bims-matara 2026-09-27 papers

on MTOR

Issue of 2026–09–27
seventeen papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
The Role of the Mammalian Target of Rapamycin in Microglial Phenotypic Polarization.
Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.
Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.
Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers.
mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
Kinase crosstalk coordinates stress adaptation and metabolic homeostasis in plants.
TOR-NOT4 signalling couples translation to co-translational quality control in plants.
Mechanistic Study of SRSF1-Mediated Inhibition of Treg Cell Function via the mTORC1/ULK1 Signalling Axis Through Mitophagy in Asthma.
Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.
Sensory neuronal mTORC1 kinase signaling establishes neuroimmune memory that initiates allergic immunity.
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
Camellia nitidissima Flower Extract Alleviates Stress-Induced Sebaceous Dysfunction by Targeting the 11β-HSD1/PI3K/Akt/mTOR Axis.
FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal Cancer Cells.
SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer.
mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.
Network Toxicology Integrates In Vivo Evidence Linking Impaired Autophagic Clearance Involving the MTOR-TFEB Axis to Polystyrene Nanoplastic-Induced Neurotoxicity.

Aging (Albany NY). 2026 Sep 19. 18(1): 1280-1315

mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.

Natalia Bobok.

  The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses. This review presents a three-section framework in which mTOR functions as a dynamic signaling hub coordinating multiple biological processes underlying the aging process. Evidence from genetic, experimental, and translational studies supports a causal role for mTOR signaling in lifespan regulation in model organisms, whereas human data remain predominantly associative but biologically consistent. mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) regulate distinct yet complementary aspects of cellular metabolism, proteostasis, autophagy, stress adaptation, and tissue homeostasis. Major geroprotective interventions-including autophagy activation, dietary interventions, physical activity, and senotherapeutics-partly converge on mTOR signaling but also engage parallel pathways. This adaptive regulation restores anabolic-catabolic balance, enhances stress resilience, and improves metabolic flexibility. Collectively, the available evidence identifies mTOR as an important integrative node linking multiple hallmarks of aging and diverse geroprotective interventions. Rather than representing a single therapeutic target, mTOR should be viewed as a context-dependent signaling hub which precise, tissue-specific modulation may promote healthy aging and support future geroscience-based interventions.

Keywords:  geroprotective interventions; hallmarks of aging; mTOR signaling; mTORC1; mTORC2

DOI:  https://doi.org/10.18632/aging.206423
Cells. 2026 Sep 14. pii: 1654. [Epub ahead of print]15(18):

The Role of the Mammalian Target of Rapamycin in Microglial Phenotypic Polarization.

Kaitlyn J Partridge, Allison D Ebert.

  Microglia are adaptive immune cells that maintain central nervous system homeostasis and respond dynamically to injury, infection, and other neurological insults. While traditionally classified into resting, pro-inflammatory "M1", and anti-inflammatory "M2" states, advances in multi-omic profiling technologies have established that microglial phenotypes exist along a multidimensional and context-dependent continuum. The mammalian target of rapamycin (mTOR), a central regulator of cellular metabolism, growth, survival, and protein synthesis, has emerged as a potential central mediator of these state transitions through distinct activities downstream of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In this review, we examine current evidence linking mTOR signaling to microglial phenotypic polarization and functional plasticity. Generally, evidence suggests that mTORC1 acts as a context-dependent amplifier of inflammatory responses, whereas mTORC2 promotes anti-inflammatory and neuroprotective programs; however, the effects of either complex vary according to disease context. Understanding the balance and coordination of mTORC1 and mTORC2 signaling programs may clarify mechanisms that underly chronic neuroinflammation and guide the development of targeted therapies for neuroinflammatory disorders including Alzheimer's disease, stroke, and epilepsy.

Keywords:  mammalian target of rapamycin; microglia; neuroinflammation

DOI:  https://doi.org/10.3390/cells15181654
Biology (Basel). 2026 Sep 16. pii: 1629. [Epub ahead of print]15(18):

Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.

