bims-matara 2026-10-11 papers

on MTOR

Issue of 2026–10–11
sixteen papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
mTOR and STING Modulation Restores Hydrolase Activities and Decreases Alpha-Synuclein Pathology in the Cells from the Patients with GBA1-Associated Parkinson's Disease.
ATP and α-ketoglutarate link nitrogen availability to TORC1-Npr1 signaling in yeast.
mTORC1 as a Therapeutic Target to Mitigate Development of Airway Stenosis in Response to Injury.
Prenatal Use of Sirolimus in Fetal Therapy: Current Evidence, Clinical Applications, and Future Directions.
The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
PDZ domain containing 1 sensitizes renal cancer cells to everolimus via inhibiting phosphatase and tensin homolog phosphorylation-mediated mTOR pathway activation.
Beyond the cerebrospinal fluid: Preclinical and clinical evidence on central nervous system penetration and functional activity of oral rapamycin (sirolimus).
ESR1 mutations are associated with enhanced MTORC1 signaling in a context-dependent manner.
Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.
Acute Hypoxia Induces Cardiomyocyte Autophagy via SIRT5/mTOR/ULK1 Pathway.
TET1 loss promotes malignant phenotypes in HeLa cells and is associated with altered PTEN-PI3K/AKT/mTOR signaling.
TCF4-driven cathepsin S promotes papillary thyroid carcinoma via PI3K/AKT/mTOR.
Improving the metabolic stability of a selective mTOR inhibitor through scaffold deconstruction and carbamate exploration.
10-gingerol potentiates paclitaxel efficacy in triple-negative breast cancer by remodeling gut microbiota and suppressing PI3K/AKT/mTOR signaling pathway.
Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.

PLoS Genet. 2026 Oct 08. 22(10): e1012330

Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.

Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.

Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.

DOI: https://doi.org/10.1371/journal.pgen.1012330
Biochemistry (Mosc). 2026 Sep;91(9): 1596-1614

mTOR and STING Modulation Restores Hydrolase Activities and Decreases Alpha-Synuclein Pathology in the Cells from the Patients with GBA1-Associated Parkinson's Disease.

Tatiana S Usenko, Anastasia I Bezrukova, Katerina S Basharova, Elena V Grigor'eva, Sofya V Pavlova, Galina V Baydakova, Irina V Miliukhina, Ekaterina Yu Zakharova, Sofya N Pchelina.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Aberrant activation of the mechanistic target of rapamycin (mTOR) and of the stimulator of interferon genes (STING) signaling pathways are increasingly recognized as central contributors to PD pathogenesis. The GBA1 variants are the most common genetic risk factor for PD. However, currently there are no disease-modifying therapies for treatment of the GBA1-associated PD (GBA1-PD). Here, we investigated the effects of selective inhibitors of mTOR (Torin 1) and STING (H-151) on the pathway activity, autophagy, lysosomal function, including hydrolase activity, and lysosphingolipid levels, in the peripheral blood monocyte cells-derived macrophages (PBMC-derived macrophages) and induced pluripotent stem cell (iPSC)-derived dopaminergic neurons from the patients with GBA1-PD. Consistent with our previous findings of the reduced glucocerebrosidase (GCase) activity, substrate accumulation, and impaired autophagy, the cells derived from the GBA1-PD patients exhibited marked activation of both mTOR and STING signaling. mTOR inhibition increased number and size of lysosomes and reduced the level of monomeric alpha-synuclein, consistent with the enhanced TFEB-mediated lysosomal biogenesis. In contrast, STING inhibition broadly attenuated the disease-associated phenotypes, reducing levels of oligomeric and phosphorylated alpha-synuclein (Ser129), lysosphingolipid accumulation, and Ras-related protein Rab-10 (Rab10) phosphorylation (Thr73), while also decreasing TFEB phosphorylation, which is consistent with TFEB activation and restoration of lysosomal trafficking via the LRRK2-dependent mechanism. Together, these findings identify mTOR and STING as central regulators of lysosomal functioning and GCase activity in the GBA1-PD, acting through the distinct but partially overlapping mechanisms. Targeting these pathways could, therefore, provide a strategy to restore lysosomal homeostasis and autophagic flux, either alone or in combination with other therapeutic approaches, and to mitigate the alpha-synuclein pathology in GBA1-PD.

