bims-matara 2026-09-06 papers

bims-matara

Biomed News

on MTOR

Issue of 2026–09–06
seventeen papers selected by
Lucas van Endert, Institut du Cerveau

mTORC1 Promotes SARS-CoV-2 Replication and Attenuates Type I Interferon Responses in the Alveolar Epithelium: A Computational and Experimental Study.
EIF4EBP1 in Breast Cancer: Translational Control, Regulatory Networks, and Therapeutic Frontiers.
High-Dose MK-801 Attenuated Early TTC-Defined Cortical Injury Even under the Conditions of Suppressed Rapamycin-Sensitive pS6 Signaling during Early Cerebral Ischemia-Reperfusion.
Rapamycin Attenuates Acute Pancreatitis-Induced Acinar Injury in Mice With Pancreatic Loss of Gα13.
Serine: From Metabolic Intermediate to Signaling Entity.
Transplacental sirolimus therapy for severe fetal cardiac rhabdomyomas in tuberous sclerosis complex: organ-specific responses and 30-month follow-up: A case report.
[Metformin Inhibits Prostate Cancer Progression via Regulation of the AKT/mTOR Signaling Pathway].
Glucose-TOR-PDCB signaling restricts cell-to-cell communication through callose deposition.
CASTOR1 regulates humoral immune responses and contributes to the pathogenesis of systemic lupus erythematosus.
Bioactive compound ginkgolide B alleviates food allergy by regulating mTOR signaling pathway.
"Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.
HOXC9 promotes cell proliferation and suppresses mitochondria-dependent apoptosis through the AKT/mTOR pathway in esophageal squamous cell carcinoma.
Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1+ pathologic fibroblasts.
Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach.
Targeting the PI3K/AKT/mTOR pathway in gastrointestinal cancers: a comprehensive review of mechanisms, preclinical evidence, and clinical challenges.
Apigenin activates AKT1 to coordinate MTOR-mediated anti-apoptosis and FOXO3-driven antioxidant defense in calcium oxalate nephropathy.
Anlotinib inhibits glioma cell proliferation, migration, and invasion by suppressing c-MET/AKT/mTOR signaling and altering autophagy-associated protein expression.

Bull Math Biol. 2026 Sep 02. pii: 171. [Epub ahead of print]88(10):

mTORC1 Promotes SARS-CoV-2 Replication and Attenuates Type I Interferon Responses in the Alveolar Epithelium: A Computational and Experimental Study.

Achyudhan R Kutuva, Henrique Al Ribeiro, Felipe T Lima, Matthew A Schaller, Borna Mehrad, Reinhard Laubenbacher.

  The mechanistic target of rapamycin complex 1 (mTORC1) has been implicated in coronavirus pathogenesis, yet its precise role in shaping antiviral defenses in pneumocytes remains unresolved. This study combines ex vivo human lung tissue assays with a literature-curated, logic-based (Boolean) signaling model to study how mTORC1 influences SARS-CoV-2 replication and type-I interferon (IFN) responses. Our in-vitro data showed that pharmacologic inhibition of mTORC1 with sirolimus was associated with reduced viral replication and increased IFN- β expression across donor samples. To interpret these data, we constructed a network integrating inflammation, stress, apoptosis, and RIG-I-IFN signaling, and evaluated four mechanistic hypotheses for explaining our experiments in which mTORC1 either promotes replication, inhibits IFN, both, or neither. The model was constructed according to the best evidence in the literature and evaluated against 56 independent protein/phosphoprotein readouts from 26 studies not used for model construction; the model achieved high qualitative accuracy overall (F1 ≳0.75 ) and on live-virus experiments (F1 ≳0.9 ). We found that the hypotheses where mTORC1 promotes viral replication, inhibits IFN, or both were able to qualitatively reproduce the empirical data, i.e., mTORC1 inhibition by sirolimus leads to lower viral replication and higher IFN expression. We queried the robustness of those predictions through a systematic edge knock-in/knockout screen generating 6,328 network variants per scenario (25,312 total). We found that the scenario where mTORC1 enhances viral replication is the more plausible, due to parsimony (this mechanism is also observed in other viral infections), higher robustness (more variants still reproduce the result), and stronger inhibition that is more likely to be observed in biological experiments with low statistical power. This scenario supports the idea that the mTORC1 effects on IFN expression are indirectly mediated by viral replication itself.

Keywords:  Boolean network; IFN; MTORC1; SARS-CoV-2

DOI:  https://doi.org/10.1007/s11538-026-01701-8
Front Biosci (Landmark Ed). 2026 Aug 14. 31(8): 45484

EIF4EBP1 in Breast Cancer: Translational Control, Regulatory Networks, and Therapeutic Frontiers.

Weijia Liu, Lili Hou, Dandan Tang, Haiyu Mou, Weijie Wang, Song-Bai Liu, Xiaohua Li.

