bims-matara 2026-09-20 papers

on MTOR

Issue of 2026–09–20
twenty papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling.
Dual Targeting of FGFR4 and PI3K-mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma.
Crosstalk Between mTOR and NF-κB Signaling Pathways in Clear Cell Renal Cell Carcinoma.
Multidimensional Roles of the Transcription Factor EB-Regulated Autophagy-Lysosomal Network in Tumor Drug Resistance.
Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.
Everolimus-Involving Immunosuppression Attenuates Renal Interstitial Fibrosis Through Modulation of Mammalian Target of Rapamycin-Related Signal Transduction.
Synergistic Anti-Tumor Effect of Chidamide and Linperlisib on Natural Killer/T-Cell Lymphoma by Inhibiting PI3K/AKT/mTOR Pathway.
PDLIM7 promotes the progression of lung adenocarcinoma by activating the mTORC1 pathway and glycolysis.
Cell-state- and compartment-dependent PI3K/Akt redox signaling in chronic kidney disease: mechanisms and translational implications.
Structure and function of TM6SF1 reveals role in mTORC1 signaling.
The Metabolic Reprogramming Mechanism of Astragalus Polysaccharide-Induced Immune Memory in HD11 Cells: Integrated Analysis Based on Glycolysis and the TLR2/mTOR Pathway.
Targeting MET and mTOR Synergistically Overcomes Adaptive Resistance in Glioblastoma.
Modulating PI3K/Akt/mTOR-driven autophagy in liver cancer. The role of phytochemicals.
Glucose-TOR Signaling Regulates Root Hair Elongation in Arabidopsis via the RHD6-RSL4 Transcriptional Cascade.
Phosphorylation of OTUB1 promotes autophagy initiation under starvation.
The role of mTORC2/RICTOR in immune cells and inflammatory diseases.
Targeting Cathepsin Z suppresses endometriosis via the AMPK/mTOR-mediated autophagy and apoptosis axis.
Rg3 suppresses gastric cancer progression via TFEB-mediated lysosomal autophagy pathway.
mTOR/Autophagy//NF-κB Axis Drives Benzalkonium Chloride-Induced Inflammatory Response in Corneal Epithelial Cells.
Medulloblastoma-associated mutations in the RNA helicase DDX3X/DED1 cause defects in the translational response to TORC1 inhibition.

Front Immunol. 2026 ;17 1889686

Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling.

Yanjie Chen, JinYin Xiao, Limin Xiao, Anni Chen, Lizhi He, Zhenquan Wang.

  Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa, whose pathogenesis is intricately linked to metabolic reprogramming within both immune and epithelial compartments. The mechanistic target of rapamycin (mTOR) signaling pathway serves as a central immunometabolic hub that integrates nutrient availability, microbial cues, and inflammatory signals to orchestrate glycolytic flux, thereby profoundly shaping the functional plasticity of diverse intestinal cell populations. This review systematically delineates, from a cell-type-specific perspective, the divergent regulatory roles of the mTOR-glycolysis axis in intestinal immunity and mucosal barrier homeostasis. We first outline the core molecular architecture of mTORC1/mTORC2-driven glycolytic reprogramming, highlighting key regulatory nodes including GLUT1/3-mediated glucose uptake, HK2-dependent rate-limiting phosphorylation, and PKM2-governed metabolic-transcriptional switching. Subsequently, we examine how aberrant mTOR-glycolysis axis activation in neutrophils, macrophages, type 3 innate lymphoid cells, and CD4+ T effector subsets propagates a feed-forward inflammatory loop-exacerbating oxidative burst, NETosis, M1 polarization, and Th17 pathogenicity-while simultaneously undermining the metabolic fitness and suppressive integrity of regulatory T cells. Moreover, we discuss the metabolic rewiring of intestinal epithelial cells via the mTOR-glycolysis axis, which compromises barrier integrity, disrupts epithelial regeneration, and initiates a "metabolic-secretory" crosstalk that perpetuates mucosal inflammation. Collectively, this review positions the mTOR-glycolysis axis as a rheostat governing the transition from homeostatic immunosurveillance to pathogenic inflammation in UC, and proposes that cell-selective metabolic checkpoint targeting-rather than broad systemic inhibition-represents a promising precision strategy for future therapeutic intervention.

Keywords:  glycolysis; immune metabolism; mTOR signaling pathway; mTOR-glycolytic axis; ulcerative colitis

DOI:  https://doi.org/10.3389/fimmu.2026.1889686
Int J Mol Sci. 2026 Aug 28. pii: 7722. [Epub ahead of print]27(17):

Dual Targeting of FGFR4 and PI3K-mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma.

Joseph A Goode, Savannah A Harris, Deborah A Altomare.

  Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive adaptive signaling plasticity and metabolic reprogramming that contribute to therapeutic resistance. While the PI3K-mTOR pathway is a central regulator of these processes, the role of the FGF19-FGFR4 axis and its interaction with PI3K-mTOR signaling remains incompletely defined in PDAC. This study investigated whether co-targeting FGFR4 and PI3K-mTOR signaling could overcome adaptive pathway reactivation and suppress tumor-promoting phenotypes. PDAC cell lines representing a spectrum of FGFR4 dependence were treated with the selective FGFR4 inhibitor fisogatinib in combination with the clinically relevant PI3K-mTOR inhibitor gedatolisib. Transcriptomic analyses of TCGA data, along with molecular and functional responses, were evaluated. Transcriptomic analysis demonstrated a positive association between FGFR4 and PI3K-mTOR signaling and linked combined pathway components with poorer overall survival. Across heterogeneous PDAC models, combined inhibition reduced viability, clonogenic survival, migration, and cell-cycle progression more consistently than monotherapy. Apoptosis induction was driven principally by fisogatinib and combination treatment, resulting in comparable apoptotic responses across cell lines. Mechanistically, combined inhibition converged on increased 4E-BP1 inhibitory activity, despite compensatory ERK-RSK pathway activation, indicating that adaptive MAPK was insufficient to restore downstream translational output. In FGFR4-dependent cells, the combined inhibition also reduced secretion of the FGFR4 ligand FGF19. The FGFR4 and PI3K-mTOR signaling comprises a partially interconnected network in PDAC that converges on 4E-BP1-dependent translational control. Dual pathway inhibition consistently and additively suppressed tumor-associated phenotypes despite compensatory MAPK activation, with the clearest added benefit over fisogatinib alone in migration, cell-cycle control, and 4E-BP1 modulation, supporting translational regulation as a shared therapeutic vulnerability. These findings provide a preliminary rationale for biomarker-guided strategies targeting FGFR4 and PI3K-mTOR signaling in pancreatic cancer.

Keywords:  combination therapy; fibroblast growth factor 19 (FGF19); fibroblast growth factor receptor 4 (FGFR4); mechanistic target of rapamycin (mTOR); pancreatic cancer; phosphoinositide 3-kinases (PI3K)

DOI:  https://doi.org/10.3390/ijms27177722
Int J Mol Sci. 2026 Aug 26. pii: 7636. [Epub ahead of print]27(17):

Crosstalk Between mTOR and NF-κB Signaling Pathways in Clear Cell Renal Cell Carcinoma.

Melanie Glueck, Alexandra Lucaciu, Sumedha Inukollu, Rushendhiran Kesavan, Amelie Janssen, Josef Pfeilschifter, Julien Subburayalu, Ramesh K Krishnan, Rajkumar Vutukuri.

  Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation.

Keywords:  NF-κB signaling; cell proliferation; inflammation; mTOR signaling; renal cell carcinoma

DOI:  https://doi.org/10.3390/ijms27177636
Eur J Pharmacol. 2026 Sep 18. pii: S0014-2999(26)00850-2. [Epub ahead of print] 179368

Multidimensional Roles of the Transcription Factor EB-Regulated Autophagy-Lysosomal Network in Tumor Drug Resistance.

Yue Lu, Yuewen Wang, Daying Sun, Zhangwei Qiao, Zhengchao Wang, Shuliang Song, Junfeng Hou.

  Chemotherapy resistance is a key factor in tumor recurrence and mortality and a barrier to durable therapeutic effectiveness. Besides canonical mechanisms, including target alterations and drug efflux, tumor cells integrate chemotherapy-induced DNA damage, oxidative stress, and metabolic stress into persistent adaptive stress-response programs in which the autophagy-lysosomal pathway (ALP) plays a pivotal role. Transcription factor EB (TFEB), a master transcriptional regulator of the ALP, undergoes stress-responsive nuclear translocation under chemotherapeutic conditions through mechanistic target of rapamycin complex 1 (mTORC1) inhibition, lysosomal Ca2+-calcineurin-mediated dephosphorylation, and related signaling cascades. Nuclear TFEB activates the canonical coordinated lysosomal expression and regulation (CLEAR) network while also engaging broader context-dependent transcriptional programs. Within the autophagy-lysosomal system, CLEAR-dependent regulation promotes autophagosome biogenesis and maturation, autophagosome-lysosome fusion, and lysosomal biogenesis, resulting in enhanced autophagic flux. TFEB-driven enhancement of ALP flux generates multiple adaptive functional outputs, including clearance of damaged cellular substrates, buffering of reactive oxygen species (ROS), recycling of metabolic substrates to meet bioenergetic demands, modulation of cell death thresholds, and reduced effective intracellular drug exposure via lysosomal sequestration, storage, efflux, and intracellular redistribution. This review presents an integrated conceptual platform linking stress-induced TFEB activation, enhanced autophagic flux, downstream functional adaptations, and the emergence of chemotherapeutic resistance. By focusing on the TFEB-ALP axis, this review further identifies a stratified therapeutic intervention model comprising upstream suppression, intermediate pathway blockade, and downstream functional counteraction. These perspectives provide a more systematic and mechanistic understanding for developing precision strategies to overcome chemotherapy resistance by targeting the TFEB-ALP axis.

Keywords:  Drug resistance; autophagic flux; lysosomes; transcription factor EB (TFEB); tumor stress adaptation

DOI:  https://doi.org/10.1016/j.ejphar.2026.179368
PLoS Biol. 2026 Sep 18. 24(9): e3003555

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.

Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero.

Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)-4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1-4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.

DOI: https://doi.org/10.1371/journal.pbio.3003555
Int J Mol Sci. 2026 Aug 26. pii: 7634. [Epub ahead of print]27(17):

Everolimus-Involving Immunosuppression Attenuates Renal Interstitial Fibrosis Through Modulation of Mammalian Target of Rapamycin-Related Signal Transduction.

