bims-matara 2026-10-25 papers

on MTOR

Issue of 2026–10–25
twenty-one papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.
Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
The PD-L1-mTOR intersection in tumor migration and invasion.
Somatic variants in focal cortical malformations.
A hormonal message for a longer life.
Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.
The Long Splice Variant of Ribosomal Protein S24 Protects Cells from Stress and Is Induced by AMPK-ULK1-Regulated Autophagy Independent of mTORC1.
Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration in adult zebrafish.
Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.
NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.
CASTOR1 functional inactivation drives KRAS-mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression.
Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis.
Betaine Attenuates Cuprizone-Induced Cortical Demyelination: The Role of the WNT4/mTOR Signalling Pathway in Regulating Astrogliosis and Synaptic Integrity.
Gedatolisib: First Approval.
Epidural Spinal Cord Stimulation Promotes the Expansion of Endogenous Neural Stem Cells and Neuroprotection via the PI3K/AKT/ mTOR Pathway after Spinal Cord Injury in Rats.
P2Y6 receptor activation promotes the migration, invasion and glycogen accumulation of colorectal cancer through AKT/mTOR signaling.
NCCRP1 promotes ovarian cancer progression and is associated with activation of the PI3K/AKT/mTOR signaling pathway and altered mitochondrial respiration.
cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.
Balloon cells in type II focal cortical dysplasia: developmental origins, molecular signatures, and epileptogenic mechanisms.
Allostery in the Ras-Raf-PI3K-PTEN signaling network at the membrane: Implications for drug discovery.
CircUGP2 inhibits tumor progression via PI3K/AKT/mTOR signaling through sponging miR-137-3p and interacting with UPF1 in hepatocellular carcinoma.

Biol Open. 2026 Oct 15. pii: bio062902. [Epub ahead of print]15(10):

Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.

Joel Karikari Nyarkoh, Matthew Wolan, Eric Barrett, Aidan M Sokolov, Rachel A Lyman, Trudy F C Mackay, David M Feliciano.

  The mammalian target of rapamycin (mTOR) is the catalytic subunit of two exclusive complexes referred to as mTORC1 and mTORC2. The mTORCs phosphorylate different substrates and control different cellular processes. Inhibitors of mTORC1 include rapamycin analogs (rapalogs) that are useful in many clinical settings. However, they have failed in cancer trials potentially due to resistance mechanisms and incomplete inhibition of mTORC1 phosphorylation of select substrates. The rapamycin sensitivity of mTORC1 substrates is likely encoded by the substrate's primary amino acid sequence determinants and the ability of substrates to fit into the catalytic region of the kinase super-complex. Thus, some mTORC1 substrates are unaffected by rapalogs. Second-generation ATP-binding pocket inhibitors are mTOR catalytic inhibitors that bind in an ATP-competitive manner. Torin1 is an exemplary second-generation mTOR inhibitor with superior inhibition of mTORC1 substrates, including 4EBP. However, these inhibitors fail to demonstrate selectivity between mTORC1 and mTORC2. Third-generation bisteric mTORC1 inhibitors are exemplified by Rapalink-1, which links a rapamycin moiety to the ATP-competitive inhibitor MLN-0128. Here, we report that Rapalink-1 inhibits three mTORC1 substrates, including 4EBP and Ulk1, which are rapamycin insensitive. To provide additional mechanistic insight into the Rapalink-1 mechanism of action, RNA sequencing of Neuro-2a cells treated with Rapalink-1 was performed. Rapalink-1 caused transcriptomic changes indicative of reductions in the mTOR pathway and brain development. Many transcripts contained a p53 binding site, and consistent with this finding, we also observed reduced levels of p53. These results confirm and expand upon the Rapalink-1 mechanism of action.

Keywords:  Cancer; Rapalink-1; mTOR; mTORC1

DOI:  https://doi.org/10.1242/bio.062902
Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2610766123

Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.

Sara Bermudez, Jung-Hyun Choi, Niaz Mahmood, Jacob W Vogel, Hashem Almousa, Ziying Huang, Sung-Hoon Kim, Vivian Yuchan Zhu, Linqiao Zhou, Diana Casas-Antillon, Moein Yaqubi, Danielle Cozachenco, Jo Anne Stratton, Oskar Hansson, Luke Healy, Argel Aguilar-Valles, Nahum Sonenberg.

  In Alzheimer's disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are elevated in AD and correlate with markers of microglial reactivity and disease progression. Using linear regression analysis, we found that elevated CSF 4E-BP1 levels strengthen the association between soluble TREM2 levels and neurodegeneration in amyloid-positive individuals. To investigate the underlying mechanism, we performed in vitro experiments demonstrating that amyloid-β inactivated 4E-BP1 in murine microglia. The mTOR-mediated inactivation is highly dependent on Spleen Tyrosine Kinase (SYK) signaling and repeated exposure to amyloid-β impaired this process, whereas prolonged exposure increased 4E-BP1 levels in microglia. Deletion of 4E-BP1/2 resulted in increased mitochondrial mass and oxidative phosphorylation, reduced pro-inflammatory signaling, and protected microglia from amyloid-induced apoptosis. Thus, impaired 4E-BP1 inactivation-due to reduced mTOR signaling or excess 4E-BP1-disrupts immune resolution, leading to metabolic exhaustion and microglial cell death. We identify the SYK-mTORC1-4E-BP1 signaling axis as a key regulator of microglial mitochondrial biogenesis and immune resolution in AD.

