bims-matara 2026-10-18 papers

on MTOR

Issue of 2026–10–18
seventeen papers selected by
Lucas van Endert, Institut du Cerveau and Alisa Kirkin, Université de Fribourg

Nutrient Sensing and Growth Control in Plasmodium: Beyond mTOR Signaling.
Gastrodin and Microglial Autophagy-Pyroptosis Crosstalk: Evidence and Hypotheses Involving the AMPK/mTOR/NLRP3 Axis.
miR-486 attenuates myocardial ischaemia/reperfusion injury by inhibiting apoptosis and autophagy activation via the FOXO1/PTEN/AKT/mTOR axis.
Ginseng alleviates fatigue by inhibiting autophagy via activation of the PI3K/AKT/mTOR signaling pathway.
ZKSCAN3 mitigates lipopolysaccharide-induced acute lung injury by restraining excessive autophagy via activation of the mTOR pathway.
Metabolic convergence on TOR signaling in the chestnut blight fungus and its regulation by host plant signals.
GP73 regulates autophagy and fibrotic responses in LX-2 cells through the PI3K/AKT/mTOR signaling pathway.
SEC31A promotes gastric cancer progression by inducing the PI3K/AKT/mTOR pathway and enhancing the CCL5‑mediated M2 polarization and recruitment of tumor‑associated macrophages.
LAMTOR2 Reprograms Energy Metabolism to Sustain Hepatocellular Carcinoma Cell Survival.
Prenatal acephate exposure induces uterine proliferative remodeling and PI3K/Akt/mTOR-associated oxidative stress, apoptosis, and autophagy in rats.
Glutaminolysis and mTOR-C/EBPβ Signaling Drives the Differentiation of Novel IL-10-Producing Regulatory T Cells.
Comprehensive transcriptomic and proteomic profiling of mTOR-related epilepsy.
Integrative Phosphoproteomic Characterization of ULK1 Phosphosites Reveals Co-Regulatory Networks in Autophagy and Metabolic Adaptation.
The AMPK/mTOR axis is linked to placental ferroptosis in human gestational diabetes mellitus.
The dual role of the PI3K/AKT/mTOR axis in glial cell survival and neuroinflammation.
Baihe Zhimu Decoction ameliorates anxious depression via PI3K/AKT/mTOR pathway-mediated neuroprotection and inhibition of hippocampal neuronal apoptosis.
Dysregulation of the miR-1825/TSC2/mTOR Axis Contributes to Prostate Cancer Aggressiveness.

Mol Microbiol. 2026 Oct 11.

Nutrient Sensing and Growth Control in Plasmodium: Beyond mTOR Signaling.

Felix Müller, Gabriele Pradel.

  The mechanistic target of rapamycin (mTOR) signaling pathway is a central regulator of nutrient sensing, metabolism, growth, and stress adaptation in most eukaryotes. Malaria parasites of the genus Plasmodium, however, lack identifiable orthologues of mTOR kinase and its associated signaling complexes, raising the question of how these organisms coordinate environmental sensing with developmental progression and proliferation. Here, we discuss emerging evidence suggesting that Plasmodium has evolutionarily replaced the canonical mTOR signaling axis with a distributed regulatory architecture composed of parasite-specific nutrient sensors, kinase-based signaling pathways, translational repression mechanisms, and unconventional autophagy processes. Components such as KIN, PI3K, eIF2α kinases, eIF4E-interacting protein DOZI, and Maf1 collectively preserve many hallmark outputs of mTOR signaling, including metabolic adaptation, stress tolerance, developmental plasticity, and reversible quiescence. In addition, malaria parasites interact with host mTOR pathways during infection, potentially exploiting host-derived anabolic signaling environments to support intracellular development. These findings suggest that Plasmodium exemplifies an extreme case of signaling plasticity in eukaryotic evolution, demonstrating how essential mTOR-associated functions can be maintained despite the apparent loss of the pathway itself.

Keywords:   Plasmodium ; kinase network; malaria; mechanistic target of rapamycin; nutrient sensing; stress adaptation

DOI:  https://doi.org/10.1111/mmi.70123
Int J Mol Sci. 2026 Sep 30. pii: 8754. [Epub ahead of print]27(19):

Gastrodin and Microglial Autophagy-Pyroptosis Crosstalk: Evidence and Hypotheses Involving the AMPK/mTOR/NLRP3 Axis.