Takuro Saito, Mitsuru Saito, Ryohei Yamamoto, Ryuichiro Sagehashi, Yu Aoyama, Mizuki Mori, Chika Kajiwara, Kengo Furihata, Hideaki Kagaya, Hironobu Yagishita, Nobuhiro Fujiyama, Soki Kashima, Kazuyuki Numakura, Shintaro Narita, Masafumi Kikuchi, Masatomo Miura, Tomonori Habuchi.

  Chronic allograft dysfunction, driven by interstitial fibrosis and tubular atrophy, remains a major cause of long-term renal allograft loss. Everolimus (EVR), a mammalian target of rapamycin (mTOR) inhibitor, may reduce fibrosis through antifibrotic effects and calcineurin inhibitor minimization. This study aimed to evaluate the impact of EVR-involving immunosuppression on renal allograft fibrosis and to identify predictors of fibrotic progression. A total of 104 living-donor kidney transplant recipients transplanted between 2011 and 2017 were retrospectively analyzed (EVR, n = 61; non-EVR, n = 43). Interstitial fibrosis was quantified in protocol biopsies using digital image analysis. Phosphorylation of the mTOR-signaling proteins p70 ribosomal S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1 was assessed using a semiquantitative immunoreactive score. Multivariable regression analyses identified independent predictors of fibrotic progression. Cytomegalovirus infection was less frequent in the EVR group, whereas acute rejection, graft function, and graft survival were comparable between groups. At 1-year posttransplantation, interstitial fibrosis was significantly lower in the EVR group. EVR significantly suppressed p-4EBP1 phosphorylation and effectively modulated the mTOR-signaling pathway. Multivariable analysis identified the absence of EVR therapy as an independent predictor of accelerated fibrosis. EVR-involving immunosuppression attenuated renal interstitial fibrosis, likely through suppression of mTOR-signaling.

Keywords:  interstitial fibrosis; kidney transplant outcomes; living kidney transplantation; mammalian target of rapamycin inhibitor; mammalian target of rapamycin-related protein

DOI:  https://doi.org/10.3390/ijms27177634
Hematol Oncol. 2026 Sep;44(5): e70256

Synergistic Anti-Tumor Effect of Chidamide and Linperlisib on Natural Killer/T-Cell Lymphoma by Inhibiting PI3K/AKT/mTOR Pathway.

Wenxing Jiang, Zhuangzhuang Shi, Zhaoming Li, Xiaoyan Feng, Xudong Zhang, Mingzhi Zhang, Lijuan Han.

  Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma subtype with limited treatment options, especially for relapsed or refractory patients. Chidamide, a histone deacetylase inhibitor, and linperlisib, a phosphatidylinositol-3-kinase (PI3K) inhibitor, have shown promise in treating peripheral T-cell lymphoma, but their effects on NKTCL are less explored. In this study, the therapeutic efficacy and mechanisms of combining chidamide and linperlisib in the treatment of NKTCL were investigated. Three human NKTCL cell lines (NKYS, KHYG1, and YT) were used to assess the effects of chidamide and linperlisib on cell proliferation, apoptosis, and the cell cycle. RNA-seq and Western blot assays were employed to uncover the underlying mechanisms, and a YT xenograft mouse model was used for in vivo validation. Both chidamide and linperlisib exhibited dose- and time-dependent anti-tumor effects, and their combination enhanced efficacy, reduced cell viability, and increased apoptosis. This combination induced G2/M cell cycle arrest. Transcriptomic, Western blot, and immunohistochemical analysis revealed significant inhibition of the PI3K/AKT/mTOR pathway, which correlated with upregulation of the tumor suppressor PRDM1. These findings were confirmed in the YT xenograft model. In conclusion, the combination of chidamide and linperlisib has synergistic anti-tumor effects on NKTCL, which are mediated through inhibition of the PI3K/AKT/mTOR pathway, suggesting a promising therapeutic strategy for NKTCL management.

Keywords:  PI3K inhibitor; PI3K/AKT/mTOR pathway; histone deacetylase inhibitor; natural killer/T‐cell lymphoma

DOI:  https://doi.org/10.1002/hon.70256
Tissue Cell. 2026 Sep 11. pii: S0040-8166(26)00647-6. [Epub ahead of print]104(Pt 2): 103952

PDLIM7 promotes the progression of lung adenocarcinoma by activating the mTORC1 pathway and glycolysis.

Na Zhu, Ze Yu.