Keywords:   GBA1 ; Parkinson’s disease; alpha-synuclein; autophagy; mTOR/STING inhibition

DOI:  https://doi.org/10.1134/S0006297926601644
Mol Biol Cell. 2026 Oct 08. mbcE26050241

ATP and α-ketoglutarate link nitrogen availability to TORC1-Npr1 signaling in yeast.

Christopher Dereppe, Minoas Evangelinos, Elie Saliba, Viktória Ďurčová, Valentin Dubois, Ann Van Schepdael, Cédric Delporte, Bruno André.

The TORC1 (Target of Rapamycin Complex 1) kinase complex coordinates eukaryotic cell growth and metabolism in response to nutrient availability. In yeast, one of the proteins under TORC1 control is the Npr1 kinase mediating nitrogen control of several plasma membrane transporters, yet the metabolic signals governing this pathway remain poorly understood. Here, we first investigated the previously described and unexpected activation of TORC1-Npr1 signaling upon acute glucose starvation. We show that this response occurs only under specific nitrogen conditions, notably in cells grown on proline or glutamine, and depends on increased ATP production driven by stimulated respiration. In proline-grown cells, this respiration is fueled by catabolism of α-ketoglutarate, while high α-ketoglutarate levels negatively affect TORC1-Npr1 activation. We next analyzed TORC1-Npr1 activation following NH4+ addition to proline-grown cells. Our results confirm that glutamine accumulation is not required for this activation and instead show that NH4+ assimilation is associated with a decrease in α-ketoglutarate levels and a sustained increase in ATP production, concomitant with TORC1-Npr1 activation. In cells lacking the NH4+-assimilating glutamate dehydrogenases, both increased ATP production and TORC1-Npr1 activation are impaired. Together, these findings identify ATP and α-ketoglutarate as important metabolic determinants of TORC1-Npr1 signaling in response to nitrogen availability.

DOI: https://doi.org/10.1091/mbc.E26-05-0241
Laryngoscope. 2026 Oct 06.

mTORC1 as a Therapeutic Target to Mitigate Development of Airway Stenosis in Response to Injury.

Julia Hermann, Beth Osterbauer, Charmi Dedhia, Laura Perin, Elizabeth P Henske, Wei Shi, Christian Hochstim.

   OBJECTIVES: Airway stenosis is a morbid health condition impacting the voice, breathing, and swallowing. Etiology involves endotracheal intubation or other mechanical injury, but the underlying molecular mechanisms are not fully understood. Emerging evidence suggests a role for mTOR complex 1 (mTORC1) in the pathogenesis of laryngotracheal stenosis (LTS) and that rapamycin, an mTOR inhibitor, can mitigate development of LTS. In the present study, mTORC1 was targeted genetically and pharmacologically in an injury-induced tracheal stenosis mouse model.
METHODS: Human tracheal tissues were immunostained for phosphorylated ribosomal protein S6 kinase (pS6K), a downstream target of mTORC1 kinase activity, to assess mTORC1 activation. mTORC1 was genetically ablated in tracheal mesenchyme of doxycycline-inducible Rptor knockout mice (Tbx4-rtTA/Tet-On-Cre/Rptorfl/fl) and compared to wildtype controls, both subjected to tracheal injury. On Day 21 post injury, tracheas were harvested and tracheal lamina propria thickness (LPT) was measured. Pharmacological ablation was performed with early (Day 0-7 post injury) and late (Day 8-21 post injury) systemic rapamycin treatment.
RESULTS: Tracheal injury increased LPT compared to sham control. This effect was eliminated by genetic ablation of mTORC1, with mutant mice having no change in LPT compared to mutant sham control and significantly lower LPT than injured wildtype littermate controls. Early rapamycin significantly reduced the expected increase in injured tracheal LPT compared to early vehicle control, while late rapamycin had no effect compared to late vehicle control.
CONCLUSION: These results indicate that mTORC1 activity within tracheal mesenchyme is required for tracheal stenosis formation following injury and is an important therapeutic target.
LEVEL OF EVIDENCE: N/A.