  Eukaryotic initiation factor 4E-binding protein 1 (EIF4EBP1/4E-BP1) is a pivotal translational regulator with context-dependent roles in breast cancer pathogenesis. Its phosphorylation status, dynamically controlled by mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, dictates a dualistic function: hypophosphorylated EIF4EBP1 suppresses oncogenesis by sequestering eIF4E and inhibiting cap-dependent translation of pro-tumorigenic mRNAs (e.g., cyclin D1 and c-MYC), while hyperphosphorylation promotes tumor progression and therapeutic resistance. EIF4EBP1 amplification (8p11-p12) is correlated with endocrine resistance and poor prognosis. EIF4EBP1 modulates cell cycle checkpoints, metabolic adaptation under stress, and resistance to cyclin-dependent kinase (CDK) 4 and 6 inhibitors and rapalogs via feedback loops (e.g., SGK3/Akt reactivation). Emerging therapeutic strategies, such as ATP-competitive mTOR inhibitors, bisteric compounds, and agents targeting polyamine metabolism or upstream kinases, exploit the dynamics of EIF4EBP1 phosphorylation. As a biomarker, phosphorylated EIF4EBP1 levels predict tumor aggressiveness and treatment failure, positioning it as a critical node for precision oncology. Future research must address spatial heterogeneity and leverage multi-omics/AI-driven approaches.

Keywords:  biological markers; breast neoplasms; eukaryotic initiation factor-4E-binding protein 1; mechanistic target of rapamycin; protein biosynthesis

DOI:  https://doi.org/10.31083/FBL45484
Naunyn Schmiedebergs Arch Pharmacol. 2026 Aug 31.

High-Dose MK-801 Attenuated Early TTC-Defined Cortical Injury Even under the Conditions of Suppressed Rapamycin-Sensitive pS6 Signaling during Early Cerebral Ischemia-Reperfusion.

Oak Z Chi, Xia Liu, Harvey R Weiss, Yoon-Seong Kim, Woom-Yee Bae.

  The interrelationship of mechanistic target of rapamycin (mTOR), brain-derived neurotrophic factor (BDNF), NMDA receptor and neuronal survival during early cerebral ischemia-reperfusion is not certain. We investigated this relationship by using MK-801, a non-competitive NMDA receptor antagonist and by determining infarct size and blood-brain barrier (BBB) disruption under the condition of markedly reduced mTORC1 activity. Rats received rapamycin (20 mg/kg, i.p.) for two days before transient middle cerebral artery occlusion (MCAO). At 15 min after MCAO, half of the rats received MK-801 (5 mg/kg i.v.). At two hours' reperfusion after 90 min MCAO, BBB permeability, plasma volume and infarct size were determined. In rats without MCAO, one hour after MK-801, protein levels of pS6 (Ser240/244), pAkt (Ser473), mBDNF, proBDNF and MMP-2 were analyzed by Western blot. MK-801 reduced the percentage of cortical infarct in the Control (8.4% ± 2.1 vs 4.7% ± 1.5) and in the Rapamycin Group (12.2% ± 2.3 vs 6.7% ± 2.0). The BBB permeability were not changed. The average plasma volume of the MK-801 Group was largest of all Groups. In the non-ischemic brain, MK-801 increased pS6 levels, which were markedly reduced by rapamycin pretreatment. MK-801 also increased proBDNF levels without affecting mBDNF levels, and neither response was altered by rapamycin pretreatment. In conclusion, our data indicate that high-dose MK-801 reduced TTC-defined cortical injury even under conditions of suppressed pS6 signaling and elevated proBDNF levels. The larger plasma volume observed in the MK-801-treated rats may have contributed to the reduced cortical injury. Therefore, mechanisms other than mTORC1 signaling should be considered in the neuroprotective effects of MK-801 during the early stage of cerebral ischemia-reperfusion.

Keywords:  BDNF; Blood–brain barrier; Cerebral ischemia–reperfusion; MK-801; MTORC1 activator; NMDA antagonist

DOI:  https://doi.org/10.1007/s00210-026-05877-7
Gastro Hep Adv. 2026 ;5(10): 101076

Rapamycin Attenuates Acute Pancreatitis-Induced Acinar Injury in Mice With Pancreatic Loss of Gα13.

Hidayatullah G Munshi, Anastasia E Metropulos, Khadijeh Karbalaei, Christina Spaulding, Nida Mubin, Yaning Xi, Apurba Majumder, Thao D Pham, Mario A Shields.