Mutsuki Ojima, Manami Matsuura, Miwako Deguchi, Dong-Ho Kim.

  In mammalian systems, translational responses to amino acid limitation are commonly framed as mechanistic target of rapamycin complex 1 (mTORC1) inhibition and activation of the general control nonderepressible 2 (GCN2)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response. Suppressing initiation, however, does not immediately relieve aminoacylated transfer RNA shortages for ribosomes already engaged on messenger RNA. Transfer RNA charging and ribosome profiling reveal codon- and isoacceptor-specific elongation constraints. Across mouse NIH3T3 and several human cell systems, leucine deprivation often appears initiation-dominant but can produce UUA-biased pausing and frameshifting in selected cancer cells. Valine deprivation can prolong decoding at all four valine codons, whereas separate isoleucine-deprivation studies report AUU/AUC-selective slowing, a cytoplasmic isoleucyl-tRNA synthetase 1 (IARS1)-linked isoleucine-to-valine signal in exogenous reporter peptides, and an isoleucine-to-methionine substitution signal of unresolved mechanism. Ribosome slowing can engage global, transcript-local, and quality-control feedback, but the inputs are stress- and system-dependent. We propose a two-layer kinetic framework separating (i) A-site competition among correct decoding, substitution, and abortive exit from (ii) collision formation set by ribosome influx and dwell time. It keeps protein quantity, sequence fidelity, retained function, and proteostasis cost separate, and defines a matched measurement roadmap from metabolite flux to protein function.

Keywords:  GCN2; aminoacyl-tRNA; branched-chain amino acids; integrated stress response; mistranslation; ribosome collision; ribosome stalling; ribosome-associated quality control

DOI:  https://doi.org/10.3390/biology15181629
Nature. 2026 Sep 23.

Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.

Jun Wang, Zixin Cai, Jiaojiao Gu, Shiqi Xiong, Jianhan Yi, Meng Yang, Kexin Chang, Xinrui Ning, Yilin Wen, Yan Yan, Jiongming Lu, Yirong Wang, Zongzhao Zhai.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.

DOI: https://doi.org/10.1038/s41586-026-11029-x
Biochim Biophys Acta Gen Subj. 2026 Sep 24. pii: S0304-4165(26)00109-1. [Epub ahead of print] 131009

Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers.

Lyvia Neves Rebello Alves Nolasco, Eldamária de Vargas Wolfgramm Dos Santos, Raquel Silva Dos Reis Trabach, Débora Dummer Meira, Iúri Drumond Louro.

  Rapamycin is a macrolide compound originally identified for its antifungal activity and subsequently recognized as a potent inhibitor of the mechanistic target of rapamycin (mTOR), a conserved signaling kinase that integrates nutrient availability, growth factor signals, and cellular stress responses to regulate cell growth and metabolism. This review examines rapamycin across biological and medical fields, covering its discovery, chemical and pharmacological properties, and the central role of mTOR as its primary molecular target. We summarize established and emerging clinical applications of rapamycin and its analogs, while critically addressing the limitations and adverse effects associated with mTOR inhibition. Furthermore, advances in translational research and future perspectives are also discussed. Collectively, current evidence supports mTOR inhibition as a unifying biological strategy for the prevention, treatment, and delayed onset of multiple chronic diseases, as well as for promoting healthspan. As the first clinically approved mTOR inhibitor, rapamycin has therefore become a foundational pharmacological tool for exploring the therapeutic potential of modulating the evolutionarily conserved mTOR signaling network across a broad spectrum of human diseases and age-related conditions.

Keywords:  Healthspan; Molecular target; Rapalogs; Rapamycin; mTOR

DOI:  https://doi.org/10.1016/j.bbagen.2026.131009
Sci Adv. 2026 Sep 25. 12(39): eaee1905

mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.