Keywords:  airway stenosis; injury‐induced stenosis; mTORC1; tracheal stenosis

DOI:  https://doi.org/10.1002/lary.70958
Cureus. 2026 Sep;18(9): e115909

Prenatal Use of Sirolimus in Fetal Therapy: Current Evidence, Clinical Applications, and Future Directions.

Zbigniew Ruszczak, Iwona Strzelecka, Maria Respondek-Liberska.

  Prenatal imaging, genomic diagnosis, and pathway-directed pharmacology increasingly permit treatment of selected fetal disorders before birth. This narrative review evaluates maternally administered sirolimus as transplacental fetal therapy, emphasizing cardiac rhabdomyomas associated with tuberous sclerosis complex and severe vascular or lymphatic malformations. Sirolimus inhibits mechanistic target of rapamycin complex-1, a pathway central to cell growth, angiogenesis, and lymphangiogenesis. Published fetal case reports and small series describe regression of symptomatic cardiac rhabdomyomas and improvement in outflow obstruction, arrhythmia, cardiac dysfunction, hydrops, or impending fetal compromise. Evidence for prenatal treatment of vascular and lymphatic malformations is earlier. Still, it includes large cervicofacial lymphatic malformations and complex capillary-lymphatic-venous malformations threatening airway obstruction, hemorrhage, hydrops, or perinatal instability. Reported maternal adverse effects include mucositis, hyperlipidemia, cytopenias, infection risk, and impaired wound healing. Transplant pregnancy data have not identified a consistent malformation pattern, but exposures are sparse and confounded, while product labeling warns of embryo-fetal toxicity based on animal studies. Prenatal sirolimus therefore remains an investigational intervention for carefully selected, life-threatening or organ-threatening fetal disease managed by specialized multidisciplinary teams. Prospective registries and multicenter studies are needed to define dosing, fetal pharmacokinetics, stopping rules, delivery planning, and long-term outcomes.

Keywords:  fetal cardiac rhabdomyoma; fetal safety; fetal tumour; lymphatic malformation; maternal; maternal safety; mechanistic target of rapamycin; transplacental treatment; tuberous sclerosis complex; vascular malformation

DOI:  https://doi.org/10.7759/cureus.115909
J Cell Biochem. 2026 Oct;127(10): e70133

The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.

Xiao-Wen Zhang, Ming-Yue Wu, Qi Zhu, Xu Zhuang, Yu Dong, Shuang Zhang, Jia-Hong Lu.

  The vacuolar ATPase (V-ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient-sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V-ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID-based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy-responsive interactors of the V-ATPase V1A subunit (encoded by ATP6V1A). We found that mTORC1 inhibition disrupts the R2TP-V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α-synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V-ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.

Keywords:  R2TP complex; V‐ATPase; autophagy; lysosomal function; mTORC1

DOI:  https://doi.org/10.1002/jcb.70133
Int J Biol Macromol. 2026 Oct 06. pii: S0141-8130(26)04713-6. [Epub ahead of print] 154763

PDZ domain containing 1 sensitizes renal cancer cells to everolimus via inhibiting phosphatase and tensin homolog phosphorylation-mediated mTOR pathway activation.

Yinong Niu, Zhiyu Fang, Lei Wang, Mingshi Liu, Shuang Chen, Peng Yang, Yuanfeng Lan, Duiping Feng, Junqi He, Ran Song, Junfang Zheng.