Chan-Yen Kuo, I-Shiang Tzeng, Yi-Chyan Chen, Mao-Liang Chen.

  Gastrodin (GAS), a bioactive glycoside from Gastrodia elata, shows anti-inflammatory and neuroprotective activity in preclinical models. This narrative review evaluates whether autophagy, mitochondrial quality control, and NOD-like receptor family pyrin domain containing 3 (NLRP3)-dependent pyroptosis may contribute to its effects on microglia. Studies in microglial cultures and animal models report reduced inflammatory activation and changes in microglial phenotype after GAS treatment. Related studies in endothelial cells, neurons, macrophages, and whole brain tissue associate GAS with AMP-activated protein kinase (AMPK) signaling, mechanistic target of rapamycin (mTOR) inhibition, autophagy or mitophagy markers, and lower inflammasome or pyroptosis markers. These findings support an AMPK/mTOR/NLRP3-centered working model, but the complete causal chain has not been demonstrated in microglia within a single experimental system. We distinguish microglia-specific observations from evidence extrapolated across cell types and disease models, compare GAS with its metabolite p-hydroxybenzyl alcohol, and discuss limitations of inhibitor-based experiments and variation in dose and sampling time. Inducible microglial genetic deletion, flux measurements, target-engagement assays, and matched pharmacokinetic studies are needed to test this model. Human evidence remains insufficient to confirm the proposed microglial mechanism or its clinical relevance.

Keywords:  NLRP3 inflammasome; autophagy; gastrodin; microglia; pyroptosis

DOI:  https://doi.org/10.3390/ijms27198754
Mol Biol Rep. 2026 Oct 16. pii: 1745. [Epub ahead of print]53(1):

miR-486 attenuates myocardial ischaemia/reperfusion injury by inhibiting apoptosis and autophagy activation via the FOXO1/PTEN/AKT/mTOR axis.

Liwenjing Xu, Wenting Xu, Guangmei Li, Qiyu Sun.

   BACKGROUND: Effective therapeutic interventions for myocardial ischaemia/reperfusion injury (MIRI) are lacking. The expression of miR-486, a cardiac-enriched microRNA, is downregulated in ischaemic myocardium; however, its functional role and underlying molecular mechanisms in MIRI remain unclear.
METHODS: To overexpress miR-486 in vivo, MIRI rat models were administered miR-486 AAV. Cardiac function was assessed using echocardiography, infarct size using 2,3,5-triphenyltetrazolium chloride staining, and collagen deposition using haematoxylin and eosin and Masson's trichrome staining. In vitro, H9c2 cardiomyocytes were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and transfected with a miR-486 mimic, miR-486 inhibitor, or respective negative controls. Dual-luciferase reporter assays were conducted in HEK-293T cells to validate FOXO1 and PTEN as direct targets of miR-486. Apoptosis- and autophagy-related protein expression was analysed using western blotting. siRNA-mediated silencing of FOXO1 or PTEN and pharmacological inhibition of AKT (MK2206) or mTOR (rapamycin) were used to establish the underlying signalling axis.
RESULTS: AAV-mediated overexpression of miR-486 significantly improved cardiac function, reduced infarct size, and attenuated myocardial histopathological injury in MIRI rats. In H9c2 cells, the miR-486 mimic suppressed OGD/R-induced elevation of FOXO1 and PTEN protein levels, whereas the miR-486 inhibitor further augmented their expression. MiR-486 directly targeted FOXO1 and PTEN via their respective 3'-UTRs in dual-luciferase reporter assays. MiR-486 overexpression markedly reduced the Bax/Bcl-2 and cleaved caspase-3/caspase-3 ratios. Additionally, it decreased Beclin 1 and LC3-II/GAPDH and increased p62 expression, indicating concurrent suppression of apoptosis and excessive autophagy. Notably, these effects were reversed with miR-486 inhibition. Consistent findings occurred in vivo. siRNA-mediated silencing of either FOXO1 or PTEN partially reversed the pro-apoptotic and pro-autophagic effects induced by miR-486 inhibition. Under OGD/R conditions, the phosphorylation levels of AKT and mTORC1 downstream targets, including S6K and 4EBP1, were restored with miR-486 overexpression. The contribution of AKT/mTOR signalling to the protective effects mediated by the miR-486 mimic was confirmed with AKT or mTOR inhibition.
CONCLUSIONS: MiR-486 attenuates MIRI by directly targeting FOXO1 and PTEN, thereby facilitating AKT/mTOR pathway activation to co-ordinately suppress cardiomyocyte apoptosis and excessive autophagy. These findings support the involvement of the miR-486/FOXO1/PTEN/AKT/mTOR axis as an important cardioprotective mechanism and identify miR-486 as a potential therapeutic target for MIRI.