Alex Zaufel, Wenfei Sun, Nunzia Pastore, Ulrike Taschler, Carina Wagner, Hubert Hackl, Judith Sommer, Dagmar Silbert-Wagner, Jan G Hengstler, Brigitte Begher-Tibbe, Rudolf Stauber, Dagmar Kolb, Martin Troetzmueller, Benjamin Gottschalk, Chelsea Thorsheim, Eva-Lena Stange, Mathias W Hornef, Olga Pivovarova-Ramich, Andreas F H Pfeiffer, Kylie P Matchett, Anne Loft, Stephan Herzig, Neil C Henderson, Andrea Ballabio, Zoltan Arany, Christian Wolfrum, Peter Fickert, Tarek Moustafa.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non-12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

DOI: https://doi.org/10.1126/sciadv.aee1905
Planta. 2026 Sep 25. pii: 140. [Epub ahead of print]264(5):

Kinase crosstalk coordinates stress adaptation and metabolic homeostasis in plants.

Teja Manda, Delight Hwarari, Raphael Dzinyela.

   MAIN CONCLUSION: Crosstalk among MAPKs, CDPKs, SnRKs, and TOR establishes a dynamic regulatory framework that balances energy homeostasis, defense, and development under stress conditions. Continued advances in systems biology and functional genomics will further clarify these complex interactions and accelerate the development of crops with enhanced stress resilience, growth stability, and resource-use efficiency. Plants rely on complex kinase signaling networks to sense, integrate, and respond to rapidly fluctuating environmental stresses. Central to these networks are mitogen-activated protein kinases (MAPKs), calcium-dependent protein kinases (CDPKs), sucrose non-fermenting-1-related kinases (SnRKs), and the Target of Rapamycin (TOR) complex, which collectively coordinate stress perception, metabolic regulation, and growth adaptation. Although the individual functions of these pathways have been extensively characterized, a unified mechanistic framework describing their interconnected roles across diverse stress conditions remains incomplete. Here, we synthesize recent advances in plant stress signaling to propose an integrated model of kinase crosstalk that highlights key nodes of convergence, reciprocal regulation, and metabolic-hormonal integration. We emphasize the antagonistic interplay between SnRK1 and TOR as a central regulatory hub controlling energy balance and stress adaptation, while MAPK and CDPK cascades intersect with SnRK1-mediated autophagy and TOR-dependent anabolic growth pathways. In addition, hormonal signaling networks involving abscisic acid (ABA), salicylic acid (SA), and jasmonic acid (JA) provide further layers of regulatory coordination that improve cellular responses to environmental stress. Collectively, these interconnected kinase networks orchestrate survival strategies, metabolic homeostasis, and resilience under adverse conditions. By integrating these signaling modules into a systems-level framework, this review provides mechanistic insights and emerging perspectives for engineering crops with enhanced stress tolerance, growth stability, and energy-use efficiency.

Keywords:  Calcium signaling; Drought; Heat; Kinase families; Phosphoproteomics; Salinity

DOI:  https://doi.org/10.1007/s00425-026-05177-7
Nat Commun. 2026 Aug 24. pii: 10101. [Epub ahead of print]17(1):

TOR-NOT4 signalling couples translation to co-translational quality control in plants.

Maximillian A Schwarze, Rory Osborne, Margot Raffeiner, Manuel González-Fuente, Anastasia Kanali, Mark Bailey, Ross D Etherington, Lina Zhou, Suayib Üstün, Daniel J Gibbs.

Protein synthesis must be tightly coordinated with quality control to prevent proteotoxic stress, yet the mechanisms underlying co-translational surveillance in plants, and how these are aligned with translational output, remain poorly understood. Here, we identify three NOT4-like E3 ubiquitin ligases in Arabidopsis thaliana as regulators of co-translational protein quality control and uncover a functional link between NOT4 and TARGET OF RAPAMYCIN (TOR) signalling that coordinates quality-control capacity with translational output. Loss of NOT4 function increases basal TOR activity and global translation rates, resulting in the accumulation of polyubiquitylated proteins and heightened sensitivity to proteasome inhibition, TOR inhibition, and protein misfolding stress. Consistent with prior evidence that NOT4 proteins are TOR-regulated phosphotargets, not4 mutants also phenocopy TOR-inhibited wild-type plants for a subset of transcriptional and growth-related processes. Furthermore, elevated translation in NOT4-deficient plants enhances resistance to Pseudomonas syringae pv. tomato. Collectively, our findings reveal a functional coupling between TOR signalling and NOT4 activity that may scale quality control with translational demand to safeguard proteome homoeostasis across eukaryotes.