   Background and Aims: While Gα13 transduces signals from G protein-coupled receptors to regulate inflammation, its role in pancreatitis remains poorly understood. This study aims to understand how Gα13 regulates pancreatitis-induced inflammation and acinar injury.
Methods: Expression of Gα13 in mouse and human pancreas tissue was examined by immunostaining. Experimental pancreatitis was induced by administering cerulein to mice with wild-type and conditional knockout of Gα13 in the pancreas. The impact of Gα13 loss on pancreatitis was assessed by histology, immunostains, and cytokine proteome array. The Gα13-deficient mice were cotreated with the mammalian target of rapamycin (mTOR) inhibitor rapamycin during cerulein treatment to determine the effects of mTOR inhibition on pancreatitis.
Results: We found reduced Gα13 expression in acute and chronic human pancreatitis samples. We show that induction of acute and chronic pancreatitis in mice with cerulein treatment reduces Gα13 expression. Moreover, we found worsening of acute and chronic pancreatitis-induced acinar injury in mice with pancreas-specific deletion of Gα13. While pancreatic deletion of Gα13 did not exacerbate acute pancreatitis-induced inflammation, we found that Gα13 loss mildly exacerbated chronic pancreatitis. Gα13 loss increased cerulein-induced mTOR signaling in the acute and chronic pancreatitis mouse models; however, the mTOR inhibitor rapamycin attenuated the effects of cerulein only in the acute pancreatitis model, whereas it exacerbated the effects of cerulein in the chronic pancreatitis model.
Conclusion: This work demonstrates that Gα13 loss promotes tissue damage in acute and chronic pancreatitis, which can be attenuated by the mTOR inhibitor rapamycin in acute pancreatitis.

Keywords:  Acinar Injury; Gα13; Inflammation; Pancreatitis

DOI:  https://doi.org/10.1016/j.gastha.2026.101076
Biochemistry. 2026 Sep 01. 65(17): 2629-2643

Serine: From Metabolic Intermediate to Signaling Entity.

Sharon Spizzichino, Giovanni Maria Varchetta, Giulia Elizabeth Borsatti, Emma Chillemi, Marzia Arese, Alessio Paone, Serena Rinaldo, Francesca Cutruzzolà.

  Serine, a nonessential amino acid classically defined as a precursor for protein synthesis and one-carbon metabolism, is increasingly recognized as a signaling metabolite that links the cellular metabolic status to regulatory decision-making. Intracellular serine availability is shaped by nutrient conditions, glycolytic flux, and activity of the serine synthesis pathway, and these fluctuations are sensed to elicit coordinated metabolic and signaling responses. This review discusses mechanisms by which serine modulates cell growth and stress responses, with particular emphasis on its interaction with central nutrient-sensing pathways, including mTORC1 and the integrated stress response. In parallel, serine-driven one-carbon metabolism is examined for its role in supporting nucleotide biosynthesis, methylation reactions, and redox homeostasis through folate-dependent pathways and NADPH generation, thereby coupling anabolic processes to the maintenance of redox balance and genome integrity. In addition to intracellular functions, serine contributes to intercellular signaling. Conversion of l-serine to d-serine mediates neuromodulatory activity via N-methyl-d-aspartate receptors, while serine availability also influences immune cell function, inflammatory signaling, and host-microbe interactions. Dysregulation of serine metabolism and signaling is further considered in the context of disease states, including cancer, neurodegeneration, and metabolic disorders. Together, these observations support a framework in which serine functions as an information-bearing metabolic signal that coordinates the biosynthetic capacity with cellular adaptation and intercellular communication.

Keywords:   N-methyl-d-aspartate (NMDA); 3-phosphoglycerate (3-PG); S-adenosylmethionine (SAM); phosphoenolpyruvate (PEP); reactive oxygen species (ROS)

DOI:  https://doi.org/10.1021/acs.biochem.6c00353
Fetal Diagn Ther. 2026 Sep 01. 1

Transplacental sirolimus therapy for severe fetal cardiac rhabdomyomas in tuberous sclerosis complex: organ-specific responses and 30-month follow-up: A case report.

Kana Naito, Yoshinori Moriyama, Yuri Kawai, Kazuyoshi Saito, Hazuki Nakajima, Masamitsu Nakamura, Takao Sekiya, Naoko Ishihara, Masafumi Miyata, Tetsushi Yoshikawa, Haruki Nishizawa.