Keywords:  Alzheimer’s disease; inflammation; mTOR; microglia

DOI:  https://doi.org/10.1073/pnas.2610766123
Mol Biol Rep. 2026 Oct 23. pii: 1793. [Epub ahead of print]53(1):

The PD-L1-mTOR intersection in tumor migration and invasion.

Rafael Palavro, Thales Thor Ramos Previato, Douglas Bottega Pazzin, Júlia Budelon Gonçalves, Marina Ottmann Boff, Daniel Marinowic, Jaderson Costa da Costa, Thamiris Becker Scheffel.

  Programmed death-ligand 1 (PD-L1) has emerged as an important player in intrinsic tumor cell biology besides its canonical immune checkpoint function. Cumulative experimental data points to a role for PD-L1 in promoting and maintaining an invasive cell phenotype within different cancer cells through its interaction with mechanistic target of rapamycin (mTOR) signaling. In this review, we summarize the main experimental data pointing to the PD-L1/mTOR interaction in tumor cell invasion capacity both in vitro and in vivo. In this crosstalk, PD-L1 expression is induced by IFN-γ/STAT1 and IL-6/STAT3 pathways, as well as mTOR activity by its upstream effectors like EGFR and other tyrosine kinase receptor ligands. Interestingly, PD-L1 itself seems to play a role in mTOR activation. In many of these models, the PD-L1 importance in cell migration capacity is evidenced by two major observations: (1) its knockout impairs cell invasion capacity and, (2) its upregulation is associated with increased cell migration and both the induction and maintenance of epithelial-mesenchymal transition (EMT) phenotype markers, such as increased N-cadherin and ZEB1 and decreased E-cadherin. We also summarize the main clinical trials combining mTOR pathway inhibitors with anti-PD-L1 antibodies in different cancer types.

Keywords:  Epithelial-mesenchymal transition; Mechanistic target of rapamycin; Programmed death-ligand 1; Tumor cell invasion

DOI:  https://doi.org/10.1007/s11033-026-12982-6
Curr Opin Genet Dev. 2026 Oct 20. pii: S0959-437X(26)00117-6. [Epub ahead of print]101 102550

Somatic variants in focal cortical malformations.

Ignacy Czajewski, Stéphanie Baulac, Sara Baldassari.

Cortical malformations are a frequent cause of infantile drug-resistant epilepsy. Somatic variants in only a fraction of brain cells are now an established cause of cortical malformations found in epilepsy surgical resections. Recent major technological and conceptual advances have improved our understanding of such mosaic neurodevelopmental disorders. Here, we review the genetics and neuropathology of focal cortical malformations caused by somatic mosaicism, focusing on the mechanistic target of rapamycin (mTOR) pathway-related focal cortical dysplasia type II and the glycosylation-defective mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). We discuss technical implementations and remaining challenges in the detection of low-level somatic variants and highlight how single-cell approaches have provided new insights into the disease mechanisms. Further, we cover the recent in vivo efforts to better characterize MOGHE, a newly defined cortical malformation.

DOI: https://doi.org/10.1016/j.gde.2026.102550
Elife. 2026 Oct 22. pii: e113125. [Epub ahead of print]15

A hormonal message for a longer life.

Kyle Feola, Peter M Douglas.

  The steroid hormone dafachronic acid may carry the effects of reduced mTOR activity between tissues to coordinate metabolism and longevity across the body.

Keywords:  C. elegans; bile acids; dafachronic acid; genetics; genomics; hormones; longevity; mTOR; physiology

DOI:  https://doi.org/10.7554/eLife.113125
Cell Death Dis. 2026 Jul 27. pii: 900. [Epub ahead of print]17(1):

Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.

Su Jong Han, Ji Hyeon Cho, Jae Ryong Lim, Jee Hyeon Yoon, Ji Yong Park, Han Seung Chang, Su Yeol Kim, Ha Jin Kim, Seung Gyu Lee, Se Jin Mun, Jong Hwa Yun, Chang Woo Chae, Young Hyun Jung, Ho Jae Han.