DOI: https://doi.org/10.1038/s41467-026-77200-0
Clin Exp Pharmacol Physiol. 2026 Oct;53(10): e70157

Mechanistic Study of SRSF1-Mediated Inhibition of Treg Cell Function via the mTORC1/ULK1 Signalling Axis Through Mitophagy in Asthma.

Chunhua Ye, Yifu Chen, Qinjun Yi, Zhu Ming, Tuoyu Gan, Rong Xiang.

   OBJECTIVE: This study examines the role of serine/arginine-rich splicing factor 1 (SRSF1) in airway inflammation in asthma and the molecular mechanisms in mitophagy and metabolic homeostasis in regulatory T cells (Tregs).
METHODS: Bronchoalveolar lavage fluid (BALF) was collected from asthma patients and healthy controls to assess SRSF1 expression and autophagy, and to analyse the correlation of SRSF1 with Treg cell functional markers and lung function. The ovalbumin (OVA)-induced asthma mouse model was established, with the OVA, OVA+shSRSF1, OVA+rapamycin, and OVA+shSRSF1+MHY1485 groups established. Additionally, an OVA+PM2.5 group was set up. Treg cells were isolated from lung tissue to evaluate Treg cell mitophagy, glucose metabolism reprogramming, mitochondrial function, and immunosuppressive activity.
RESULTS: SRSF1 levels in BALF cells from asthma patients were notably elevated and showed negative correlations with FOXP3 expression in Treg cells and FEV1% pred. In OVA-induced asthmatic mice, SRSF1 was upregulated in Treg cells, accompanied by increased phosphorylation of mTOR and ULK1 at Ser757, leading to defects in mitophagy and metabolic reprogramming. Silencing SRSF1 or rapamycin treatment reversed the aforementioned autophagy inhibition and metabolic dysregulation, restored Treg cell numbers and suppressive function, and alleviated airway inflammation and airway hyperresponsiveness. In contrast, the mTORC1 activator MHY1485 counteracted the protective effects of shSRSF1. PM2.5 exposure further exacerbated these changes, which were dependent on SRSF1 expression.
CONCLUSION: SRSF1 modulates the mTORC1/ULK1 axis and is associated with impaired Treg mitophagy and metabolic reprogramming in asthma. Targeting SRSF1 or mTORC1 may represent a promising therapeutic strategy for the prevention and treatment of asthma.

Keywords:  SRSF1; Treg cells; ULK1; bronchial asthma; mTOR; metabolic reprogramming; mitophagy

DOI:  https://doi.org/10.1111/1440-1681.70157
Circulation. 2026 Sep 22.

Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.

Yufeng Hu, Wei Li, Manli Hu, Song Tian, Siyi Zhou, Jiayi Liu, Xu Cheng, Changjiang Zhang, Yingjie Zuo, Jiaxing Zhang, Dianyu Liu, Yang Hu, Yuanbao Chen, Xin Li, Lei Luo, Hailong Yang, Lan Bai, Hui Liu, Péter Ferdinandy, Mario Chiong, Mayarling Francisca Troncoso, Jinying Wen, Jingjing Cai, Xiao-Jing Zhang, Zhi-Gang She, Xin Zhang, Hongliang Li.