BACKGROUND: Transplacental mammalian target of rapamycin (mTOR) inhibition has emerged as a promising therapeutic strategy for severe fetal cardiac rhabdomyomas in tuberous sclerosis complex (TSC). However, its impact on neonatal cardiovascular adaptation and long-term neurological outcomes remains poorly understood.
CASE PRESENTATION: We report a fetus with clinically diagnosed TSC presenting with multiple large cardiac rhabdomyomas causing progressive hemodynamic compromise. Transplacental sirolimus therapy was initiated at 30 weeks of gestation and continued for 7 weeks, resulting in marked regression of cardiac tumors, improved left ventricular outflow tract patency, and recovery of fetal cardiac function. In contrast, serial fetal imaging demonstrated no apparent change in the size or number of intracranial lesions. Elective cesarean delivery was performed at 38 weeks of gestation. Despite favorable prenatal structural improvement, the neonate developed severe left ventricular dysfunction immediately after birth, requiring ductal-dependent circulatory support and intensive cardiovascular management. Postnatal everolimus therapy was initiated on the day of birth, leading to complete regression of cardiac rhabdomyomas by 5 months of age. However, central nervous system lesions persisted, epilepsy developed during infancy, and cognitive and language delays remained evident at 30 months of follow-up. Wolff-Parkinson-White syndrome was also identified during infancy. Genetic analysis ultimately revealed a heterozygous deletion involving exons 11-16 of TSC2.
CONCLUSIONS: This case demonstrates organ- and tissue-specific therapeutic responses to prenatal and postnatal mTOR inhibition in TSC. Although transplacental mTOR inhibition may be life-saving for severe fetal cardiac involvement, prenatal structural improvement may not necessarily predict neonatal cardiovascular stability or favorable long-term neurological outcomes. These findings underscore the importance of careful perinatal planning, realistic prenatal counseling, and extended multidisciplinary follow-up.

DOI: https://doi.org/10.1159/fdt/acuag007
Sichuan Da Xue Xue Bao Yi Xue Ban. 2026 Jul 20. 57(4): 1022-1031

[Metformin Inhibits Prostate Cancer Progression via Regulation of the AKT/mTOR Signaling Pathway].

Zhengkun Zhang, Zhiyou Quan, Panpan Dai, Keyi Xu, Zhaoru Yin, Dan Chen, Ruiman Geng, Xuxu Ji, Dingxue Wang, Shu Chen, Lihong Chen, Ji Liu.

   Objective: To investigate the effects of metformin on the proliferation, migration, and invasion of prostate cancer cells, and to determine whether its antitumor effects are mediated by regulation of human antigen R (HuR) and the AKT/mammalian target of rapamycin (mTOR) signaling pathway.
Methods: Human prostate cancer cell lines PC3 and 22RV1 were used as the research models and were treated with metformin. HuR knockdown and overexpression experiments were performed to further verify the underlying mechanism. Cell proliferation was assessed using the cell counting kit-8 (CCK-8) assay. Cell migration and invasion were evaluated by Transwell assays. The expression levels of HuR and AKT/mTOR pathway-related proteins were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.
Results: Metformin treatment reduced the proliferation, migration, and invasion abilities of PC3 and 22RV1 cells, and inhibited the expression of proteins associated with the AKT/mTOR signaling pathway (P < 0.05). HuR knockdown also decreased the proliferation, migration, and invasion abilities of prostate cancer cells and inhibited AKT/mTOR pathway activity. In contrast, HuR overexpression partially attenuated the inhibitory effects of metformin on the malignant biological behaviors of prostate cancer cells and its inhibitory effects on the AKT/mTOR signaling pathway. In addition, metformin downregulated HuR mRNA and protein expression levels in PC3 and 22RV1 cells in a concentration-dependent manner (P < 0.01).
Conclusion: Metformin may inhibit the activation of the AKT/mTOR signaling pathway by downregulating HuR expression, thereby reducing the proliferation, migration, and invasion of prostate cancer cells.

Keywords:  AKT; Humanantigen R; Metformin; Prostate cancer; mTOR

DOI:  https://doi.org/10.12182/20260760204
Sci Adv. 2026 Sep 04. 12(36): eaeg9566

Glucose-TOR-PDCB signaling restricts cell-to-cell communication through callose deposition.

Michael Busche, Anne M Runkel, Min Xu, Katherine A Klimpel, Sannidhi Menon, Katherine M Lund, Kyle Koch, Snigdha Chatterjee, Erin R Alberts, Ryan E Martinez, M Regina Scarpin, Jacob O Brunkard.

Plant cells are connected by plasmodesmata (PD), membrane-lined channels that facilitate cell-to-cell transport. Forward genetic screens to uncover regulators of PD transport identified mutants with increased (ise1 to ise4) or decreased (dse1) PD trafficking during embryogenesis. Despite their opposite effects on PD transport, we found that the transcriptional profiles of dse1, ise3, and ise4 were notably similar with one notable exception: the set of genes controlled by the conserved kinase TARGET OF RAPAMYCIN (TOR) and ABI5, a bZIP transcription factor that acts downstream of TOR. We then showed that the glucose-TOR-ABI5 signaling axis regulates PD transport by driving expression of PD-localized callose binding proteins (PDCBs), which are oppositely regulated in ise versus dse mutants and promote callose deposition at PD. Together, this study establishes a mechanism for metabolic regulation of cell-to-cell transport by TOR-ABI5-PDCB signaling.