Keywords:  AKT/mTOR pathway; Apoptosis; Autophagy; FOXO1; Myocardial ischaemia/reperfusion injury; PTEN; miR-486

DOI:  https://doi.org/10.1007/s11033-026-12913-5
Mol Biol Rep. 2026 Oct 10. pii: 1707. [Epub ahead of print]53(1):

Ginseng alleviates fatigue by inhibiting autophagy via activation of the PI3K/AKT/mTOR signaling pathway.

Hengxu Liu, Rui Xiong, Shipeng Zhang, Pan Zhang, Lu Wang, Qian Wang, Xiaodan Lai.

   BACKGROUND: Panax ginseng C. A. Mey. (PG) is a commonly used traditional Chinese medicine to relieve fatigue-related symptoms. However, the underlying mechanisms by which PG alleviates fatigue are still not fully understood. This study aims to elucidate the anti-fatigue mechanism of PG in a hyperammonemia induced fatigue mouse model.
METHODS: The therapeutic effects of PG on hyperammonemia-induced fatigue mice were evaluated using behavioral assessments, including rotarod, open field, grip strength, and tail suspension tests, along with serum biochemical analysis and hematoxylin-eosin (HE) staining. To investigate the molecular mechanisms, an integrated approach combining transcriptomics, proteomics, network pharmacology, immunohistochemistry, immunofluorescence, and Western blot was employed.
RESULTS: PG significantly enhanced the exercise tolerance of hyperammonemia-induced fatigue mice, ameliorated skeletal muscle fiber atrophy, and restored the serum ammonia, creatine kinase, blood urea nitrogen, lactate dehydrogenase, and blood glucose levels. Comprehensive analysis of transcriptomics, proteomics and network pharmacology indicated that the mechanism of anti-fatigue of PG may be mediated by regulating autophagy via the PI3K/AKT signaling pathway. In addition, immunohistochemistry, Western blot, and immunofluorescence analysis confirmed that PG protected against fatigue by activating the PI3K/AKT/mTOR pathway to restore dysregulated autophagy in skeletal muscle under hyperammonemia conditions.
CONCLUSIONS: PG may alleviate fatigue by inhibiting excessive autophagy via the PI3K/AKT/mTOR pathway and restoring the protein balance within skeletal muscle.

Keywords:   Panax ginseng C. A. Mey. ; Autophagy; Fatigue; PI3K/AKT/mTOR pathway; Skeletal muscle

DOI:  https://doi.org/10.1007/s11033-026-12902-8
J Thorac Dis. 2026 Sep 30. 18(9): 1050

ZKSCAN3 mitigates lipopolysaccharide-induced acute lung injury by restraining excessive autophagy via activation of the mTOR pathway.

Lei Zhang, Xinyu Yang, Yiwei Li, Xueshan Bu.

   Background: Acute lung injury (ALI) is a critical condition marked by dysregulated inflammation and autophagic imbalance. Zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3) is a master transcriptional repressor of autophagy, yet its role in ALI pathogenesis remains unclear. The aim of this study is to elucidate the functional role and underlying mechanisms of ZKSCAN3 in ALI.
Methods: ALI was induced in C57BL/6 mice and A549 alveolar epithelial cells by lipopolysaccharide (LPS). ZKSCAN3 was overexpressed using plasmid transfection to evaluate its therapeutic potential. Lung injury was assessed by histopathology, wet-to-dry ratio (W/D ratio), and inflammatory cytokine levels [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6]. Autophagic activity was evaluated via transmission electron microscopy(TEM), immunofluorescence, and western blotting for LC3-II, Beclin-1, and P62. The involvement of the mTOR pathway was investigated by examining the phosphorylation status of mTOR.
Results: ZKSCAN3 expression was significantly downregulated in both LPS-induced lung tissues and A549 cells. Overexpression of ZKSCAN3 markedly alleviated LPS-induced pulmonary edema, alveolar damage, and the surge of pro-inflammatory cytokines. Mechanistically, ZKSCAN3 overexpression suppressed excessive autophagic flux, as evidenced by a decreased LC3-II/LC3-I ratio and Beclin-1 expression, and increased accumulation of P62. Furthermore, this protective effect was associated with a notable increase in mTOR phosphorylation, indicating reactivation of the mTOR-autophagy inhibitory axis.
Conclusions: Our findings reveal that downregulation of ZKSCAN3 contributes to the pathogenesis of LPS-induced ALI. Restoration of ZKSCAN3 exerts a protective effect by reining in excessive autophagy, through activation of the mTOR signaling pathway. This positions the ZKSCAN3-mTOR axis as a potential therapeutic target for ALI.