   BACKGROUND: Excessive unnecessary protein accumulation in cardiomyocyte is a leading contributor for pathological cardiac hypertrophy and has been found closely regulated by the mTORC1 (mechanistic target of rapamycin complex 1) signaling and lysosome transmembrane proteins. However, the precise regulatory mechanism stratifying mTORC1 signaling and the specific functions of lysosomal proteins in protein homeostasis of cardiomyocytes remain largely unidentified.
METHODS: We screened lysosomal genes conserved in mice, rats, and humans. Adenoviral infection of rat cardiomyocytes was used to assess the functional role of LAPTM4A (lysosome-associated protein transmembrane 4A). To evaluate its effects in vivo, adeno-associated virus 9 driven by the cardiac troponin T promoter was used for cardiomyocyte-specific expression. RNA sequencing and mass spectrometry-based proteomics were performed to elucidate the underlying molecular mechanisms. Last, a dual-luciferase reporter assay was used to screen a Food and Drug Administration-approved drug library for compounds that suppress LAPTM4A expression.
RESULTS: Lysosomal transmembrane proteins expressed in cardiomyocytes were screened for their roles in regulating hypertrophy, and LAPTM4A emerged as a potent promoter of cardiomyocyte hypertrophy and prohypertrophic gene expression. Overexpression of LAPTM4A aggravated cardiac remodeling and dysfunction by enhancing mTORC1-p70S6K (70-kDa ribosomal protein S6 kinase)/4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1)-mediated protein synthesis, without affecting lysosomal autophagy, in a NEDD4L (neural precursor cell expressed developmentally downregulated 4-like)-dependent manner. Mechanistically, LAPTM4A directly interacted with NEDD4L, facilitating K63-linked ubiquitination of AKT (protein kinase B [v-akt murine thymoma viral oncogene homolog]) and subsequent activation of mTORC1 signaling. Cardiomyocyte-specific deletion of LAPTM4A significantly attenuated myocardial hypertrophy and fibrosis induced by transverse aortic constriction in mice. Furthermore, a dual-luciferase reporter screen identified magnolol, a Food and Drug Administration-approved compound, as a suppressor of LAPTM4A expression with marked cardioprotective effects in vivo.
CONCLUSIONS: Our study identified a novel mTORC1 booster LAPTM4A and verified interrupting the LAPTM4A-mTORC1 axis can significantly inhibit excessive protein synthesis and pathological cardiac hypertrophy, which might represent an attractive therapeutic approach for this disease.

Keywords:  LAPTM4A; abnormal protein accumulation; cardiac hypertrophy; mTORC1

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080371
Immunity. 2026 Sep 22. pii: S1074-7613(26)00349-3. [Epub ahead of print]

Sensory neuronal mTORC1 kinase signaling establishes neuroimmune memory that initiates allergic immunity.

Xueping Zhu, Haibo Yang, Haoting Zhan, Isabela J Kernin, Dean R Buttaci, Ngoc Le, Cai Han, Parth R Naik, Peri R Matatia, Sarah Zaghouani, Lillian R Delacruz, Lukas M Altenburger, Neal P Smith, Elena Wu, Rebecca Londoner, Cameron H Flayer, Zhengwang Sun, Alison E Ringel, Alexandra-Chloe Villani, Rod A Rahimi, Caroline L Sokol.

  Environmental allergens are enriched in protease activity, which activates cutaneous sensory neurons, triggering itch and substance P release to promote migration of T helper (Th)2 cell-skewing CD301b+ dendritic cells and initiate allergic immunity. However, allergens are typically encountered through repeated subthreshold exposures, and how these cumulatively induce sensitization is unknown. We identified a sensory neuron-intrinsic mechanism of neuroimmune memory. Protease allergen exposure induced sustained mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling and transcriptional activator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-associated mitochondrial remodeling in sensory neurons, establishing a metabolically primed state with enhanced neuronal responsiveness. Upon allergen re-exposure, this state drove enhanced itch, CD301b+ dendritic cell migration, and Th2 cell differentiation. Disrupting neuronal mTORC1 signaling or mitochondrial stability abrogated this amplification while sparing primary responses. This mechanism generalized across distinct protease allergens, revealing mTORC1-driven metabolic reprogramming in sensory neurons as a form of innate neuroimmune memory underlying allergen cross-sensitization and polysensitization.