DOI: https://doi.org/10.1126/sciadv.aeg9566
Arthritis Rheumatol. 2026 Sep 04.

CASTOR1 regulates humoral immune responses and contributes to the pathogenesis of systemic lupus erythematosus.

Takeshi Kusuda, Toshihiko Komai, Takahiro Itamiya, Tatsuki Abe, Tomohisa Okamura, Keishi Fujio.

OBJECTIVES: CASTOR1 senses arginine and regulates mammalian target of rapamycin complex 1 (mTORC1), a central metabolic signaling molecule. This study aimed to elucidate the roles of CASTOR1 in humoral immune responses.
METHODS: We analyzed human B cell transcriptomes from healthy controls and patients with systemic lupus erythematosus (SLE) via correlation analysis and gene set variation analysis using our database, Immune Cell Gene Expression Atlas from the University of Tokyo (ImmuNexUT). Castor1-deficient and B cell-specific Castor1-deficient mice were used for analyses of serum immunoglobulins and autoantibodies, urinary proteins, renal pathology, gene expression, and flow cytometry in spleen and bone marrow cells. The culture supernatant of splenic B cells was used for immunoglobulin analysis.
RESULTS: Transcriptomic analysis of bulk RNA sequencing data from various B cell subsets in SLE patients (n = 136; n = 129 included in the primary analysis) revealed a correlation between CASTOR1 expression and disease activity, with CASTOR1 expression in plasmablasts inversely correlated with SLEDAI-2K (r = -0.32, p = 0.00031). Castor1-deficient mice exhibited increased plasma cell populations in the spleen and bone marrow, elevated serum IgG levels, production of anti-dsDNA antibodies, and glomerulonephritis with IgG deposits, reflecting SLE-like autoimmunity. Moreover, B cell-specific Castor1-deficient mice showed increased plasma cell counts, elevated serum IgG levels, and glomerulonephritis, indicating that Castor1 might regulate systemic humoral immunity via a B cell-intrinsic mechanism.
CONCLUSIONS: CASTOR1 plays a regulatory role in humoral immunity and may contribute to the pathogenesis of autoimmune diseases such as SLE, representing a potential therapeutic target.

DOI: https://doi.org/10.1002/art.70314
Front Immunol. 2026 ;17 1893204

Bioactive compound ginkgolide B alleviates food allergy by regulating mTOR signaling pathway.

Rongqin Zhou, Xiaotong Yang, Panpan Tan, Huan Wang, Dan Zeng, Xiaojuan Ma.

   Background: The prevalence of food allergy has been rising over the past decade, but effective treatments remain limited. The purpose of this study was to investigate the effect of ginkgolide B (GB), a natural bioactive compound with well-documented anti-inflammatory and immunoregulatory properties, on a mouse model of food allergy and to elucidate the mechanism mediated by the mTOR signaling pathway.
Methods: BALB/c mice were randomly divided into five groups, namely: NC group, food allergy group (Model), low-dose GB intervention group (GBL, 5 mg/kg/day), high-dose GB intervention group (GBH, 40 mg/kg/day), and a positive control group treated with food allergy herbal formula-2 (FAHF-2). At the end of the sensitization period, the mice were intervened by gavaging GB or FAHF-2. Allergy-related factors such as serum titers, cytokines in the spleen, and intestinal morphology were detected. mTOR signaling pathway in the splenocytes was also detected.
Results: After treatment, the levels of serum IgE, IgG, IgG1, and IgG2a in the GBL group were significantly lower than those in the GBH and model groups. The analysis of intestinal morphology indicated that a low dose of GB and FAHF-2 alleviated food allergy more effectively than a high dose of GB. The results of the analysis of splenic cytokines and flow cytometry showed more balanced Th1/Th2 ratio and Th17/Treg ratio after GB and FAHF-2 treatment, especially for GBL, whose effect was comparable to those of FAHF-2. The expression levels of p-STAT3, p-STAT6, and GATA-3 were significantly decreased, and the expression levels of p-STAT4 and Foxp3 were significantly increased after GB and FAHF-2 treatment. Moreover, the reductions in p-mTOR, p-AKT, p-SGK1, and p-4EBP1 induced by allergic sensitization were restored in the GBL intervention group.
Conclusion: GB (5 mg/kg/day) exerts a significant therapeutic effect on food allergy, possibly by regulating the mTOR signaling pathway.

Keywords:  allergy; bioactive compound; food allergy; ginkgolide B; mTOR signaling pathway

DOI:  https://doi.org/10.3389/fimmu.2026.1893204
J Am Chem Soc. 2026 08 26. 148(33): 35538-35550

"Trojan" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway.

Zixin Sang, Yiqiang Zheng, Xia Wang, Cang Wu, Jiaqi Zhao, Jun Joelle Wang, Senfang Sui, Jie Wang.

Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Using chemoproteomic profiling and biochemical validation, we found that PKM2 is a specific methionine sensor that transduces methionine availability signals through the interaction with the GATOR2 complex, which, in turn, modulates the downstream response of the mTORC1 pathway through a novel methionine-recognition pocket on PKM2. As our findings indicate that the sensing of methionine by PKM2 is independent of its enzymatic activity, we envision that disrupting the binding of methionine to PKM2 or stabilizing the PKM2-GATOR2 interaction would create a methionine pseudostarvation state in living cells, which holds promise as a novel therapeutic avenue that could emulate the physiological benefits of a methionine-restricted diet and circumvent the drawbacks of dietary methionine restriction.

DOI: https://doi.org/10.1021/jacs.6c06772
Mol Cell Biochem. 2026 Aug 31.

HOXC9 promotes cell proliferation and suppresses mitochondria-dependent apoptosis through the AKT/mTOR pathway in esophageal squamous cell carcinoma.

Xinya Yu, Yajun Wang, Xinyu Ju, Zhen Li, Jieli Song, Boning Wu, Qi Ding, Yuan Jiang, Yupeng Wu.

  Homeobox C9 (HOXC9) is aberrantly expressed in multiple malignancies; however, its functional role in esophageal squamous cell carcinoma (ESCC) remains elusive. This study investigated the expression, function, and underlying molecular mechanisms of HOXC9 in ESCC. HOXC9 was evaluated via immunohistochemistry in 118 ESCC and paired normal tissues. Stable cell lines with HOXC9 knockout, knockdown, and overexpression were established in KYSE70 and KYSE150 cells. Cell proliferation, apoptosis, mitochondrial membrane potential, and in vivo xenograft growth were assessed. Mechanistic studies were performed using RNA-seq, Western blotting, and PI3K inhibitor LY294002 (30 µM). IHC analysis revealed significantly elevated HOXC9 expression in ESCC versus paired adjacent normal tissues (high expression rate: 57.6% vs. 22.9%, P < 0.0001) and associated with poorer overall survival. Receiver operating characteristic (ROC) curve analysis showed favorable diagnostic value for HOXC9 (area under the curve [AUC] = 0.97). Functional assays showed that HOXC9 promoted ESCC cell proliferation and inhibited mitochondria-dependent apoptosis. Mechanistically, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Western blot analyses indicated that HOXC9 is associated with activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Pharmacological blockade and xenograft experiment further supported the involvement of this pathway in HOXC9-driven oncogenic phenotypes. This study identifies a potential mechanism by which HOXC9 contributes to ESCC progression via AKT/mTOR-mediated inhibition of mitochondria-dependent apoptosis and promotion of cell proliferation. These findings suggest HOXC9 as a candidate prognostic biomarker and preliminary therapeutic target for ESCC, requiring further validation across clinical and molecular subtypes.

Keywords:   HOXC9 ; Apoptosis; Cell proliferation; ESCC; PI3K/AKT/mTOR pathway

DOI:  https://doi.org/10.1007/s11010-026-05715-7
Sci Adv. 2026 Sep 04. 12(36): eadx9868

Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1+ pathologic fibroblasts.

Jo-Anne Am Wilson, Rachel Walters, Greg Contento, Madeleine Rossanese, Delphine Guillotin, Alexander I Ward, Robert E Hynds, Mariam Jamal-Hanjani, Naftali Kaminski, Silvia Parolo, Manuela Platé, Rachel C Chambers.

Fibrosis, marked by excess extracellular matrix (ECM) deposition, is the end stage of many diseases. Single-cell studies have highlighted the emergence of disease-specific fibroblast populations, including a high collagen-synthesizing CTHRC1+ subpopulation. The profibrotic cytokine TGF-β1 promotes fibrogenesis via cooperation between Smad and mTORC1/4E-BP1 signaling axes. Using CRISPR-Cas9 gene editing, we report that more than one-third of TGF-β1-regulated matrisome genes are under mTORC1 control. Mapping the transcriptome of TGF-β1-stimulated fibroblasts revealed similarity to CTHRC1+ fibroblasts identified in idiopathic pulmonary fibrosis (IPF). This overlap is lost when mTORC1 is disabled. Using the selective mTORC1 inhibitor RMC-5552, we confirm a causal role for mTORC1 in promoting the acquisition of the collagen-high, CTHRC1+ phenotype in response to TGF-β1 stimulation in fibroblasts derived from patients with either IPF or lung adenocarcinoma. We conclude that mTORC1 plays a key role in shaping the transcriptional identity of these fibroblasts, with implications for therapeutic inhibition of mTORC1 in fibrosis and cancer.

DOI: https://doi.org/10.1126/sciadv.adx9868
PLoS One. 2026 ;21(9): e0343189

Comprehensive analysis of non-synonymous single-nucleotide polymorphism of human TSC1 and TSC2 genes: An in silico approach.