  Aberrant activation of the phosphatase and tensin homolog (PTEN)-PI3K/AKT/mTOR pathway is a key driver of renal cell carcinoma (RCC) progression, making mTOR inhibition with everolimus a critical therapeutic strategy. However, the mechanisms driving mTOR pathway activation and the emergence of drug resistance remain poorly understood. In this study, we found that phosphorylated PTEN (pPTEN at S380/T382/T383) level was increased in RCC. Increased pPTEN level was associated with impaired suppression of mTOR pathway activation, and was accompanied by RCC progression and resistance to everolimus. Conversely, inhibition of PTEN phosphorylation restored PTEN function, reducing tumor growth and restoring sensitivity to everolimus. Further investigation revealed that downregulation of PDZ domain-containing 1 (PDZK1) in RCC tissues increased pPTEN level, resulting in mTOR pathway activation. PDZK1 was found to inhibit RCC malignancy by preventing PTEN phosphorylation and mTOR activation. Moreover, PDZK1 overexpression sensitized RCC cells to everolimus across cell, animal and organoid models. In conclusion, our findings indicate that PDZK1 downregulation in RCC cells contributes to pPTEN accumulation, mTOR pathway activation, and everolimus resistance. This highlights the PDZK1-pPTEN axis as a potential therapeutic target in RCC, suggesting that modulating PDZK1 or PTEN phosphorylation could enhance the efficacy of everolimus treatment.

Keywords:  Everolimus; PDZ domain containing 1; Phosphatase and tensin homolog; Renal cell carcinoma; mTOR

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154763
J Alzheimers Dis. 2026 Oct 09. 13872877261495936

Beyond the cerebrospinal fluid: Preclinical and clinical evidence on central nervous system penetration and functional activity of oral rapamycin (sirolimus).

Jeffrey M Melin, Nancy A Young, Joseph Camardo.

  Rapamycin, a potent mTORC1 inhibitor, is a leading candidate for treating age-related neurodegenerative disease. Numerous studies demonstrate beneficial effects in a variety of diseases that affect the brain. Yet a persistent belief among researchers is that rapamycin cannot penetrate brain tissue, citing as evidence its absence of detection in cerebrospinal fluid (CSF). This narrative review synthesizes clinical and preclinical evidence challenging this "CSF misconception." In humans, direct tissue sampling in glioblastoma detects rapamycin in brain at mTORC1-inhibitory concentrations, while functional measures-tumor regression and seizure control in tuberous sclerosis complex, cerebral metabolic preservation on PET in Alzheimer's disease, increased cerebral blood flow in APOE4 carriers, and prolonged antidepressant response-demonstrate incontrovertible activity in the brain. In mice, LC-MS/MS confirms dose-dependent brain accumulation, and rapamycin modulates mTORC1 signaling, autophagy, and synaptic, epigenetic, and inflammatory pathways. Rapamycin cannot be reliably detected in CSF because of four pharmacological factors-high lipophilicity with parenchymal sequestration, extreme red-cell and protein binding, P-glycoprotein efflux at the blood-CSF barrier, and assay insensitivity-none of which supports the contention that rapamycin fails to enter brain tissue. We flag the field's central gap: direct measurement of parent drug in intact human brain parenchyma at therapeutic doses is lacking. CSF concentration is a flawed proxy for rapamycin's CNS penetration. Alzheimer's disease and related dementias (ADRD) trials should instead track surrogate markers of mTORC1 inhibition, functional neuroimaging, clinical outcomes, and ADRD fluid biomarkers. These pharmacodynamics measurements are essential to the rational design and interpretation of prevention trials for the aging brain.

Keywords:  Alzheimer's disease; age-related neurodegenerative disease; blood-brain barrier; cerebrospinal fluid; mTOR; mTORC1; pharmacokinetics; rapamycin; sirolimus

DOI:  https://doi.org/10.1177/13872877261495936
Commun Biol. 2026 Oct 07. pii: 1304. [Epub ahead of print]9(1):

ESR1 mutations are associated with enhanced MTORC1 signaling in a context-dependent manner.