Keywords:  Th2 differentiation; allergy; cross-sensitization; dendritic cells; itch; mTORC1; metabolism; neuroimmune memory; neuroimmunology; sensory neurons

DOI:  https://doi.org/10.1016/j.immuni.2026.08.012
Sci Adv. 2026 Sep 25. 12(39): eadz6907

RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.

Pushpamali De Silva, Samantha Fitzgerald, Jules Cazaubiel, Kristin Qian, Matan Hofree, Jia-Ren Lin, Roxanne Pelletier, Mariana Lopez Leon, Phuong Vu Mai Ho, Yasutoshi Takashima, Juha P Väyrynen, Kosuke Matsuda, Tomotaka Ugai, Dane Ford-Roshon, Pratyusha Bala, Nir Hacohen, Kimmie Ng, Jonathan A Nowak, Shuji Ogino, Peter K Sorger, Marios Giannakis.

The RNF43 p.G659fs (RNF43659mut) mutation occurs in 8% of colorectal cancers (CRCs) and is enriched in microsatellite instability-high (MSI-H) tumors. Although RNF43659mut promotes tumor growth through phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) activation independent of WNT signaling, its immunologic effects are poorly defined. We show that RNF43659mut shapes an immunosuppressive natural killer (NK) cell landscape in MSI-H CRC. Single-cell RNA sequencing and multiplex immunohistochemistry revealed increased NK cell infiltration in RNF43659mut tumors, yet these cells displayed inhibitory phenotypes. Bulk RNA sequencing and flow cytometry of NK cells cocultured with RNF43659mut isogenic lines and MSI-H patient-derived organoids demonstrated reduced functional NK subsets, decreased activation markers, increased inhibitory receptors, and impaired cytotoxicity. Mechanistically, RNF43659mut-mediated PI3K/AKT activation induced HLA-E expression, suppressing NK cell function. Pharmacological or small interfering RNA-mediated PI3K/AKT inhibition restored NK cell activity and enhanced tumor cell killing. Spatial analysis of MSI-H patient tumors revealed close proximity between NKG2A+NK cells and HLA-E+ tumor cells, which were themselves adjacent to PI3K/AKT-activated tumor cells, highlighting a localized immunosuppressive niche. These findings uncover an immune evasion mechanism in MSI-H CRC, implicating the PI3K/AKT-HLA-E/NKG2A axis as a promising therapeutic target to overcome immunotherapy resistance.

DOI: https://doi.org/10.1126/sciadv.adz6907
Molecules. 2026 Sep 08. pii: 3156. [Epub ahead of print]31(18):

Camellia nitidissima Flower Extract Alleviates Stress-Induced Sebaceous Dysfunction by Targeting the 11β-HSD1/PI3K/Akt/mTOR Axis.

Meng Zhang, Jiayi Fan, Zhenyu Qin, Timson Chen, Zhizhen Li, Ya Chen, Ling Ma, Guang-Li Wang, Jing Wang.