Tasnim Alam, Shangida Akther.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder resulting from the mutations in the TSC1 and TSC2 genes and is distinguished by benign hamartoma formation in multiple organs. The TSC1-TSC2 complex regulates mTORC1 signaling in response to cellular growth conditions. This study aims to predict the structural stability and functional effects of non-synonymous single-nucleotide polymorphisms (nsSNPs) in human TSC1 and TSC2 using computational approaches. Twelve computational tools were assessed using receiver operating characteristic (ROC) analysis and applied to identify deleterious nsSNPs. Protein stability was predicted using I-Mutant 2.0 and MUpro, while evolutionary conservation was analyzed with ConSurf. NetPhos 3.1 identified potential PTM sites, and MutPred2.0 evaluated their functional impact. Project HOPE assessed mutation-induced physicochemical changes. Structural models were validated using multiple tools, visualized in ChimeraX 1.9, and further evaluated by molecular dynamics simulation to confirm wild-type and mutant stability. A combined in silico analysis identified twelve high-risk nsSNPs in TSC1 and sixteen in TSC2, all reducing protein stability, located in conserved regions, and potentially disrupting phosphorylation sites. MutPred and Project HOPE confirmed their impact on protein function. Functional analysis showed TSC1 and TSC2 affect mTORC1 and PI3K-Akt pathways. RMSF and RMSD analyses revealed that TSC1 variants rs1846545280 (G236E), and rs2132135678 (V234E), and TSC2 variants rs45517223 (S758C), rs2151354925 (T836P), and rs45517365 (R1570W) had the largest structural fluctuations. Substitution with glutamic acid, a negatively charged and bulkier residue, may disrupt local folding of TSC1. Similarly, replacement of arginine with tyrosine at position 1570 may impair Rheb binding at the GAP domain of TSC2. These findings highlight potentially pathogenic nsSNPs in TSC1 and TSC2.

DOI: https://doi.org/10.1371/journal.pone.0343189
Med Oncol. 2026 Aug 29. pii: 256. [Epub ahead of print]43(10):

Targeting the PI3K/AKT/mTOR pathway in gastrointestinal cancers: a comprehensive review of mechanisms, preclinical evidence, and clinical challenges.

Faride Kaikavoosnejad, Hamed Haddad Kashani, Khadijeh Dizaji Asl, Zeinab Mazloumi, Ali Keyhani, Seyyede Sepide Ashraf Moosavi, Milad Verdi, Ali Rafat.

  Gastrointestinal (GI) cancers encompass malignant conditions of the GI tract and accessory digestive organs, including the esophagus, gastric cancer (GC), biliary system, hepatocellular carcinoma (HCC), pancreatic cancer (PC), and colorectal cancer (CRC). Globally, CRC ranks as the third most commonly diagnosed cancer, with gastric, hepatic, and esophageal cancers following in fifth, sixth, and seventh places, respectively. PC contributes notably to cancer mortality, ranking 12th in incidence and 7th in mortality. Despite major advances in diagnosis and treatment, GI cancers remain among the most aggressive malignancies and continue to drive substantial global morbidity and mortality. In 2020, GI cancers accounted for more than 4.8 million new cases and 3.4 million deaths. Although early-stage GI tumors can be surgically resected with curative intent, the overall 5-year relapse rate remains high. Neoadjuvant or adjuvant chemotherapy and radiotherapy provide only modest long-term survival improvements when applicable. In recent decades, prognosis for advanced GI cancers has improved due to tailored therapies that combine cytotoxic and targeted agents and integrate systemic treatments with more effective surgical and locoregional approaches. Nevertheless, GI malignancies remain a leading cause of cancer death, underscoring the need for novel therapeutic options. A central molecular driver is the PI3K/AKT/mTOR signaling axis, which governs chemotherapy resistance, metastasis, survival, metabolism, and growth, and modulates the tumor microenvironment via angiogenesis and inflammatory infiltration. Dysregulation of this axis is common across GI cancers, guiding exploration of pathway-targeted therapies, alone or in combination. Although several agents show promise, toxicities such as neuropsychiatric effects, diarrhea, hepatotoxicity, and hyperglycemia limit clinical utility. Therefore, refined personalization and combination strategies targeting PI3K/AKT/mTOR are critical to improving efficacy and reducing resistance in GI malignancies.

Keywords:  Gastrointestinal cancers; PI3K/AKT/mTOR pathway; Targeted therapy

DOI:  https://doi.org/10.1007/s12032-026-03374-8
Int J Surg. 2026 Apr;112(4): 10982-10999

Apigenin activates AKT1 to coordinate MTOR-mediated anti-apoptosis and FOXO3-driven antioxidant defense in calcium oxalate nephropathy.

Lei Li, Xiong Xu, Linfa Guo, Tongzu Liu.