Tommaso De Marchi, Magdalena Kuras, Lazaro Hiram Betancourt, Sven Kjellström, Jeanette Valcich, Johan Vallon-Christersson, Christian Brueffer, Lao H Saal, Johan Malmström, Emma Niméus.

ESR1 mutations are a driver of endocrine therapy resistance in breast cancer, however their impact on protein signaling pathways and clinical outcomes remains poorly understood. We analyzed the transcriptomic, proteomic, and phosphoproteomic landscape of tumors harboring ESR1 mutations. Here we show that ESR1 mutated cancers exhibit a higher mutational burden associated with increased cell proliferation, and display enhanced activation of the mTOR pathway via MTORC1, suggesting an ER-driven amplification of existing oncogenic mechanisms. Analysis of an independent proteomic dataset from breast cancer cell lines further supported a convergence between MTORC1 and ER signaling programs. Integrative multi-omic data analysis incorporating features related to tumor grade, MTORC1 signaling, and ESR1 mutations, enabled the development of a predictive signature that distinguishes patients with ESR1 mutation and identified those at high risk of recurrence. This study provides insights into the mechanisms underlying tumor aggressiveness and poor clinical outcome modulated by ESR1 mutations and highlights the potential of proteogenomic approaches to identify signaling pathways and molecular signatures.

DOI: https://doi.org/10.1038/s42003-026-11096-w
Mol Cell Neurosci. 2026 Oct 05. pii: S1044-7431(26)00058-8. [Epub ahead of print]139 104128

Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.

Hosam Al-Jehani, Hayder M Al-Kuraishy, Ahmed M Abdelaziz, Ahmed A Mohamed, Ahmed M Mamdoh, Arafa Musa, Omar Mohamed Abdu Mursy, Gaber El-Saber Batiha.

  Brain aging is driven by progressive failure of neuronal proteostasis, culminating in the accumulation of toxic protein aggregates characteristic of Alzheimer's, Parkinson's, and Huntington's diseases. The AMPK-mTOR-autophagy signaling hub integrates cellular energy status with protein clearance machinery, making it a critical therapeutic node. Caloric restriction mimetics (CRMs), including rapamycin, metformin, resveratrol, and spermidine, exploit this axis by activating AMPK via AMP/ATP modulation and simultaneously suppressing mTORC1 kinase activity. This dual action relieves mTORC1-mediated inhibition of the ULK1 complex, triggering autophagosome nucleation, while sustained mTORC1 suppression promotes TFEB-driven lysosomal biogenesis, collectively restoring autophagic flux. Preclinically, these molecular events enhance clearance of amyloid-β, tau, α-synuclein, and mutant huntingtin and improve mitochondrial quality control via mitophagy. Despite robust mechanistic evidence, clinical translation remains constrained by poor CNS bioavailability, context-dependent autophagic outcomes, and the absence of validated pharmacodynamic biomarkers (e.g., LC3-II turnover, p62 flux) to confirm neuronal target engagement in humans. This review integrates CRM action on the AMPK/mTOR/autophagy axis with both the hallmarks of neuronal aging and disease-specific pathology, providing a molecular framework to guide the rational design of CNS-penetrant formulations, combination strategies, and personalized approaches to modify neurodegeneration.

Keywords:  AMPK; Autophagy; Brain aging; CRMs; Neurodegeneration; Proteostasis; mTOR

DOI:  https://doi.org/10.1016/j.mcn.2026.104128
Biomed Res Int. 2026 ;2026(1): e8867024

Acute Hypoxia Induces Cardiomyocyte Autophagy via SIRT5/mTOR/ULK1 Pathway.

Yunle Wang, Hongqi Wei, Yuxuan Wu, Yang Luo.