Neuronal senescence, triggered by oxidative stress and inflammatory responses, is a significant risk factor for brain aging, ultimately leading to cognitive decline. Apelin-13, an exercise-induced myokine, exhibits potential neuroprotective effects by the APJ system, but its protective effects against neuronal senescence and the underlying mechanisms are unknown. This study aimed to elucidate how apelin-13 prevents D-galactose-induced neuronal senescence in SH-SY5Ys, human induced pluripotent stem cell-derived neuronal differentiated cells (iPSC-NDs), and an aging mouse model. The administration of ML233, an apelin receptor APJ agonist, attenuated brain aging and cognitive impairment in D-galactose-induced aging mice. In vitro findings showed that apelin-13 failed to scavenge the excessively generated D-galactose-induced reactive oxygen species (ROS) but prevented aging through APJ-Gαq-mediated signaling in SH-SY5Y cells. Apelin-13 activated protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) to phosphorylate AMPK, which led to the inhibition of mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 promoted the nuclear translocation of transcription factor EB (TFEB), restoring lysosomal function and autophagic flux impaired by D-galactose. Furthermore, D-galactose treatment increased the expression of GATA binding protein 4 (GATA4), a transcription factor that contributes to paracrine senescence by increasing the expression of pro-inflammatory cytokines. Neuronal autophagy restored by apelin-13 promoted GATA4 clearance, ultimately preventing pro-inflammatory cytokine-induced paracrine senescence under D-galactose conditions. Collectively, these results demonstrate that apelin-13 prevents neuronal senescence by inhibiting the mTORC1-GATA4 axis through the restoration of autophagy. Our study highlights apelin-13 as a promising therapeutic candidate for age-related cognitive decline by targeting the oxidative stress-inflammation-neuronal senescence axis through the modulation of autophagy.

DOI: https://doi.org/10.1038/s41419-026-09121-1
Biochemistry. 2026 Sep 15. 65(18): 2916-2927

The Long Splice Variant of Ribosomal Protein S24 Protects Cells from Stress and Is Induced by AMPK-ULK1-Regulated Autophagy Independent of mTORC1.

Runqi Qian, Jenna Goodbrand, Shannon N Adams, Erin Trella, James Uniacke.

All living organisms have developed complex mechanisms to detect and react to environmental changes to maintain internal balance and support survival. One strategy that cells employ to respond to stress is to refocus the translation machinery to express select stress response proteins, this includes the emerging field of specialized ribosomes. We have previously shown that a long splice variant of ribosomal protein S24 (RPS24L) is induced by several fold in hypoxic monolayers and spheroids in several human cell lines in an autophagy-dependent manner. Here, we show that an allosteric activator of AMPK is sufficient to induce RPS24L and autophagy in normoxia in an ULK1-dependent, but mTORC1-independent manner. Overexpression of RPS24L protected cells from serum starvation and hypoxia, while RPS24 short isoform overexpression during stress impaired autophagy and the ability for cells to survive relative to controls. We show that SRSF1 interacts with RPS24 mRNA and its autophagy-dependent decrease shifts splicing toward the RPS24L variant. This study provides new insights into the signaling and mechanisms that regulate a ribosomal protein splice isoform that protects cells from stress and that has been previously linked to cancer progression.

DOI: https://doi.org/10.1021/acs.biochem.6c00572
iScience. 2026 Nov 20. 29(11): 117826

Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration in adult zebrafish.

Anyi Zhang, Luca Masin, Steven Bergmans, Elena Putti, Shahad Albadri, Fabienne E Poulain, Filippo Del Bene, Lieve Moons.

  Dendrite degeneration is an early pathological feature following axonal damage, yet its role during successful axonal regeneration remains poorly understood. Using sparse labeling of retinal ganglion cells in adult zebrafish, we show that axonal regeneration is accompanied by a transient phase of dendritic pruning following optic nerve crush. Dendritic pruning occurs during axon elongation and is reversed after brain reinnervation. Although insulin-mechanistic target of rapamycin (mTOR) signaling is rapidly upregulated immediately after injury, it is subsequently suppressed, coinciding with dendritic pruning and sustained axonal growth. Prolonging mTOR activation through insulin treatment or direct pathway stimulation reduces dendritic pruning in an mTORC1-dependent manner but significantly delays axonal regrowth. Together, these findings identify dendritic remodeling as a temporally regulated component of axonal regeneration in zebrafish and reveal a functional trade-off between dendritic preservation and axon regrowth. This warrants further investigation on whether temporal modulation of dendritic remodeling could promote axonal regeneration in the mammalian central nervous system (CNS).

Keywords:  axonal regeneration; dendritic remodeling; insulin signaling; mTOR signaling; zebrafish

DOI:  https://doi.org/10.1016/j.isci.2026.117826
Nat Commun. 2026 Sep 23. pii: 11057. [Epub ahead of print]17(1):

Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.

Ahmed Magdy, Hyunsoo Rho, Muzamil Mushtaq, William Putzbach, Veronique Nogueira, Vaibhav Chand, Nissim Hay.

Combined Akt1 and Akt2 systemic deletion in adult mice elicits rapid mortality, preceded by body weight loss, diarrhea, and inflammation. Here, we show that lethality induced by systemic Akt1/Akt2 deletion is caused by intestinal damage, as intestinal Akt1/Akt2 deletion induces mortality phenocopying systemic deletion. Consistently, Akt ablation impairs intestinal organoid formation in vitro. Both in vivo and in vitro results show that Akt is essential for the survival of Paneth cells and survival and proliferation of Lgr5+ and transit-amplifying cells. Additional intestinal deletion of either FoxO1 or Tsc1 activates mTORC1 and rescues this phenotype. Thus, mTORC1 emerges as the most critical downstream effector of Akt in maintaining intestinal integrity. Indeed, mTORC1 inhibition by Raptor deletion phenocopies intestinal deletion of Akt1/Akt2. Remarkably, systemic Akt1/Akt2 deletion is tolerated when FoxO1 is deleted concurrently. This study unravels a critical role for Akt in maintaining intestinal homeostasis and the interplay between its downstream effectors FoxO1 and mTORC1.