   Background: Kidney stone disease, primarily composed of calcium oxalate (CaOx) crystals, represents a significant global health burden with high recurrence rates. Current therapeutic strategies fail to adequately address the oxidative stress and apoptosis triggered by CaOx crystals in renal tubular cells. While the natural flavonoid apigenin (API) shows promise, its precise mechanism in CaOx nephropathy remains unclear.
Methods: We employed an integrated strategy combining network pharmacology and machine learning to identify potential therapeutic targets of apigenin in kidney stone disease. Experimental validation was conducted using both in vivo and in vitro models: a mouse model of CaOx nephropathy induced by glyoxylate and HK-2 cells exposed to calcium oxalate monohydrate crystals. The interaction between apigenin and AKT1 was investigated through surface plasmon resonance, molecular docking, cellular thermal shift assays, and drug affinity responsive target stability assays. Downstream signaling effects were analyzed using quantitative PCR, Western blotting, reactive oxygen species measurement, and apoptosis assessment. The functional role of AKT1 was further examined using the specific inhibitor MK-2206, siRNA-mediated knockdown, and FOXO3 overexpression experiments.
Results: Apigenin treatment significantly reduced CaOx crystal deposition, improved renal function markers, and attenuated tubular damage in mice in a dose-dependent manner. Bioinformatic analysis identified AKT1 as the core target, and experimental validation confirmed that apigenin directly binds to AKT1 with high affinity, leading to enhanced phosphorylation. This activation modulated two critical downstream pathways. The mTOR pathway suppressed apoptosis through downregulation of BAX and upregulation of BCL-2; Phosphorylation of FOXO3 decreased its transcriptional activity on Keap1, resulting in reduced Keap1 expression, subsequent Nrf2 stabilization, nuclear translocation, and upregulation of the antioxidant enzyme HO-1. The essential role of AKT1 was further supported by the finding that MK-2206 and si-AKT1 treatment abolished apigenin's protective effects. Additionally, FOXO3 overexpression reversed apigenin-induced Nrf2 activation, confirming the involvement of the AKT1-FOXO3-Keap1-Nrf2 axis.
Conclusion: Apigenin alleviates CaOx-induced renal injury through direct activation of AKT1, which coordinates dual protective mechanisms. Anti-apoptosis via the mTOR pathway and antioxidant defense through the FOXO3-Keap1-Nrf2 axis. This study provides comprehensive evidence of apigenin's AKT1-centered mechanism of action in CaOx nephropathy, supporting its potential as a novel therapeutic agent for kidney stone disease.

Keywords:  CaOx crystal-induced kidney injury; anti-apoptosis; anti-oxidative stress; apigenin; signaling pathway

DOI:  https://doi.org/10.1097/JS9.0000000000005023
Anticancer Drugs. 2026 Sep 01.

Anlotinib inhibits glioma cell proliferation, migration, and invasion by suppressing c-MET/AKT/mTOR signaling and altering autophagy-associated protein expression.

Chunmiao Bao, Xibang Liu.

  Glioma remains difficult to treat because malignant cells show rapid proliferation, diffuse invasion, and frequent recurrence. This study investigated the direct antitumor effects of anlotinib in human glioma cells and examined whether these effects were associated with hepatocyte growth factor receptor/protein kinase B/mechanistic target of rapamycin (c-MET/AKT/mTOR) signaling, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated proteins. U87 and U251 cells were treated with anlotinib in vitro. Cell viability was assessed using Cell Counting Kit-8 assays, migration and invasion were evaluated using wound-healing and Transwell assays, Hoechst 33342 staining was used for qualitative assessment of apoptosis-associated nuclear morphology; and protein expression was analyzed by western blotting. Anlotinib reduced cell viability in a concentration-dependent manner, with estimated 24 h IC50 values of 68.00 μM for U87 cells and 45.53 μM for U251 cells. At lower concentrations, anlotinib reduced wound closure and Transwell invasion, decreased Vimentin, N-cadherin, and β-catenin expression, increased B-cell lymphoma 2 (BCL-2)-associated X protein, decreased BCL-2, altered poly(ADP-ribose) polymerase/caspase-9 expression, reduced total c-MET expression, and decreased AKT/mTOR phosphorylation. Analysis of autophagy-associated proteins showed an increased LC3-II/LC3-I and time-dependent p62 changes. Anlotinib may suppress malignant glioma-cell phenotypes in vitro. These phenotypic changes were associated with alterations in c-MET/AKT/mTOR pathway proteins, apoptosis-associated responses, mesenchymal-transition-related proteins, and autophagy-associated protein expression.

Keywords:  anlotinib; apoptosis; autophagy; c-MET/AKT/mTOR; glioma; invasion; mesenchymal transition

DOI:  https://doi.org/10.1097/CAD.0000000000001844