   OBJECTIVE: The aim of this study is to investigate the expression of SIRT5 in acute myocardial hypoxia and to further explore its function during this pathological process.
MATERIAL AND METHODS: We analyzed the microarray dataset GSE27975 derived from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs) between hypoxic and normoxic cardiomyocytes. We divided C57BL/6 J mice into two groups: the sham group and the acute myocardial infarction (MI) group. Heart functions were detected by echocardiogram, and heart tissue was harvested on the 3rd day after MI for the detection of autophagy and SIRT5 expression. To further study the mechanism of Sirt5 in hypoxic cardiomyocytes, we divided H9C2 cells into four groups: the control group, the hypoxia group, the Sirt5-knockdown group and the Sirt5-knockdown + hypoxia group and detected Sirt5 expression, cell autophagy and potential pathway.
RESULTS: A total of 156 genes were highly expressed, and 185 genes were expressed at low levels between hypoxic and normoxic cardiomyocytes. SIRT5 was expressed at low levels in the hypoxia group. In vivo, we generated the MI mouse model, and heart function was decreased. The expression of SIRT5 in heart tissue was decreased after MI, whereas the autophagy level was increased. In vitro, after we knocked down Sirt5 in H9C2 cardiomyocytes, autophagy was significantly increased. Meanwhile the expression of p-mTOR and p-ULK1 changed, whereas both mitochondrial membrane potential and respiratory capacity were maintained.
CONCLUSION: Acute hypoxia reduces SIRT5 expression may be associated with cardiomyocyte autophagy. Knockdown Sirt5 in H9C2s could activate autophagy via mTOR/ULK1 pathway and preserve mitochondrial function.

Keywords:  SIRT5; acute myocardial infarction; autophagy; hypoxia; mTOR; mitochondrial

DOI:  https://doi.org/10.1155/bmri/8867024
Front Oncol. 2026 ;16 1963427

TET1 loss promotes malignant phenotypes in HeLa cells and is associated with altered PTEN-PI3K/AKT/mTOR signaling.

Yan Liu, Lujia Liu, Lusheng Wang, Juan Ren, Fanle Meng, Mengling Chen, Xiaoyan Yao, Ping Zou, Jingjing Wu, Xiaoyan Zhou, Heng Tang, Weiwei Ma.

   Objective: To investigate the biological significance of ten-eleven translocation 1 (TET1) in cervical cancer and its association with PTEN-PI3K/AKT/mTOR signaling.
Methods: Publicly available bulk and single-cell transcriptomic datasets were analyzed, with histology-restricted analyses focused on cervical squamous cell carcinoma (SCC). TET1 immunoreactivity was assessed in five paired cervical adenocarcinoma and adjacent non-neoplastic tissues using nuclear H-scores. TET1 loss of function was modeled in HeLa cells by shRNA-mediated knockdown, with Bobcat339 used as a complementary TET-family inhibitor. Cellular metabolic activity, clonogenicity, cell-cycle distribution, apoptosis, migration, and invasion were evaluated using CCK-8, colony-formation, flow-cytometric, wound-healing, and Transwell assays. Protein expression and phosphorylation were examined by western blotting.
Results: SCC-restricted bulk analyses consistently showed lower TET1 expression in cervical SCC than in normal cervical tissues. In TCGA-CESC SCC, TET1 expression was not significantly associated with PTEN expression or the PI3K-AKT-mTOR transcriptional score after multiple-testing correction, whereas an inverse association with the apoptosis score remained significant. Patient-level pseudobulk analysis of 12 SCC cases likewise identified no pathway association that remained significant after false-discovery-rate correction. In five paired cervical adenocarcinoma cases, TET1 nuclear H-scores were lower in all tumor samples than in their matched adjacent tissues, although the difference did not reach statistical significance (exact P = 0.0625). In HeLa cells, TET1 depletion increased cellular metabolic activity and clonogenicity, altered cell-cycle distribution, reduced apoptosis, and enhanced migration and invasion. These changes were accompanied by reduced PTEN expression and increased phosphorylation of PI3K, AKT, and mTOR.
Conclusion: Reduced TET1 expression was observed in SCC-restricted public cohorts, while TET1 depletion promoted malignant phenotypes in HeLa cells. The accompanying changes in PTEN expression and PI3K/AKT/mTOR phosphorylation identify a candidate signaling association that warrants validation through rescue experiments and locus-specific epigenetic studies.