  Stress-induced sebaceous hyperactivity is a key driver of acne and seborrheic dermatitis; however, research investigating the pathway-specific mechanisms through which stress exerts its effects and the suppression of sebum production via targeting stress signaling remains relatively limited. In this study, we investigated whether Camellia nitidissima flower extract (CNF) could counteract stress-induced sebaceous dysfunction and its underlying mechanisms. Using a cortisone-stimulated SZ95 human sebocyte model, we evaluated lipid accumulation, cortisol production, signaling pathway activation, and apoptotic markers. CNF treatment dose-dependently suppressed cortisone-induced lipid production, reducing triglyceride, cholesterol, and free fatty acid levels by up to 35.44%, 38.02%, and 46.39%. Mechanistically, CNF inhibited 11β-HSD1 expression (17.17% reduction) and cortisol secretion (32.84% decrease), thereby blocking local cortisol reactivation. This upstream interception subsequently attenuated PI3K/Akt/mTOR hyperphosphorylation, downregulated lipogenic transcription factors (SREBP-1, PPARγ, LXRα, C/EBP-α) and their target enzymes (FAS, ACC, DGAT). Beyond lipid synthesis inhibition, CNF reversed cortisone-induced apoptosis resistance by reducing the Bcl-2/Bax ratio and suppressing PCNA-mediated hyperproliferation, thereby decreasing sebocyte number. These findings demonstrate that CNF exerts dual oil-control effects: reducing lipid production per cell and reducing lipid-producing cell abundance. Collectively, CNF represents a promising multi-target botanical agent for managing stress-related sebaceous disorders and cosmetic sebum regulation.

Keywords:  11β-HSD1; Camellia nitidissima flower extract; PI3K/Akt/mTOR; lipogenesis; sebaceous gland; stress-induced sebaceous dysfunction

DOI:  https://doi.org/10.3390/molecules31183156
Oncol Res. 2026 ;34(10): 24

FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal Cancer Cells.

Zhen Li, Xinya Yu, Boning Wu, Jialin Zhang, Xinyu Ju, Yajun Wang, Jieli Song, Qiao Liu, Peng Huang, Qi Ding, Yupeng Wu.

  Background: Fascin actin-bundling protein 1 (FSCN1) modulates the expression of key lipogenic enzymes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) in colorectal cancer (CRC), but the underlying mechanisms remain elusive. Methods: Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following FSCN1 knockdown were assessed by Nile Red/DAPI co-staining and triglyceride quantification, and further validated by Oil Red O staining of xenograft tumors. Expression levels of key metabolic enzymes were measured by qRT-PCR and Western blotting. RNA sequencing identified FSCN1-associated pathways, which were functionally investigated using pharmacological inhibitors. Results: FSCN1 was significantly upregulated in CRC (p < 0.001; AUC = 0.796) and was correlated with poorer overall survival (p = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators-sterol regulatory element-binding transcription factor 1 (SREBF1; protein product: SREBP1), FASN, and SCD1-and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors-peroxisome proliferator-activated receptor alpha (PPARA; protein product: PPARα) and acyl-CoA oxidase 1 (ACOX1). Mechanistically, FSCN1 was associated with activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) pathways; pharmacological inhibition with LY294002 or SB203580 phenocopied the lipid-lowering effects of FSCN1 knockdown. Conclusion: Collectively, these findings link FSCN1 to the AKT/mTOR/SREBP1/(FASN/SCD1) lipogenic axis and the p38 MAPK/PPARα/ACOX1 peroxisomal FAO pathway, implicating FSCN1 in lipid metabolic regulation and CRC progression, while suggesting a putative functional regulatory axis and a promising candidate therapeutic target for CRC.

Keywords:  AKT/mTOR pathway; Colorectal cancer; FSCN1; metabolic regulation; p38 MAPK pathway

DOI:  https://doi.org/10.32604/or.2026.084987
Nat Commun. 2026 Aug 25. pii: 10147. [Epub ahead of print]17(1):

SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer.

Bo Tang, Rui Sun, Jingwei Shao, Qi-You Wu, Yuqian Yan, Dejie Wang, Zhixian Yu, Lianxin Hu, Yicheng Chen, Chengheng Liao, Qiang Wei, Yige Bao, Haojie Huang.