   BACKGROUND: The PDZ and LIM domain 7 (PDLIM7) has been reported to play a critical role in cancer progression, but its specific role and underlying mechanisms in lung adenocarcinoma (LUAD) remain unexplored.
METHODS: We investigated PDLIM7 in LUAD using bioinformatics tools, cell counting kit-8, colony formation, flow cytometry, wound healing assay, transwell, western blotting, glucose uptake, lactate production assay, and seahorse extracellular flux analysis. Rescue experiments with mTOR inhibitor rapamycin and constitutively active S6K1 (caS6K1) were performed to verify the mechanism by which PDLIM7 drives LUAD progression. In addition, in vivo mouse models were conducted to explore the effects of PDLIM7 on tumor growth.
RESULTS: PDLIM7 expression was elevated in LUAD tissues and correlated with a poor overall survival. PDLIM7 knockdown inhibited LUAD cell proliferation, migration, invasion, and glycolysis, but promoted cell apoptosis. However, its overexpression produced the opposite effects. Mechanistically, PDLIM7 drove LUAD progression via mTORC1 activation, as evidenced by the findings that rapamycin abrogated the promoting effects of PDLIM7 overexpression on proliferation, invasion, and glycolysis, while caS6K1 counteracted the inhibition of proliferation, invasion, and glycolysis resulting from PDLIM7 knockdown. Furthermore, in a xenograft mouse model, PDLIM7 knockdown suppressed tumor growth, while PDLIM7 overexpression promoted tumor growth. The enhanced tumor growth induced by PDLIM7 overexpression was abrogated by treatment with the mTORC1 inhibitor rapamycin.
CONCLUSIONS: PDLIM7 promotes LUAD progression by activating the mTORC1 signaling pathway and glycolysis.

Keywords:  Glycolysis; Lung adenocarcinoma; MTORC1; PDLIM7

DOI:  https://doi.org/10.1016/j.tice.2026.103952
Front Pharmacol. 2026 ;17 1951798

Cell-state- and compartment-dependent PI3K/Akt redox signaling in chronic kidney disease: mechanisms and translational implications.

Jianzong Xuan, Renhua Ding, Haiyin Zhang, Yiyuan Wang, Liangliang Wu, Yuan Liu, Jianrui Dong, Ran Hu.

  Chronic kidney disease (CKD) progression results from coordinated pathological processes across diverse renal cell types and cannot be reduced to extracellular matrix accumulation alone. Tubular stress, disruption of the glomerular filtration barrier, microvascular rarefaction, immune activation, and interstitial remodeling collectively contribute to the progressive loss of renal structure and function. Although oxidative stress occurs throughout CKD progression, modern redox biology emphasizes that the effects of reactive oxygen species (ROS) depend on their source, concentration, chemical identity, duration, and subcellular localization. As a central hub in this redox regulatory network, the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway integrates redox sensing with cell survival, metabolic reprogramming, inflammation, and fibrosis. In experimental systems, oxidative signals such as hydrogen peroxide (H2O2) can reversibly oxidize phosphatase and tensin homolog (PTEN) and other protein tyrosine phosphatases, thereby favoring localized phosphatidylinositol 3,4,5-trisphosphate (PIP3) accumulation and Akt activation. Activated Akt engages downstream effectors including nuclear factor erythroid 2-related factor 2 (Nrf2), forkhead box O (FOXO) transcription factors, mechanistic target of rapamycin (mTOR), glycogen synthase kinase 3 beta (GSK3β), nuclear factor kappa B (NF-κB), sterol regulatory element-binding proteins (SREBPs), autophagy-related pathways, and mitochondrial quality-control programs, thereby reshaping redox homeostasis and influencing injury and repair trajectories. PI3K/Akt signaling exhibits marked context dependence in CKD. The GSK3β/Nrf2 branch can enhance antioxidant defenses and limit inflammation, whereas sustained AKT serine/threonine kinase 1 (AKT1), mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), or PI3K/Akt/mTOR/hexokinase II (HKII) signaling can promote maladaptive tubular repair, podocyte injury, and interstitial cell activation. PI3K/Akt therefore represents a key signaling node linking redox regulation, cell-state changes, and tissue remodeling. This review examines PI3K/Akt-mediated redox regulation across four dimensions: redox inputs, organellar microdomains, renal cell states, and clinical translation, while discussing therapeutic strategies tailored to specific cell states and spatial compartments.

Keywords:  PI3K/Akt signaling; cell states; chronic kidney disease; mitochondrial redox signaling; oxidative stress; renal fibrosis; subcellular compartments; therapeutic targeting

DOI:  https://doi.org/10.3389/fphar.2026.1951798
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2622424123

Structure and function of TM6SF1 reveals role in mTORC1 signaling.

Sen Hong, Liangjie Jia, Rong Wang, Nadia Elghobashi-Meinhardt, Helen H Hobbs, Xiaochun Li.

  The transmembrane 6 superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for bulk lipidation of Apolipoprotein B-containing lipoproteins. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9-Å resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising 10 transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule. Cell-based assays revealed that loss of TM6SF1 perturbs mTORC1 signaling, resulting in reduced phosphorylation of S6 kinase 1 and 4E-BP1 and constitutive activation of transcription factor EB (TFEB), and that cholesterol is required for these effects. Biochemical analyses support the model that TM6SF1 directly engages LAMTOR1, a component of Ragulator complex, in a cholesterol-dependent manner. Together, these findings identify TM6SF1 as a lysosomal cholesterol binding protein involved in regulating mTORC1 signaling.

Keywords:  LAMTOR1; TM6SF1; cryo-EM; mTORC1; transcription factor EB

DOI:  https://doi.org/10.1073/pnas.2622424123
Poult Sci. 2026 Sep 04. pii: S0032-5791(26)01363-5. [Epub ahead of print]105(12): 107729

The Metabolic Reprogramming Mechanism of Astragalus Polysaccharide-Induced Immune Memory in HD11 Cells: Integrated Analysis Based on Glycolysis and the TLR2/mTOR Pathway.