DOI: https://doi.org/10.1038/s41467-026-77283-9
J Mol Med (Berl). 2026 Oct 20. pii: 122. [Epub ahead of print]104(1):

NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.

Acily Skadon Worral Wilfred Raj, Jaithanya Yesupogu Moorthy Babu, Rajalakshmi Sabanayagam, Sridhar Muthusami, Ravi Manoharan.

  Colorectal cancer (CRC) cells undergo significant alterations in glucose and glutamine metabolism to support rapid growth and migration. However, the molecular mechanisms underlying these metabolic changes remain incompletely understood. Although NUAK1 and NUAK2, members of the NUAK kinase family have been implicated in CRC tumorigenesis, their specific roles in metabolic reprogramming that drives CRC progression and metastasis have not been elucidated. In this study, we demonstrate that NUAK1 and NUAK2 are overexpressed in human CRC tissues and that their expression is associated with increased tumor metastasis and poorer patient survival. NUAK1/2 promotes CRC cell proliferation and migration, whereas their depletion markedly reduces cell growth and migratory capacity. Furthermore, knockout of NUAK1/2 disrupts key metabolic pathways, including aerobic glycolysis, pentose phosphate pathway (PPP), and glutamine metabolism. Mechanistically, NUAK1/2 facilitates mTOR-driven metabolic reprogramming and promotes CRC growth and migration by suppressing AMPK activity. Depletion of NUAK1/2 impairs metabolic function, cellular growth, and migration potential in CRC cells, effects that are further enhanced by pharmacological activation of AMPK with AICAR and inhibition of mTOR using Rapamycin. In conclusion, these findings identify NUAK1/2 as critical regulators of CRC progression and migration through AMPK/mTOR-mediated metabolic reprogramming, highlighting their potential as therapeutic targets in colorectal cancer.

Keywords:  AMPK/mTOR signalling; Colorectal cancer; Glucose and glutamine metabolic reprogramming; NUAK1/2

DOI:  https://doi.org/10.1007/s00109-026-02730-5
Sci Adv. 2026 Oct 23. 12(43): eaeb9836

CASTOR1 functional inactivation drives KRAS-mutant NSCLC and therapy resistance by a noncanonical mechanism of tumor suppression.

Xian Wang, Ling Ding, Wen Meng, Elaine Byrnes, Suet Kee Loo, Shenyu Sun, Luping Chen, Tingting Li, Man-Tzu Wang, Arjun Pennathur, Yufei Huang, Shou-Jiang Gao.

CASTOR1, a cytosolic arginine sensor and regulator of mTORC1 signaling, is identified here as a tumor suppressor in KRAS-driven non-small cell lung cancer (NSCLC). In a KRASG12D mouse model, CASTOR1 deletion enhances tumor initiation and progression, accompanied by increased proliferation. Although CASTOR1 is rarely mutated or deleted in human cancers, its expression progressively declines during tumor progression and is associated with increased AKT activation and CASTOR1 phosphorylation, consistent with functional inactivation. Loss of CASTOR1 results in constitutive mTORC1 hyperactivation, impaired arginine-dependent regulation of mTORC1 signaling, elevated p-4EBP1 and p-S6 levels, increased AKT and ERK activation, genomic instability, and resistance to KRASG12D inhibitors. Tumors and tumor-derived organoids deficient in CASTOR1 are resistant to KRAS inhibition, but this resistance can be overcome by cotargeting mTORC1 or dual PI3K/mTOR inhibition. These findings identify CASTOR1 as a critical link between nutrient sensing and oncogenic signaling and reveal its functional inactivation as an important mechanism contributing to KRAS-driven NSCLC progression and therapeutic resistance. The results further support rational combination therapies to overcome KRAS inhibitor resistance in CASTOR1-low NSCLC.

DOI: https://doi.org/10.1126/sciadv.aeb9836
Front Immunol. 2026 ;17 1961240

Metabolic reprogramming of NK cells in chronic brucellar arthritis: role of the HIF-1α/mTOR axis.

Ganggang Sheng, Wenxuan Li, Da Liu, Xuanchen Ren, Mingyang Wei, Zijing Yang, Weiyu Tian, Fengbo Zhang, Yuejie Zhu, Fanxuan Zeng, Zhiqiang Zhao, Ping Xu, Hongyu Tian, Nannan Pang, Chaopeng Li, Zhendong Zhang.