mTOR inhibitors including everolimus and temsirolimus have been approved by US FDA for treatment of clear cell renal cell carcinoma (ccRCC) in clinic. However, resistance to these drugs has been inevitable and the underlying mechanism remains poorly understood. Histone modifier ZMYND8 paradoxically acts as a transcription coactivator or corepressor. Here we show that SPOP, a CULLIN3-RING E3 ubiquitin ligase (CRL) substrate-binding protein that is often overexpressed in ccRCC in patients, promotes K63-linked polyubiquitination of ZMYND8 at lysine 398, which inhibits ZMYND8 to form phase separation compartments and drives the formation of ZMYND8-ZHX2 transactivation complex, resulting in aberrant NEK7 kinase gene transcription, alternative activation of p70S6K, and mTOR inhibitor-resistant cell growth. Inhibition of either SPOP or NEK7 increases ccRCC cell sensitivity to mTOR inhibitor. Treatment with a NEK7 proteolysis-targeting chimera (PROTAC) effectively inhibits aberrant p70S6K activation and overcame everolimus resistance in ccRCC cells in vitro and in mice. Our findings uncover a function switch of ZMYND8 driven by overexpressed SPOP as a key mechanism that causes mTOR inhibitor resistance and nominate NEK7 as a potential target of thwarting mTOR inhibitor resistance in ccRCC.

DOI: https://doi.org/10.1038/s41467-026-77043-9
Nature. 2026 Sep 23.

mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.

Thomas L Li, John D Blair, Taesun Yoo, Gerald A Grant, Dirk Hockemeyer, Brenda E Porter, Helen S Bateup.

Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy1. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling2. Glial abnormalities are commonly observed in tubers3; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear. To address this question, we used human brain organoid models to track the developmental fate of mutated progenitor cells in the absence of seizures. Here we show, using single-cell transcriptomics and cyclic immunostaining across human brain organoids and resected tuber tissue from patients, that loss of TSC2 biases neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell autonomous manner. These mutant astrocytes show downregulated glutamate transporter expression, increased inflammatory cytokine secretion and elevated expression of neurodegenerative disease risk genes such as APOE and CLU. Our findings demonstrate that reactive astrocytes emerge as a primary consequence of TSC2 loss. These results implicate glial dysfunction as a driver of TSC pathogenesis and highlight reactive astrocytes as potential therapeutic targets for TSC-related neuropathology.

DOI: https://doi.org/10.1038/s41586-026-11054-w
Toxics. 2026 Sep 09. pii: 801. [Epub ahead of print]14(9):

Network Toxicology Integrates In Vivo Evidence Linking Impaired Autophagic Clearance Involving the MTOR-TFEB Axis to Polystyrene Nanoplastic-Induced Neurotoxicity.

Na Tang, Chun Wang, Meng Zhang, Yajie Li, Yongkang Liang, Jingjing Zhang, Qiang Niu.

  Long-term exposure to polystyrene nanoplastics (PS-NPs) causes neurotoxicity, but the underlying mechanisms remain unclear. We combined network toxicology, molecular docking, and in vivo experiments to investigate the role of MTOR-TFEB-regulated autophagy in PS-NP-induced neurotoxicity. Potential targets related to PS-NPs and neurodegenerative diseases were screened from public databases. Enrichment analysis indicated involvement of neurodegenerative and autophagy pathways. Protein-protein interaction and docking simulations prioritized MTOR as a candidate target. Sprague-Dawley rats were gavaged with PS-NPs (0.15 or 1.5 mg/kg) for 60 days. Morris water maze tests showed impaired spatial learning and memory. Western blotting of hippocampal tissues revealed increased p-MTOR/MTOR ratios, decreased total cytoplasmic and nuclear TFEB, reduced lysosomal proteins (LAMP2, CTSD, and CTSB), elevated autophagy markers SQSTM1 and MAP1LC3B-II, and altered apoptosis regulators (BAX up and BCL2 down). Collectively, PS-NPs disrupt the MTOR-TFEB axis, impair lysosomal function and autophagic clearance, and promote apoptosis, leading to neurocognitive deficits. These findings provide mechanistic insights into the MTOR-TFEB axis and highlight it as a candidate pathway warranting further evaluation as a potential intervention target.

Keywords:  MTOR-TFEB signaling pathway; PS-NPs; impaired autophagic clearance; network toxicology; neurotoxicity

DOI:  https://doi.org/10.3390/toxics14090801