Haisheng Jiang, Xueyan Gu, Jianxi Li, Fubin Chen, Xiaodan Wang, Jingyan Zhang, Huub F J Savelkoul.

  This study aimed to investigate the immunomodulatory effects of APS on HD11 cells and its potential mechanisms. This study aimed to investigate the immunomodulatory effects of APS on HD11 cells and its underlying mechanisms. CCK-8 assays revealed that APS significantly promoted HD11 cell proliferation in a dose-dependent manner. Griess and lactate dehydrogenase (LDH) assays indicated that APS dose-dependently increased nitric oxide (NO) release and LDH activity, although these levels remained lower than those in the lipopolysaccharide (LPS) group. RT-qPCR analysis demonstrated that APS significantly upregulated the mRNA levels of IL-8, CXCL13, and iNOS, while downregulating CCR5. Additionally, APS enhanced the expression and activity of glycolysis-related enzymes while suppressing those of the pentose phosphate pathway. Western blot analysis revealed that APS upregulated the protein expression of TLR1, MyD88, p-mTOR, and HIF-1α, but downregulated TLR2, ERK, and NF-κB p65. Metabolic assays showed a dose-dependent increase in Acetyl-CoA concentration and a decrease in glutathione (GSH) content following APS treatment. Mechanistically, small interfering RNA (siRNA)-mediated knockdown of TLR2 and mTOR demonstrated that APS regulates the mTOR signaling pathway via TLR2. Furthermore, mTOR silencing significantly attenuated the APS-induced expression of immune-related factors, accumulation of Acetyl-CoA, and reduction of GSH, confirming the central role of the mTOR signaling pathway in APS-mediated immunomodulation. In conclusion, APS enhances the immune response of HD11 cells by regulating TLRs signaling pathways, promoting glycolytic metabolism, and activating the mTOR pathway, providing a theoretical basis for the application of APS in poultry immunomodulation.

Keywords:  Astragalus polysaccharide; HD11 cells; Immunomodulation; TLR2; mTOR signaling pathway

DOI:  https://doi.org/10.1016/j.psj.2026.107729
Int J Mol Sci. 2026 Aug 30. pii: 7780. [Epub ahead of print]27(17):

Targeting MET and mTOR Synergistically Overcomes Adaptive Resistance in Glioblastoma.

Yunzhan Li, Hanif Khan, Seyma Demirsoy, Muhammad Younis, Guilan Shi, Hannah Valensi, William Bernhardt, Jeongwu Lee, Mitchell Machtay, Dawit Aregawi, Michael Glantz, Pierre Giglio, Shengyu Yang, Todd Schell, Vonn Walter, Yasin Uzun, Inan Olmez.

  Glioblastoma (GBM) is the most aggressive primary brain tumor with limited therapeutic options and extremely poor prognosis. Aberrant activation of the receptor tyrosine kinase MET drives tumor progression, therapeutic resistance, and reduced survival, particularly in the mesenchymal GBM subtype. Given its crucial role in GBM recurrence and progression, we investigated the mechanisms of resistance to MET inhibition using patient-derived glioma-initiating cells (GICs) and orthotopic xenograft mouse models. GICs were treated with the MET inhibitor crizotinib to elucidate the mechanism of adaptive resistance. Prolonged MET inhibition induced a senescent-like phenotype in GICs, associated with downregulation of BNIP3, a mitochondrial protein regulating mitophagy. We showed that BNIP3 downregulation led to activation of mTOR signaling, promoting cellular survival and adaptive resistance. Combining crizotinib with the mTOR inhibitor everolimus effectively suppressed mTOR activity, reduced cell viability, and induced mitochondrial alterations, apoptosis, and necroptosis. In orthotopic GBM xenograft models, combined MET and mTOR inhibition significantly prolonged survival compared with single-agent treatments. Notably, sequential treatment-crizotinib followed by everolimus-further enhanced therapeutic efficacy. These effects were achieved without significant weight loss, supporting tolerability of the treatment regimen. Our findings identify the BNIP3-mTOR axis as a critical mediator of resistance to MET inhibition and demonstrate that combined inhibition of MET and mTOR exhibits significant synergy against GBM.

Keywords:  BNIP3; Glioblastoma; MET; crizotinib; everolimus; mTOR

DOI:  https://doi.org/10.3390/ijms27177780
Cancer Chemother Pharmacol. 2026 Sep 17. pii: 101. [Epub ahead of print]96(1):

Modulating PI3K/Akt/mTOR-driven autophagy in liver cancer. The role of phytochemicals.

Poonam Lal, Jitendra Patel.