   Background: Brucellar arthritis is the most common complication of brucellosis, and its chronic progression is closely associated with immune cell dysfunction. Natural killer (NK) cells play a central role in anti-infective immunity; however, their functional status and regulatory mechanisms in brucellar arthritis remain poorly understood.
Methods: Peripheral blood and synovial tissue samples were collected from healthy controls, as well as from patients with acute-phase and chronic-phase brucellar arthritis. Single-cell RNA sequencing (scRNA-seq), flow cytometry, quantitative real-time PCR (qPCR), JC-1 mitochondrial membrane potential assay, Seahorse metabolic analysis, and Western blotting were employed to systematically evaluate NK cell phenotypes, functions, metabolic profiles, and HIF-1α/mTOR pathway activity. In vitro, heat-killed Brucella melitensis 16M (HKBA) was used to stimulate NK-92 cells and HIF-1α-knockout (KO) cell lines, with mTOR inhibitor intervention, to dissect the regulatory mechanism of the HIF-1α/mTOR axis in NK cell metabolic reprogramming.
Results: scRNA-seq revealed enrichment of NK cells in the synovium of brucellar arthritis patients, with aberrant expression of oxidative phosphorylation (OXPHOS)-related genes. Clinical sample analyses showed that, compared with healthy controls, the proportion of peripheral blood NK cells increased in both acute- and chronic-phase patients; however, NK cells from chronic-phase patients exhibited significantly reduced IFN-γ, Granzyme B, and CD107a degranulation levels. HIF-1α protein was consistently overexpressed in patient NK cells, whereas phosphorylated mTOR-pathway proteins (p-PI3K, p-AKT, p-mTOR) were markedly suppressed. In vitro, HKBA treatment inhibited mTOR pathway activity in NK-92 cells in a dose- and time-dependent manner and reduced mitochondrial membrane potential as shown by JC-1 staining. HIF-1α knockout significantly restored NK cell cytotoxic function, upregulated OXPHOS- and glycolysis-related gene expression, and improved mitochondrial membrane potential. Transcriptomic sequencing confirmed enrichment of mTOR signaling and energy metabolism gene sets after knockout. Importantly, mTOR pathway inhibition completely blocked the HIF-1α-knockout-mediated restoration of NK cell function and mitochondrial fitness, indicating that HIF-1α primarily drives NK cell metabolic and functional abnormalities through mTOR suppression.
Conclusions: Brucella infection induces HIF-1α overexpression, which suppresses mTOR signaling and drives metabolic reprogramming of NK cells characterized by impaired OXPHOS and functional exhaustion, thereby promoting chronicity of brucellar arthritis. Targeting the HIF-1α/mTOR axis may offer a novel therapeutic strategy for brucellar arthritis.

Keywords:  HIF−1α; brucellar arthritis; functional exhaustion; mTOR; metabolic reprogramming; natural killer cells

DOI:  https://doi.org/10.3389/fimmu.2026.1961240
J Biochem Mol Toxicol. 2026 Nov;40(11): e71138

Betaine Attenuates Cuprizone-Induced Cortical Demyelination: The Role of the WNT4/mTOR Signalling Pathway in Regulating Astrogliosis and Synaptic Integrity.

Yara M Said, Heba-Tallah Abd Elrahim Abd Elkader, Gihad Jamal Bekheet, Sherine Abdel Salam, Amina E Essawy.

  Cortical grey matter pathology manifests early demyelinating diseases and is a primary driver of permanent neurological impairment. Our study investigated the neuroprotective effects of betaine against cuprizone (CPZ)-induced damage to the cerebral cortex in rats, focusing on its ability to modulate the upstream WNT4/mTOR signalling pathway. Cortical tissues were collected for biochemical assessments of oxidative and inflammatory markers, real-time PCR analysis for WNT4, GFAP, and mTOR gene expressions, histopathological examination, and immunohistochemical analysis of vimentin, S100, and synaptophysin. Exposure to CPZ resulted in severe cortical damage with profound oxidative stress. This oxidative status triggered a pronounced neuroinflammatory response, leading to elevated levels of IL-17A, IL-1β, and TNF-α, which in turn caused chronic, hyper-reactive astrogliosis. This was confirmed by the upregulation of GFAP gene expression and enhanced immunohistochemical staining of vimentin and S100β, resulting in extensive loss of cortical synaptic integrity (depletion of synaptophysin). Importantly, treatment with betaine served as a molecular brake, significantly downregulating the aberrant gene expressions of WNT4 and mTOR. This targeted downregulation effectively reduced the overactive glial response, leading to a significant reduction in astrogliosis (GFAP, vimentin, and S100β), alleviated the pro-inflammatory cytokines, restored endogenous antioxidant functions, and ultimately preserved cortical synaptophysin expression and cellular structure. Overall, these results demonstrate that betaine exerts a neuroprotective effect against CPZ-induced cortical injury, which is strongly associated with the attenuation of WNT4/mTOR signalling pathway hyperactivation, suppression of astrogliosis, and preservation of synaptic density. The preservation of cortical grey matter integrity is directly associated with alleviating cognitive deficits and long-term physical disabilities in multiple sclerosis patients, emphasising the translational relevance of targetable neuroprotective therapies.

Keywords:  WNT4/mTOR signalling pathway; astrogliosis; betaine; cerebral cortex; cuprizone

DOI:  https://doi.org/10.1002/jbt.71138
Drugs. 2026 Oct 23.

Gedatolisib: First Approval.

Hannah A Blair.