Keywords:  HeLa cells; PTEN–PI3K/AKT/mTOR signaling pathway; TET1; cell migration and invasion; cervical cancer

DOI:  https://doi.org/10.3389/fonc.2026.1963427
Endocr Relat Cancer. 2026 Oct 05. pii: ERC-25-0517. [Epub ahead of print]

TCF4-driven cathepsin S promotes papillary thyroid carcinoma via PI3K/AKT/mTOR.

Xinyi Zhang, Shengyi Zhou, Shuyi Zhang, Yizhou Sun, Wei Yuan, Hongjie Xu, Chengzhi Zhang, Andong Xu, Linsen Zhou, Guangjun Zhou.

  Papillary thyroid carcinoma (PTC) usually has a good prognosis, but a subset of patients develops lymph node metastasis, radioiodine resistance and recurrence, and lacks effective molecular biomarkers and therapeutic targets. Cathepsin S (CTSS), a lysosomal cysteine protease, has been implicated in several malignancies, yet its role and regulation in PTC remain unclear. We integrated GEO and TCGA-THCA datasets with eQTL-based genetic instrument analyses to screen PTC-related genes and evaluate their association with clinicopathological features and DFS. CTSS expression was examined in clinical tissues and cell lines by immunohistochemistry, qRT-PCR and Western blotting. Gain- and loss-of-function models were used to assess the effects of CTSS on PTC cell proliferation, colony formation, migration, apoptosis and nude-mouse tumor growth. RNA-seq, TCGA pathway-score correlation analysis were used to explore downstream pathways, and transcriptional regulation was investigated by in silico prediction, ChIP-qPCR and dual-luciferase assays. CTSS emerged as a candidate gene associated with PTC occurrence, lymph node metastasis and shorter DFS. CTSS was markedly upregulated in PTC tissues and cell lines. Functionally, CTSS knockdown suppressed proliferation and migration/invasion and promoted apoptosis, whereas CTSS overexpression enhanced malignant phenotypes in the examined PTC cell models. CTSS expression was associated with activation of the PI3K/AKT/mTOR pathway, and CTSS inhibition attenuated pathway activation and tumor growth. TCF4 bound the CTSS promoter, increased CTSS transcription, and TCF4 knockdown reduced CTSS expression and PI3K/AKT/mTOR pathway activity. These findings suggest that CTSS promotes malignant phenotypes in PTC and is associated with PI3K/AKT/mTOR activation, while TCF4 may contribute to CTSS transcriptional regulation.

Keywords:  CTSS; PI3K/AKT/mTOR signaling pathway; TCF4; papillary thyroid carcinoma

DOI:  https://doi.org/10.1530/ERC-25-0517
RSC Med Chem. 2026 Aug 13.

Improving the metabolic stability of a selective mTOR inhibitor through scaffold deconstruction and carbamate exploration.

Álvaro Lorente-Macías, Jonathon Mok, Margaret C Frame, Asier Unciti-Broceta.

We describe a focused medicinal chemistry program directed towards the metabolic stability optimization of eALM1137, a highly potent and selective mTOR inhibitor with demonstrated antiproliferative activity in cancer cell lines. Through scaffold deconstruction and systematic nitrogen atom exploration of the central pyrazolo[3,4-d]pyrimidine core, combined with optimization of the carbamate moiety, we identified the key structural features governing both mTOR inhibitory activity and metabolic liability in this chemotype. This effort culminated in the discovery of 2w (eALM1192), a pyrrolo[2,3-d]pyrimidine-based analog bearing a propargyl carbamate, an underexplored motif in the field, which exhibits sub-nanomolar antiproliferative activity across colorectal cancer cell lines, an mTOR IC50 of 2.3 nM with 37-fold selectivity over DNA-PK, excellent kinome selectivity, and an 8-fold improvement in the metabolic half-life (t ½ = 109 min).