  Hepatocellular carcinoma is one of the major cancer related causes of mortality all over the world that is mainly caused by successive activation of PI3K/Akt/mTOR signalling axis and subsequent regulation of autophagy by the medium. This review analyses the molecular picture of PI3K/Akt/mTOR pathway in liver cancer, such as PTEN, receptor tyrosine kinase, Akt isoform, mTOR complex, GSK 3Β, CREB, FOXO protein, MDM2 p53 axis, NF kB, and lipid metabolic controller. The dual role of autophagy as a tumour suppressive and tumour promoting process is particularly focused on in regard to the therapeutic resistance to agents like sorafenib. The review summarizes preclinical evidence demonstrating that major classes of phytochemicals, including polyphenols, flavonoids, alkaloids, and terpenoids, target key regulatory components of the PI3K/Akt/mTOR mediated autophagy network. These substances regulate the ULK1 activation, AMPK signalling, reactive oxygen species processes and autophagy crosstalk to apoptosis, and hepatocellular carcinoma model metabolic remodelling. The in vitro and in vivo studies done using the mechanism of action reinforce the idea that phytochemicals are multi target regulators that can restore cytoprotective and cytotoxic autophagy. Finally, the existing challenges in translational research, such as pharmacokinetic issues, biomarker voids, tumour heterogeneity, and resistance, are critically evaluated to set priorities of introducing phytochemicals into the liver cancer treatment in a precision-based fashion.

Keywords:  Autophagy modulation; Hepatocellular carcinoma; PI3K/Akt/mTOR signalling; Phytochemicals

DOI:  https://doi.org/10.1007/s00280-026-04949-y
Plants (Basel). 2026 Aug 25. pii: 2586. [Epub ahead of print]15(17):

Glucose-TOR Signaling Regulates Root Hair Elongation in Arabidopsis via the RHD6-RSL4 Transcriptional Cascade.

Bingru Wang, Jueru Zhang, Wei Yan, Xiumei Dai, Jiankui Zhang, Tian Zhang, Kexuan Deng.

  Root hairs are tubular protrusions of root epidermal cells that expand the root surface area to facilitate water and nutrient uptake. The target of rapamycin (TOR) kinase has been identified as a positive regulator of root hair elongation, and the RHD6-RSL4 bHLH transcriptional cascade is well established as a core module that governs root hair morphogenesis. However, whether TOR signaling acts upstream of the RHD6-RSL4 pathway and how glucose signals are integrated into this transcriptional regulatory network during root hair development remain incompletely understood. In this study, transcriptome profiling combined with pharmacological and genetic functional assays was performed to elucidate the TOR-mediated transcriptional regulatory pathway of root hair elongation in Arabidopsis. Chemical inhibition of TOR triggered genome-wide transcriptional reprogramming in seedling roots, including disruption of auxin and ethylene signal transduction and pronounced downregulation of hundreds of genes related to root hair development. Glucose-activated TOR signaling modulates the expression of root hair-specific (RHS) genes mainly through the core RHD6-RSL4 transcriptional cascade. The transcription of RSL1-RSL5 was strongly dependent on functional TOR activity, whereas RHD6 transcript abundance was specifically induced by glucose-TOR signaling under carbon-starvation recovery conditions. Genetic overexpression of either RHD6 or RSL4 partially rescued root hair elongation defects caused by TOR suppression, confirming that the RHD6-RSL4 cascade functions as a critical downstream transcriptional module of glucose-TOR signaling. Collectively, this work establishes a transcriptional framework in which glucose-TOR signals modulate root hair elongation via transcriptional activation of the master bHLH regulators RHD6 and RSL4.

Keywords:  RHD6-RSL4 cascade; RHS genes; TOR; root hair elongation

DOI:  https://doi.org/10.3390/plants15172586
Nat Commun. 2026 Aug 15. pii: 9820. [Epub ahead of print]17(1):

Phosphorylation of OTUB1 promotes autophagy initiation under starvation.

Liangbo Sun, Meng He, Dong Liu, Jiahong Liu, Meihua Shan, Mingzhen Yang, Yan Zhang, Xufang Dai, Jie Yao, Yanhao Zhang, Haojun Xiong, Fengtian He, Jiqin Lian.

Eukaryotes initiate autophagy in response to environmental challenges such as nutrient deprivation. However, the mechanisms governing autophagy initiation remain incompletely understood. Here, we demonstrated that OTUB1 phosphorylation plays a key role in starvation-induced autophagy initiation. Specifically, ERK phosphorylates OTUB1 at S118 during starvation. This phosphorylation enables competitive binding of ANXA2 to OTUB1, disrupting its interaction with TRIM29 and enhancing OTUB1 stability. Stabilized OTUB1 upregulated DEPTOR, thereby inhibiting mTOR and inducing autophagy. Furthermore, in vivo studies reveal that fasting-induced OTUB1-mTOR-autophagy axis counteracted Western diet-mediated mTOR activation by restoring ERK-dependent OTUB1 phosphorylation, ultimately ameliorating MASLD progression. Collectively, this study uncovers a phosphorylation-dependent regulatory mechanism controlling OTUB1's function in nutrient deficiency-triggered autophagy initiation, providing cellular and molecular evidence supporting the therapeutic potential of fasting in alleviating MASLD.

DOI: https://doi.org/10.1038/s41467-026-76796-7
Inflamm Res. 2026 Sep 17. pii: 215. [Epub ahead of print]75(1):

The role of mTORC2/RICTOR in immune cells and inflammatory diseases.

Jingting Xu, Wenxin Zhong, Fei Xin, Fei Xu, Zehang Zheng, Fengjing Guo.