Gedatolisib (REVTORPYK®) is a kinase inhibitor of class I phosphatidylinositol 3-kinase (PI3K) isoforms and mechanistic target of rapamycin (mTOR) complexes. It is being developed by Celcuity, under a license from Pfizer, for the treatment of various cancers. PIK3CA, which encodes the catalytic subunit of PI3K, is frequently mutated in a range of cancers, including breast cancer. Gedatolisib received its first approval in the USA on 14 July 2026 for use in combination with fulvestrant, with or without palbociclib, for the treatment of adult patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer without a PIK3CA mutation detected following progression on or after treatment with at least one line of endocrine therapy in the metastatic setting. This article summarizes the milestones in the development of gedatolisib leading to this first approval for HR+/HER2- breast cancer.

DOI: https://doi.org/10.1007/s40265-026-02394-y
Brain Res Bull. 2026 Oct 23. pii: S0361-9230(26)00451-X. [Epub ahead of print] 112164

Epidural Spinal Cord Stimulation Promotes the Expansion of Endogenous Neural Stem Cells and Neuroprotection via the PI3K/AKT/ mTOR Pathway after Spinal Cord Injury in Rats.

Gang Li, Feifei Shen, Jian Li, Zhongkai Fan, Shisheng He.

  Spinal cord injury (SCI) often leads to severe motor and sensory dysfunction, yet no effective treatment currently exists. Epidural spinal cord stimulation (ESCS) is a treatment for chronic neuropathic pain in the trunk and extremities, and exerts a significant effect on the recovery of motor function, although the underlying mechanisms remain unclear. The present study aimed to investigate the effects of ESCS on the endogenous neural stem cells (eNSCs) proliferation and neuroprotection as well as the underlying mechanisms following SCI in rats. In the present study, results showed that ESCS improved hindlimb motor function and markedly increased the numbers of surviving ventral horn neurons of the spinal cord at 7 and 28 days after SCI. ESCS significantly reduced the apoptosis of anterior horn cells in the spinal cord on day 28 post-SCI. Moreover, ESCS remarkably increased the expressions of NSCs markers nestin and sox2, as well as the proportion of nestin/sox2/DAPI-double positive cells (eNSCs) at 7 days after SCI. Notably, ESCS induced only a negligible number of Sox2/NeuN/DAPI double-positive cells at 28 days after SCI. LY294002, a selective inhibitor of phosphoinositide 3-kinase (PI3K) markedly decreased the ratios of eNSCs and surviving ventral horn neurons after ESCS treatment. Finally, ESCS increased the protein levels of phosphorylated-protein kinase B (p-Akt) and phosphorylated-mammalian target of rapamycin (p-mTOR) at 7 days after SCI, and LY294002 significantly attenuated the effects of ESCS on p-Akt and p-mTOR. This report suggests that ESCS treatment after SCI enhances the expansion of eNSCs and neuroprotection via the PI3K/AKT/mTOR signaling pathway.

Keywords:  Endogenous neural stem cells; Epidural spinal cord stimulation; Expansion; Neuronal neuroprotection; Spinal cord injury

DOI:  https://doi.org/10.1016/j.brainresbull.2026.112164
Tissue Cell. 2026 Oct 22. pii: S0040-8166(26)00778-0. [Epub ahead of print]104(Pt 3): 104082

P2Y6 receptor activation promotes the migration, invasion and glycogen accumulation of colorectal cancer through AKT/mTOR signaling.

Zi-Long Hu, Jing-Wen Hu, Wen-Tao Xiong.

  Recent studies have shown that G protein-coupled P2Y6 receptor (P2Y6R) can play a promoting or inhibitory role in some tumors, but the functional effect of P2Y6R on the migration and invasion of colorectal cancer (CRC) is still poorly understood. Therefore, this study comprehensively investigated whether the P2Y6R plays a promoting or inhibiting role in the migration and invasion of CRC. Public databases were used to investigate the intrinsic association between P2Y6R and CRC tissue. Functional experiments was used to investigate the effects of P2Y6R activation or inhibition on CRC migration, invasion, cytoskeleton and glycogen accumulation. The results showed that high expression of P2Y6R was negatively correlated with overall survival and prognosis of CRC patients. The P2Y6R agonist (UDP) opened the function of the pore on the cell membrane and increased the influx of calcium ions, while antagonistic to its activation could produce a significant inhibitory effect. UDP promoted the migration and invasion capabilities of CRC cells, enhanced the fibrin stress capabilities of the cytoskeleton, and promoted the glycogen accumulation capabilities of cells. However, the P2Y6R antagonist MRS2578 or MRS4853 significantly inhibited these changes induced by UDP. Moreover, the P2Y6R had a clear correlation with AKT/mTOR in patients with CRC tissues. UDP increased the protein expression levels of p-AKT and p-mTOR in CRC cells, while P2Y6R antagonists decreased the protein expression levels of p-AKT and p-mTOR by inhibiting P2Y6R activity. In addition, based on P2Y6R activation, the application of AKT/mTOR pathway inhibitor BGT226 inhibited UDP-induced migration, invasion, cytoskeleton and glycogen accumulation of CRC cells. Combined intervention of P2Y6R antagonists and BGT226 produced additive inhibitory pharmacological effects. These data reveal that high expression of P2Y6R contributes to poor overall survival outcomes in patients with CRC. Activation of P2Y6R promotes the migration, invasion and glycogen accumulation of CRC cells, and the mechanism may be related to the AKT/mTOR pathway. This also reveals that the P2Y6R can be used as another important target for the prevention and treatment of CRC.