Keywords:  ZKSCAN3; acute lung injury (ALI); excessive autophagy; inflammation; mammalian target of rapamycin (mTOR)

DOI:  https://doi.org/10.21037/jtd-2026-1611
New Phytol. 2026 Oct 13.

Metabolic convergence on TOR signaling in the chestnut blight fungus and its regulation by host plant signals.

Yo-Han Ko, Jeesun Chun, Geonmin Kim, Jiwon Yu, Dae-Hyuk Kim.

  Transcriptomic analysis of the chestnut blight fungus Cryphonectria parasitica identified 22 core genes regulated by Cryphonectria hypovirus 1 (CHV1) infection and sectorization. Twelve genes with common phenocopies were analyzed: all mutants displayed restricted colonial growth, intense pigmentation, hyperbranched terminal hyphae with swollen globose cells, and reduced conidiation. Although gene-specific mutant phenotypes existed, responses to most stressors were similar to those of the wild-type. Mutant growth was highly sensitive to nutrient conditions, and growth restriction was notably alleviated by supplementation with 1.0 M sorbitol, nutrient-deficient media, or skim milk. All mutants showed hallmarks consistent with reduced target of rapamycin (TOR) signaling. Trehalose accumulation, a canonical fungal response to TOR inhibition, was observed in mutants via transcriptional upregulation of core trehalose biosynthetic genes, resulting in altered hyphal osmolarity and common mutant cell phenotypes. Plant signals overrode the mutants' phenotypes, strongly promoting their growth and differentiation. Although a severely retarded growth defect was observed in mutants, mutants' virulence remained intact, which can be ascribed to the host-plant signals. Cryphonectria hypovirus 1 (CHV1)-infected mutants exhibited greater growth restriction, accompanied by genotype-specific CHV1 titers. Despite gene-specific variation, common phenocopies indicate that diverse metabolic pathways converge on the TOR pathway in the fungal response to host-plant and CHV1 infection.

Keywords:  Cryphonectria parasitica; TOR pathway; autophagosome; hypovirus; osmotic stability; plant signals

DOI:  https://doi.org/10.1111/nph.71631
Cytotechnology. 2026 Dec;78(6): 211

GP73 regulates autophagy and fibrotic responses in LX-2 cells through the PI3K/AKT/mTOR signaling pathway.

Shuangyan Luo, Ying He, Lianying Cai, Liu Liu, Yuxu Zhang, Lu Si, Qiuchen Cheng, Yunxiao Liang.

  Golgi protein 73 (GP73) has been identified as a potential biomarker for liver diseases. Numerous studies have consistently shown that GP73 expression is significantly elevated in the serum of patients suffering from various types of liver injury. Nevertheless, the underlying regulatory mechanisms by which GP73 contributes to liver fibrosis remain largely undefined. A liver fibrosis model was established by treating LX-2 cells with TGF-β1 for 24 h. LX-2 cells were subsequently cultured and subjected to various treatments, including transfection with plasmids (sh-NC, sh-GP73, oe-GP73) and administration of inhibitors (3-MA and LY294002). Western blot analysis was conducted to quantify protein levels of GP73, fibrosis markers, autophagy-related proteins, and components of the PI3K/AKT/mTOR signaling pathway. Quantitative PCR (qPCR) was utilized to measure GP73 mRNA expression across different samples. Additionally, immunofluorescence assays were performed to evaluate autophagic activity in LX-2 cells. Both mRNA and protein levels of GP73 in LX-2 cells were upregulated following TGF-β1 induction. Activation of the PI3K/AKT/mTOR pathway, as evidenced by increased phosphorylation of PI3K, AKT, and mTOR, along with enhanced autophagy, was observed upon treatment with TGF-β1 or GP73 overexpression. Conversely, silencing GP73 mitigated TGF-β1-induced fibrotic responses. Furthermore, inhibition of the PI3K/AKT/mTOR signaling axis using LY294002 alleviated GP73-mediated suppression of autophagy. The findings suggest that GP73 is associated with autophagy-related changes and fibrotic responses in LX-2 cells, potentially involving modulation of the PI3K/AKT/mTOR signaling pathway.