   BACKGROUND: mTORC2, defined by its core component RICTOR, is a key regulator of immune cell function and inflammation, yet its roles have long been underappreciated due to lack of specific inhibitors and in vivo tools.
OBJECTIVE: This review summarizes the current understanding of mTORC2-specific signaling (via AKT, SGK1, and PKC) in regulating the development, differentiation, and effector functions of diverse immune cells, and discusses its emerging roles in immune cell inflammation and tissue-specific inflammation.
METHOD: We synthesized findings from recent studies using conditional knockout mouse models, pharmacological inhibitors, and clinical samples.
CONCLUSION: mTORC2 controls Th1/Th2 differentiation, Treg stability, and memory T cell formation; regulates BCR signaling and plasma cell survival; and modulates macrophage M2 polarization, DC maturation, and NK cell function. In tissue inflammation, mTORC2 plays context-dependent roles-exacerbating osteoarthritis and pancreatitis but restraining pro-inflammatory polarization in colorectal cancer. Dual mTORC1/2 inhibitors (e.g., AZD2014) have shown early promise, though challenges remain regarding efficacy, toxicity, and immunomodulatory complexity.

Keywords:  Immune cell; Inflammation; RICTOR; mTORC2

DOI:  https://doi.org/10.1007/s00011-026-02365-9
Front Med (Lausanne). 2026 ;13 1681467

Targeting Cathepsin Z suppresses endometriosis via the AMPK/mTOR-mediated autophagy and apoptosis axis.

Mengjun Zhang, Jialin Wang, Haodi Yue, Zidi Zhang, Lindong Zhang, Xin Zhao.

   Background: The key biomarkers, therapeutic targets, and pathological mechanisms of endometriosis are urgently needed to be elucidated. The role of CTSZ in EM needs to be clarified, and the potential regulatory mechanisms and corresponding therapeutic drugs of CTSZ need to be explored to demonstrate the feasibility of CTSZ as a biomarker and therapeutic target.
Methods: Based on transcriptome sequencing of local clinical tissue samples and public data, the key pathogenic gene (CTSZ) was screened out using machine learning algorithms (LASSO and SVM-RFE), and the expression of CTSZ was evaluated at multiple levels. The effects of knocking down CTSZ on the proliferation and migration of endometriosis cell lines (12Z) were assessed. The effects of knocking down CTSZ on apoptosis, autophagy and AMPK/mTOR signaling pathways were predicted and investigated.
Results: CTSZ was found to be abnormally overexpressed in sequencing data, endometriosis clinical tissue samples, and corresponding cell lines (12Z), suggesting it is a potential pathogenic gene. Knockdown of CTSZ significantly inhibited the proliferation and migration of 12Z. CTSZ may be related to key processes and proteins of apoptosis, autophagy and AMPK/mTOR signaling pathways. Knockdown of CTSZ significantly promoted apoptosis and autophagy by activating AMPK and subsequently inhibiting mTOR signaling.
Conclusion: CTSZ is a potential pathogenic gene and therapeutic target. Its knockdown could activate AMPK and subsequently inhibit mTOR signaling, thereby inducing autophagy and synergistically promoting apoptosis, inhibiting proliferation and migration, and ultimately inhibiting endometriosis.

Keywords:  AMPK/mTOR signaling pathway; autophagy; cathepsins; endometriosis; therapeutic targets

DOI:  https://doi.org/10.3389/fmed.2026.1681467
Cell Signal. 2026 Sep 13. pii: S0898-6568(26)00551-6. [Epub ahead of print] 112892

Rg3 suppresses gastric cancer progression via TFEB-mediated lysosomal autophagy pathway.

Jian Yuan, Yangxian Xu, Yizhe Diao, Tao Ding, Guorong Yuan.

   BACKGROUND: Gastric cancer (GC) ranks among the most prevalent malignant tumors globally, characterized by elevated incidence and mortality rates. As a natural active component isolated from Panax ginseng, Rg3 has demonstrated anti-tumor activity across multiple malignancies. Nevertheless, its specific functions and underlying molecular mechanisms in GC remain incompletely elucidated.
METHODS: Rg3 exerted effects in viability, proliferative capacity, apoptotic progression, and autophagy-associated protein expression in AGS cells, evaluated via CCK-8 assay, colony formation, EdU staining, flow cytometry, and Western blot. To investigate the direct interaction between Rg3 and TFEB, as well as the mechanism by which Rg3 modulated apoptosis via lysosomal autophagy, the molecular docking, CETSA, immunofluorescence, mRFP-GFP-LC3 dual-labeling system, LysoTracker/Magic Red staining, and gene knockdown/overexpression approaches were employed. The expression of AKT/mTOR pathway-related proteins was analyzed by Western blot. A nude mouse xenograft tumor model was established to monitor tumor development, while H&E staining and IHC were employed to dissect histopathological alterations and the expression of pivotal proteins.
RESULTS: Rg3 attenuated the proliferation of AGS cells in a concentration-dependent manner, induced apoptosis, and inhibited the AKT/mTOR pathway. Mechanistic investigations unveiled that Rg3, on one hand, reduced TFEB phosphorylation by inhibiting the AKT/mTOR pathway, thereby driving TFEB nuclear translocation; on the other hand, it bound to TFEB to enhance its protein stability, maintained the activated state of TFEB, and upregulated TFEB protein expression, consequently activating the lysosomal autophagy pathway. TFEB knockdown reversed Rg3-mediated autophagy activation, apoptosis induction, and development inhibition, whereas TFEB overexpression recapitulated these effects, which were abrogated by the autophagy inhibitor chloroquine. In vivo experiments further verified that Rg3 prominently suppressed xenograft tumor development, concurrent with upregulated TFEB and LC3B expressions, downregulated Ki67, and elevated Bax levels in tumor tissues.
CONCLUSION: Rg3 upregulates and activates TFEB, thereby triggering the lysosomal autophagy pathway, which ultimately induces GC cell apoptosis and suppresses tumor progression.