DOI: https://doi.org/10.1039/d6md00572a
Toxicol Appl Pharmacol. 2026 Oct 07. pii: S0041-008X(26)00367-4. [Epub ahead of print]517 118071

10-gingerol potentiates paclitaxel efficacy in triple-negative breast cancer by remodeling gut microbiota and suppressing PI3K/AKT/mTOR signaling pathway.

Yaning Xu, Ruirui Zhao, Haopeng Chen, Xiaohan Li, Qian Zhang, Saixuan Zhang, Xinyu Bai, Hai Lu, Zhiyong Xie.

  Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and chemoresistance, particularly to first-line agents such as paclitaxel (PTX). 10-Gingerol (10-G), the main pungent constituent of ginger, has been shown to possess anti-tumor and chemosensitizing properties. However, the mechanisms by which it potentiates PTX efficacy in TNBC remain incompletely understood. We established a 4T1 TNBC-bearing BALB/c mouse model to assess the in vivo therapeutic effect of 10-G combined with PTX. Multi-omics analyses integrating 16S rRNA gene sequencing and transcriptome sequencing were performed to characterize gut microbial remodeling and tumor transcriptomic alterations. Results showed that combination therapy significantly inhibited tumor growth and cell proliferation with favorable safety and remodeled the gut microbiota by enriching beneficial genera (Limosilactobacillus, Lactobacillus) and reducing potentially pathogenic genera (Enterocloster, Mucispirillum). Transcriptomic profiling revealed that the PI3K/AKT/mTOR signaling pathway in tumor tissues following combination treatment was markedly suppressed. Mechanistic validation through molecular docking, molecular dynamics simulations, and Western blotting confirmed that 10-G directly binds to PI3K, AKT, and mTOR, and that combination therapy significantly suppressed phosphorylation of PI3K, AKT, and mTOR in tumor tissues. Collectively, this study demonstrates that 10-G augments the anti-tumor efficacy of PTX in TNBC, and this potentiation is mechanistically linked to favorable gut microbiota remodeling and targeted inhibition of the PI3K/AKT/mTOR signaling axis, thereby positioning 10-G as a promising chemosensitizing adjuvant for TNBC therapy.

Keywords:  10-Gingerol; Gut microbiota; PI3K/AKT/mTOR signaling pathway; Paclitaxel; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.taap.2026.118071
Mol Biol Cell. 2026 Oct 08. mbcE25090457

Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.

Shiraz Anwar, Solmaz Ebrahimi-Iranpour, Maria R Narciso, Jennifer Li, Saaimatul Huq, Tracy Lackraj, Tamara Beriia, Nazia Chowdhury, Mojca Mattiazzi Usaj, Roberto J Botelho.

While lysosomes are typically globular in morphology, lipopolysaccharide-activated macrophages reorganize lysosomes into an expanded tubular network. Here, we sought to determine if the V-ATPase and the lysosomal pH contribute to LPS-mediated lysosome tubulation in macrophages. We found that inhibition of the V-ATPase prevented lysosome tubulation and collapsed preformed tubules. However, the V-ATPase also controls mTORC1 activity, which itself is needed for tubulation. To distinguish between lysosomal pH and mTORC1, we turned to NH4Cl, which alkalinized lysosomal pH but did not interfere with mTORC1; yet NH4Cl blocked tubulation showing that an acidic lysosomal pH is needed for lysosome remodelling. Moreover, clamping the pH to either acidic or alkaline pH caused tubules to collapse, indicating that the pH gradient promotes tubulation, rather than a specific pH. These effects were not due to altered microtubule organization or impaired lysosome motility, suggesting that motors remained associated with lysosomes. On the other hand, while LPS did not alter the average pH of spherical or tubular lysosomes, growing tubules displayed a more acidic peripheral end relative to the pericentral end. Based on this observation, we propose that a localized pH gradient along the tubule may enable tubulation by modulating factors that catalyse tubule growth. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-09-0457