Keywords:  AKT; Autophagy; GP73; Liver fibrosis; PI3K; mTOR

DOI:  https://doi.org/10.1007/s10616-026-01082-9
Oncol Rep. 2026 Dec;pii: 205. [Epub ahead of print]56(6):

SEC31A promotes gastric cancer progression by inducing the PI3K/AKT/mTOR pathway and enhancing the CCL5‑mediated M2 polarization and recruitment of tumor‑associated macrophages.

Xixian Zhao, Liuye Huang.

  SEC31 homolog A (SEC31A) is associated with a variety of cancers. This study elucidated the role of SEC31A in gastric cancer (GC). The expression of SEC31A in GC was analyzed using western blotting and immunohistochemistry. Functional experiments were performed to detect the impact of SEC31A on GC proliferation, migration and invasion. The PI3K inhibitor LY294002 was used to explore the regulation of the biological functions by SEC31A through the PI3K/AKT/mTOR pathway in GC cells. Co‑culture of THP‑1 (human leukemia cell line of monocytic origin) and GC cells was conducted to investigate the impact of SEC31A on the M2 macrophage polarization in tumor immune microenvironment. Our investigation observed elevated expression of SEC31A in both GC tissue and cell lines. Through functional studies, suppression of SEC31A was found to decrease epithelial‑mesenchymal transition (EMT), proliferation, migration and invasion in GC cells. Overexpression of SEC31A led to activation of the PI3K/AKT/mTOR signaling cascade. The PI3K inhibitor LY294002 counteracted the increases in proliferation, migration, invasion and EMT triggered by SEC31A. Co‑culture experiments involving THP‑1 and GC cells indicated that SEC31A enhanced the recruitment and M2 polarization of macrophages via CCL5 within the GC tumor microenvironment (ME). To assess the influence of M2 macrophages on malignant behavior of GC cells, M2 macrophage‑conditioned medium (M2‑CM) was applied. M2‑CM mitigated the inhibitory effects on malignant phenotypes in GC cells following SEC31A knockdown. Moreover, diminished SEC31A expression enhanced the efficacy of anti‑PD‑1 therapy in GC models. Collectively, SEC31A promoted GC progression via activating the PI3K/AKT/mTOR pathway and facilitating CCL5‑mediated M2 polarization and recruitment of tumor‑associated macrophages. SEC31A knockdown may augment the anti‑tumor response to anti‑PD‑1 treatment in GC. These findings highlight SEC31A as a valuable prognostic indicator and potential target for immunotherapy in GC, offering novel strategies to enhance the effectiveness of anti‑PD‑1 therapy.

Keywords:  M2 macrophage; PI3K/AKT/mTOR; SEC31 homolog A; anti‑PD‑1; gastric cancer

DOI:  https://doi.org/10.3892/or.2026.9211
FASEB J. 2026 Oct 31. 40(20): e72355

LAMTOR2 Reprograms Energy Metabolism to Sustain Hepatocellular Carcinoma Cell Survival.

Jie Xiao, Dewen Fan, Yinbing Wu, Xiuye Cao, Ziqiang Yang, Hongye Li, Wenbin Zhong, Mingchuan Li, Daoguang Yan.

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming to support rapid proliferation and survival under nutrient stress. However, the central regulatory hubs that coordinate these diverse metabolic programs remain poorly understood. Here, we identify LAMTOR2 as a critical coordinator of energy metabolism and survival in HCC cells. LAMTOR2 is markedly upregulated in HCC tissues, and high LAMTOR2 expression correlates with poor survival. LAMTOR2 depletion inhibits HCC cell proliferation and induces significant cell death, effects that are substantially rescued by LAMTOR2 reconstitution. Mechanistically, LAMTOR2 deficiency suppresses mTORC1 signaling, leading to the concomitant downregulation of HIF1α and PPARα transcriptional activities. This dual inhibition disrupts both glycolytic flux and fatty acid β-oxidation, resulting in an energy deficit and the consequent persistent activation of the AMPK-ULK1 axis, thereby leading to autophagic cell death. Our findings identify LAMTOR2 as a pivotal oncogenic regulator that maintains HCC metabolic homeostasis, suggesting that targeting the LAMTOR2-mediated metabolic network may offer a promising therapeutic strategy for HCC.