Keywords:  Colorectal cancer; Invasion; Migration; P2Y6R; UDP

DOI:  https://doi.org/10.1016/j.tice.2026.104082
Am J Cancer Res. 2026 ;16(9): 4115-4128

NCCRP1 promotes ovarian cancer progression and is associated with activation of the PI3K/AKT/mTOR signaling pathway and altered mitochondrial respiration.

Junhao Jiang, Xuedong Fan, Zhipeng Wang, Man Gao, Ning Zhang, Yang Liu, Rumeng Wang, Kong Qiao, Lizhou Jia.

  Non-specific cytotoxic cell receptor protein 1 (NCCRP1) is a membrane protein involved in cell proliferation, but its role in ovarian cancer (OC) progression remains unclear. In this study, a prognostic model for OC was constructed using LASSO-penalized Cox regression analysis. NCCRP1 expression in ovarian tissues was detected by immunohistochemical staining, and its associations with clinicopathological features and prognosis were analyzed. The effects and underlying mechanism of NCCRP1 on the malignant biological behaviors of OC cells were further investigated in vitro and in vivo. The prognostic model consisted of 28 genes with significant prognostic value. Among these genes, NCCRP1 mRNA showed differential expression in ovarian tissues and potential prognostic significance. NCCRP1 protein was overexpressed in OC tissues compared with adjacent ovarian tissues, and high NCCRP1 expression was associated with ascites, tumor cells in ascites, lymph node metastasis, distant metastasis and advanced FIGO stage. Patients with high NCCRP1 expression tended to have poorer overall survival. Knockdown of NCCRP1 inhibited the proliferation, migration and invasion of OC cells and promoted apoptosis, whereas NCCRP1 overexpression produced the opposite effects. In addition, NCCRP1 knockdown decreased oxygen consumption rate, whereas NCCRP1 overexpression produced the opposite effect. NCCRP1 expression was also positively associated with the phosphorylation levels of PI3K, AKT and mTOR. These findings suggest that NCCRP1 promotes malignant biological behaviors in OC, is associated with altered mitochondrial respiratory activity and may exert its tumor-promoting effects, at least in part, through activation of the PI3K/AKT/mTOR signaling pathway. Therefore, NCCRP1 may serve as a novel prognostic marker and potential therapeutic target for OC patients.

Keywords:  NCCRP1; PI3K/AKT/mTOR; mitochondrial respiration; ovarian cancer

DOI:  https://doi.org/10.62347/OXEM5735
J Cell Sci. 2026 Oct 20. pii: jcs.264721. [Epub ahead of print]

cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.

Saumya Bhatt, Mohammad Ali Abbas Zaidi, Hadley R Taggart, Nicholas Woods, Yiyang Wu, Subramanian P Ramanathan, Cody N Rozeveld, Micah B Schott.

  Cyclic adenosine monophosphate (cAMP) signaling is a major stimulus for lipid and glucose catabolism, yet catabolic processes like these can also coordinate with lysosome-dependent degradation. However, the impact of cAMP signaling on lysosomal dynamics remains unclear. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is regulated by stimulus-dependent nuclear-cytoplasmic shuttling through a variety of phosphorylation events. Here, we find that elevating intracellular cAMP with forskolin and IBMX induces rapid nuclear import of TFEB-GFP within 30 minutes and coincides with a transient upregulation of TFEB target lysosome genes. By 8 hours, TFEB returns to the cytoplasm, accompanied by transcriptional downregulation. Inhibition of cAMP-dependent protein kinase A (PKA) using H89 did not block nuclear import but unexpectedly caused sustained nuclear accumulation, indicating that PKA promotes TFEB nuclear export. Consistent with this, phosphoproteomic profiling revealed increased phosphorylation of a PKA-consensus motif (RRxS) during the export phase. These findings suggest that cAMP-PKA signaling plays a novel role in temporally "tuning" lysosomal gene expression by regulating TFEB nuclear-cytoplasmic shuttling.

Keywords:  Lysosome; Nuclear Export; Nuclear import; Protein Kinase A; Transcription Factor EB; cAMP

DOI:  https://doi.org/10.1242/jcs.264721
Front Cell Dev Biol. 2026 ;14 1963535

Balloon cells in type II focal cortical dysplasia: developmental origins, molecular signatures, and epileptogenic mechanisms.

Yan Gao, Xinna Ji, Shuo Feng, Yanyan Gao, Lingxue Li, Bing Wang, Xue Zhang, Qian Chen.

