a potential strategy to overcome immune resistance in TNBC.

Keywords:  PI3K/Akt/mTOR pathway; RAB27A; immune checkpoint inhibitor; immune escape; triple‐negative breast cancer

DOI:  https://doi.org/10.1111/1440-1681.70159
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2612904123

TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression in regulatory T cells via TET protein translation.

Tomohide Kinoshita, Akira Nakajima, Toru Kobayashi, Mai Ohno, Yuxi Wei, Tatsumasa Hasegawa, Norihito Hayatsu, Shoshiro Hirayama, Yu-Ichi Tsukada, Atsushi Hirao, Shigeo Murata, Shohei Hori.

  Regulatory T (Treg) cell differentiation and function rely on stable expression of the master transcription factor Foxp3. While Foxp3 expression is epigenetically stabilized through DNA demethylation of a Foxp3 enhancer (the Treg-specific demethylated region, TSDR), the mechanisms underlying this process remain unclear. Here, we show that strong and sustained T cell receptor (TCR) signaling promotes TSDR demethylation, stabilizes Foxp3 expression, and confers suppressive activity in in vitro-induced Treg (iTreg) cells through activation of mTORC1. Mechanistically, TCR-mTORC1 signaling promotes TSDR demethylation by enhancing translation of TET2, and likely TET3, enzymes that mediate DNA demethylation. Rescue of impaired TSDR demethylation under mTORC1 inhibition by the TET2 catalytic domain, together with dose-dependent impairment following heterozygous deficiency of TET2 and/or TET3, supports a causal link between TET protein abundance and TSDR demethylation. In vivo, mTORC1 inactivation increases the frequency of cells harboring a methylated TSDR among peripheral Foxp3+ T cells, but not among developing Foxp3+ thymocytes, supporting in vivo relevance of mTORC1-dependent epigenetic remodeling. Thus, TCR-mTORC1 signaling promotes epigenetic stabilization of Foxp3 expression through translational control of TET proteins, revealing an unrecognized role for mTORC1 in iTreg cell differentiation.

Keywords:  DNA demethylation; Foxp3; T cell receptor; mTORC1; regulatory T cells

DOI:  https://doi.org/10.1073/pnas.2612904123
Cell. 2026 Sep 30. pii: S0092-8674(26)01080-9. [Epub ahead of print]

Salicylic acid engages central metabolic regulators SnRK1 and TOR to govern immunity by differential phosphorylation of NPR1.

Yixuan Chen, John Withers, Yulin Sun, Tianyuan Chen, Sargis Karapetyan, Jan Draken, Yezi Xiang, Yuzhe Yuan, Yang He, Wolfgang Dröge-Laser, Jing-Ke Weng, Xinnian Dong.

  Immunity requires a delicate balance between combating infection and preserving metabolic functions. However, the mechanisms by which immune responses are coordinated with cellular metabolism remain largely unknown. Here, we show that NONEXPRESSER OF PR GENES 1 (NPR1), the central plant immune regulator of salicylic acid (SA)-mediated defense responses, is controlled by a cascade of post-translational modifications (PTMs) involving two master nutrient-sensing kinases. In the absence of pathogen challenge, TARGET OF RAPAMYCIN (TOR) inhibits NPR1 through phosphorylation at Ser-55/59. During defense responses, elevated SA reduces sugar phosphate levels and enhances SNF1-RELATED PROTEIN KINASE 1 (SnRK1) activity, which in turn inhibits TOR signaling and phosphorylates NPR1 at Ser-557, a modification required for subsequent PTMs and NPR1 activation. Together, our findings identify SA as a coordinator of growth and immunity in response to pathogen challenge by modulating the central metabolic regulators SnRK1 and TOR, which antagonistically control NPR1 immune activity through differential phosphorylation.

Keywords:  NPR1; SA; SAR; SnRK1; TOR; metabolism; phosphorylation; plant immune response; salicylic acid; systemic acquired resistance

DOI:  https://doi.org/10.1016/j.cell.2026.09.011
Nature. 2026 Sep 30.

A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.

Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.

Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.