Keywords:  Apoptosis; Gastric cancer; Lysosomal autophagy; Rg3; TFEB

DOI:  https://doi.org/10.1016/j.cellsig.2026.112892
J Ocul Pharmacol Ther. 2026 Sep 17. 10807683261486972

mTOR/Autophagy//NF-κB Axis Drives Benzalkonium Chloride-Induced Inflammatory Response in Corneal Epithelial Cells.

Jing Du, Zhe Yu, Yang Xiao, Jing Li, Shengsheng Wei, Yong Li, Jin Yan.

   PURPOSE: Benzalkonium chloride (BAK), a quaternary ammonium antimicrobial agent widely utilized in ophthalmic formulations, is associated with chronic ocular surface toxicity. BAK induces corneal epithelial inflammation and autophagic impairment, yet their interrelationship remains unclear.
METHODS: Mouse corneal epithelial cell lines (MCECs) were subjected to short-term BAK exposure (10-20 μg/mL, 15 min + 8 h recovery). TLR4/MyD88/NF-κB pathway activation and proinflammatory cytokines (Il-1α, Il-1β, Il-6) were assessed. Autophagic flux was evaluated via LC3-II/I ratio, p62 accumulation, GFP-RFP-LC3 autolysosome formation assay, and lysosomal function. Pharmacological interventions with rapamycin (mTOR blockade) and TAK-242 (TLR4 inhibition) were used to dissect pathway interactions.
RESULTS: Short-term BAK exposure dose-dependently activated the TLR4/MyD88/NF-κB pathway and elevated proinflammatory cytokines. Concurrently, BAK inhibited autophagic flux through mTOR hyperactivation, evidenced by reduced LC3-II/I ratio, p62 accumulation, impaired autolysosome formation, and lysosomal dysfunction. Both rapamycin and TAK-242 significantly attenuated BAK-induced MyD88/NF-κB activation and inflammation. Critically, BAK activates parallel TLR4-MyD88 and mTOR pathways that synergistically amplify NF-κB signaling.
CONCLUSIONS: These results unveil mTOR as a therapeutic target for mitigating BAK-induced corneal damage, thereby proposing mTOR suppression or autophagic activation as viable interventions for BAK-associated ocular surface disorders. Particularly at lower concentration (0.001%) and shorter exposure (15 min) of BAK.

Keywords:  TLR4; autophagy; benzalkonium chloride; corneal epithelial cells; inflammation; mTOR

DOI:  https://doi.org/10.1177/10807683261486972
J Biol Chem. 2026 Sep 18. pii: S0021-9258(26)02452-X. [Epub ahead of print] 113580

Medulloblastoma-associated mutations in the RNA helicase DDX3X/DED1 cause defects in the translational response to TORC1 inhibition.

Akanksha Swarup, Ryan A Kuhs, Vanessa U Hardman, Kennedy L Howard, Shradha Subbaraman, Timothy A Bolger.

  Medulloblastoma is the most common pediatric brain cancer, but current treatments are largely non-specific, often causing developmental side effects. Genomic sequencing identified the RNA helicase DDX3X as one of the most frequently mutated genes in this cancer and a potential treatment target, yet its role in tumor progression remains elusive. Prior studies have indicated that the mutations cause specific defects in translation; however, both DDX3X and its yeast ortholog Ded1 have also been associated with cellular stress responses, suggesting that the contribution of the DDX3X mutations to medulloblastoma might result from defects in the translational response to stress. Building on our prior study that replicated the DDX3X mutations in yeast DED1 (ded1-mam), we examined the mutants' effects following TOR pathway inactivation. First, we demonstrated that ded1-mam displayed substantial rapamycin-resistant growth compared to wild-type cells. Additionally, similar to other ded1 mutants, the ded1-mam had increased protein abundance of Ded1 and the translation factor eIF4G1 under TOR inactivation. Notably, these differences did not result in increased bulk translation following rapamycin; rather, the growth phenotypes appeared to be driven by translation of specific mRNAs. Reporter assays demonstrated enhanced translation of mRNA with an unstructured 5' UTR in ded1-mam following TOR inhibition and a decrease in a structured reporter. Furthermore, known Ded1 target genes with relatively unstructured 5' UTRs showed upregulated protein levels in rapamycin. We hypothesize that mutant DDX3X selectively upregulates translation of unstructured, pro-growth transcripts while downregulating other structured transcripts, allowing tumor cells to bypass stress-induced growth controls and promoting medulloblastoma progression.

Keywords:  RNA helicase; Saccharomyces cerevisiae; cancer; eukaryotic translation initiation; medulloblastoma; stress response; target of rapamycin (TOR)

DOI:  https://doi.org/10.1016/j.jbc.2026.113580