  Type II focal cortical dysplasia (FCD II) is a major cause of drug-resistant epilepsy in children, with balloon cells representing a defining histopathological feature of FCD IIb. Although diagnostically important, the biological identity and epileptogenic contribution of balloon cells remain incompletely understood. Current evidence links balloon cells to disrupted cortical development, often driven by somatic mosaic mutations in the PI3K-AKT-mTOR pathway, resulting in impaired differentiation, cellular enlargement, and hybrid neuroglial phenotypes. This review examines current evidence on the developmental origins and lineage states, molecular signatures, electrophysiological features, and network effects of balloon cells in FCD II. Persistent mTOR hyperactivation appears to interact with cytoskeletal abnormalities, oxidative stress, and local inflammatory signaling, thereby creating a microenvironment that favors epileptogenic remodeling. Despite being largely electrically silent, BCs are embedded within lesion microenvironments characterized by disrupted inhibitory circuitry, altered neurotransmitter homeostasis, and complement-associated synaptic remodeling. BCs may participate indirectly in these processes, although their cell-specific causal contribution remains unresolved. Recent single-cell and spatial transcriptomic studies further distinguish balloon cells from dysmorphic neurons and implicate them in local immune activation. Understanding balloon cell biology may reveal cell-specific therapeutic targets and support precision treatment strategies beyond surgical resection.

Keywords:  balloon cells; epilepsy; focal cortical dysplasia; mTOR signaling; neuroinflammation; targeted therapy

DOI:  https://doi.org/10.3389/fcell.2026.1963535
J Chem Phys. 2026 Oct 28. pii: 161001. [Epub ahead of print]165(16):

Allostery in the Ras-Raf-PI3K-PTEN signaling network at the membrane: Implications for drug discovery.

Ruth Nussinov, Hyunbum Jang.

Here, we review the active roles and mechanisms of the plasma membrane and phospholipids in peripheral membrane proteins and lipid-anchored membrane proteins, focusing on the Ras-Raf-PI3K-PTEN signaling network. Data for some phospholipids are scant (or non-existent), whereas for others the mechanistic details are often incomplete-likely due to the challenging nature of membrane dynamics. Identification of the direct, specific interactions of the phospholipids with proteins is often lacking; instead, these lipids are frequently described as creating a negatively charged lipid environment, transiently interacting with proteins. To clarify these elusive yet cardinal mechanisms, we contrast lipid-coupled conformational changes with macroscopic bilayer effects-including altered dimensionality, curvature, and lateral pressure-that collectively modulate protein function by shifting conformational ensembles and local concentration. These lead us to consider specific lipid-binding allostery, membrane-property-mediated conformational coupling, recruitment and orientation effects, and proximity, avidity, and clustering effects. While specific lipid-protein interactions are often transient, both components serve vital active roles in protein function. This is reinforced by distinguishing between canonical, site-specific allosteric regulation and broader membrane-mediated phenomena. Pharmacology at the membrane has been challenging; direct specific lipid-binding allostery is complicated by the often-transient membrane lipid-protein interactions. Coupled with macroscopic bilayer effects, such pharmacology can elicit toxic side-effects. Specifically targeting the regulation of membrane-associated proteins, autoinhibition and activation, may fare better in the clinic. The Ras-Raf-PI3K-PTEN signaling network, which is anchored and controlled by membrane interaction and can be viewed as the heart of cell proliferation, is an especially relevant system to explore.

DOI: https://doi.org/10.1063/5.0354338
Front Immunol. 2026 ;17 1926747

CircUGP2 inhibits tumor progression via PI3K/AKT/mTOR signaling through sponging miR-137-3p and interacting with UPF1 in hepatocellular carcinoma.

Longfei Xie, Suxin Li, Huahu Guo, Wenhui Zhang, Mengjie Shang, Bailin Cheng, Dingyang Li, Luhao Li, Zhaochen Liu, Lin Li, Liang Bao, Kaiwei Tian, Chengxuan Li, Xiaowei Dang.

   Background: Circular RNA (circRNA) has been shown to have a pivotal role in the initiation and evolution of multiple tumors, but its function in hepatocellular carcinoma (HCC) requires further elucidation.
Methods: circUGP2 (hsa_circ_0001020) was identified in the GEO database by HCC circRNA microarray. Subsequently, an assessment was conducted to determine the biological effects of circUGP2, employing a series of analytical methods, including CCK8, EdU, colony formation, transwell, scratch assays, and in vivo experimentation. To explore the functions of circUGP2 as a sponge, including RNA pull-down, microRNA-seq, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed. Mass spectrometry (MS), RIP, and co-inmunoprecipitation (Co-IP) were employed to examine the interaction between cirrcUGP2 and up-frameshift protein 1 (UPF1).
Results: circUGP2 was downregulated in HCC tissues and cells, which inhibited the growth and spread of HCC in vitro and in vivo. In the mechanisms, circUGP2 has the capacity to modulate KLF4 by sponging miR-137-3p, thereby suppressing HCC growth and migration. In addition, circUGP2 could combine with UPF1 and facilitate an interplay between UPF1 and AKT, influencing tumor progression in HCC via inactivation of the PI3K/AKT signaling pathway.
Conclusion: circUGP2 has a crucial function in HCC development by modulating the miR-137-3p/KLF4 axis to inactivate the PI3K/AKT/mTOR pathway and by interacting with UPF1. The findings indicate the potential of circUGP2 as a novel biomarker and target for HCC.

Keywords:  KLF4; PI3K/Akt/mTOR pathway; UPF1; circUGP2; hepatocellular carcinoma

DOI:  https://doi.org/10.3389/fimmu.2026.1926747