DOI: https://doi.org/10.1038/s41586-026-11093-3
Epilepsy Behav. 2026 Sep 28. pii: S1525-5050(26)00424-5. [Epub ahead of print]185 111303

Neurobehavioral outcomes following epilepsy surgery in tuberous sclerosis complex: A retrospective study.

Kevin Pearsson, Mikaela Selby, Ellen Broekhuizen, Daan Pijs, Scellig Stone, Mustafa Sahin, Colin Reilly, Alyssa Ailion, Jurriaan Peters.

   INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare genetic disorder with a high prevalence of drug-resistant epilepsy. In such cases, epilepsy surgery may render 60% of suitable candidates seizure-free. Although seizure reduction may contribute to improvements in cognitive or language skills, little is known about neurobehavioral changes overall.
METHODS: This retrospective single-center study included children with TSC who underwent epilepsy surgery and had ≥ 12 months of follow-up data. We collected pre- and postoperative neurobehavioral data, structured around the TSC-Associated Neuropsychiatric Disorders (TAND) questionnaire, from medical and neuropsychological records. Surgical outcomes were dichotomized as seizure-free or not seizure-free.
RESULTS: Of 21 surgeries, 13 (62%) achieved complete seizure freedom, and 15 (71%) achieved seizure freedom from the targeted seizure type. The most prevalent TAND problems at baseline were in language (n = 19), motor skills (n = 17), and attention (n = 13). After surgery, 18 (86%) showed improvement in at least one cluster, most often language (n = 12) or attention (n = 7). Postoperative behavioral worsening in at least one cluster was observed in 13 (62%), most often in repetitive behaviors (n = 5) and tantrums (n = 4). Surgical outcomes were unrelated to the improvement or worsening of symptoms.
CONCLUSION: Neurobehavioral improvement was often observed following epilepsy surgery in TSC, with seizure outcomes unrelated to neurobehavioral outcomes. However, some worsening of behavior was observed. Many TAND items were not routinely documented in the clinical records, underscoring the need for a more structured, prospective approach to neuropsychiatric comorbidity assessment in TSC.

Keywords:  Drug-resistant epilepsy; Epilepsy surgery; Pediatric neurosurgery; TSC-associated neuropsychiatric disorders; Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.yebeh.2026.111303
Oncogene. 2026 Sep 30.

ACTB promotes ESCC progression by regulating the AKT-mTOR signaling pathway through an m6A-dependent mechanism.

Yunshan Jiang, Dan Zhao, Dongxia Liao, Fengling Yang, Canyang Lin, Pengfei Liu, Zheyuan Chen, Fang Shaobo, Xiaoxue Deng, Xiaolei Ni, Baoling Guo.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, and the upstream regulatory mechanisms driving oncogenic signaling remain insufficiently defined. In this study, we identify a previously unrecognized nuclear function of the cytoskeletal protein ACTB in promoting ESCC progression. We show that ACTB translocates to the nucleus and directly binds to the promoter of the m6A reader gene YTHDC2, transcriptionally activating its expression. YTHDC2, in turn, binds to m6A-modified sites on AKT mRNA, preventing its degradation and enhancing its stability. This results in sustained activation of the PI3K-AKT-mTOR signaling pathway, a key oncogenic cascade that promotes tumor growth and survival. Integrated CUT&Tag and RNA-seq analyses revealed a direct ACTB-YTHDC2 transcriptional axis, while RNA immunoprecipitation and MeRIP-qPCR confirmed YTHDC2-AKT interaction via m6A recognition. Functional assays in ESCC cell lines, patient-derived organoids, and xenograft mouse models demonstrated that both ACTB and YTHDC2 are essential for ESCC proliferation and tumorigenicity. Notably, pharmacological inhibition of mTOR with rapamycin effectively suppressed ACTB-driven tumor phenotypes in vitro and in vivo, supporting the therapeutic relevance of this signaling axis. Together, our findings define a novel ACTB-YTHDC2-AKT-mTOR regulatory network that integrates transcriptional and epitranscriptomic control in ESCC. This study reveals a noncanonical nuclear role for ACTB and identifies a mechanistically tractable pathway that may be exploited for targeted therapy in ACTB-driven esophageal cancer.

DOI: https://doi.org/10.1038/s41388-026-03995-3