DOI: https://doi.org/10.1096/fj.202602088R
Food Chem Toxicol. 2026 Oct 12. pii: S0278-6915(26)00521-1. [Epub ahead of print]219 116446

Prenatal acephate exposure induces uterine proliferative remodeling and PI3K/Akt/mTOR-associated oxidative stress, apoptosis, and autophagy in rats.

Maroua Jalouli, Anouar Feriani, Waleed Aldahmash, Saber Nahdi, Musafau Oloyede Sanni, Nizar Tlili, Md Ataur Rahman, Abdel Halim Harrath.

  Prenatal exposure to organophosphate pesticides has been increasingly associated with long-term reproductive failure; nevertheless, their effects on uterine developmental programming are still little understood. This study examined whether in utero exposure to acephate causes lasting uterine damage in female rat progeny and analyzed the associated molecular processes. Pregnant Wistar rats were administered oral acephate (14 or 28 mg/kg) from gestational days 6 to 21, and uterine tissues from female progeny were analyzed at postnatal day 28. Prenatal exposure to acephate caused significant histopathological changes, including endometrial glandular hyperplasia. Oxidative stress was indicated by increased malondialdehyde and protein carbonyl levels, alongside substantial decreases in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Molecular investigations revealed elevated expression of LC3 and caspase-3 at both the mRNA and protein levels, corroborated by immunofluorescence, signifying the activation of autophagy and apoptosis. Acephate altered PI3K/Akt/mTOR signaling in a dose-dependent manner, exhibiting suppression of PI3K/mTOR at lower doses and compensatory Akt activation despite ongoing mTOR inhibition at higher doses. These findings collectively indicate that prenatal exposure to acephate alters uterine development via oxidative stress-induced, dysregulation of PI3K/Akt/mTOR signaling, leading to autophagy, apoptosis, and abnormal proliferative remodeling that could jeopardize long-term female reproductive health.

Keywords:  Acephate; Apoptosis; Autophagy; Prenatal exposure; Signaling pathway; Uterine toxicity

DOI:  https://doi.org/10.1016/j.fct.2026.116446
Int J Mol Sci. 2026 Sep 22. pii: 8447. [Epub ahead of print]27(19):

Glutaminolysis and mTOR-C/EBPβ Signaling Drives the Differentiation of Novel IL-10-Producing Regulatory T Cells.

Masaki Tajima, Ivan J Fuss, Naoko Ikuta, Liming Mao, Timothy G Myers, Paul J Gardina, Atsushi Kitani, Warren Strober.

  Here we report that Dectin-1-stimulated dendritic cells (DCs) induce unique IL-10-producing T cells with strong regulatory function during fungal infection or experimental asthma. These T cells, which we call Dect-10 T cells, are induced by DC-initiated signaling that sets in motion two complementary mechanisms of IL-10-producing T cell differentiation. The first involves induction of nascent Dect-10 T cell IL-4 synthesis and attendant GATA3 production, the latter being a factor that exerts canonical and epigenetic transcriptional function at separate IL-10 promoter sites. The second involves TGFβ superfamily signaling associated with induction of glutaminolysis and generation of alpha-ketoglutarate, a factor that induces rapamycin-sensitive TORC1 activation; in turn, such activation causes the translation of the LIP isoform of C/EBPβ and the formation of a CREB1-LIP complex that binds to adjacent sites on the IL-10 promoter to facilitate the transactivation of the IL10 gene. Dect-10 T cell regulatory function is manifested through its capacity to down-regulate normally protective immune responses to hyphal C. albicans renal infection. In addition, Dect-10 T cells, in accord with their IL-4-dependent genesis, suppress dust mite-induced experimental asthma.

Keywords:  ActRIB (ALK4); C-type lectins; C. albicans infection; IL-10; asthma; glutaminolysis; mTOR

DOI:  https://doi.org/10.3390/ijms27198447
Epilepsia. 2026 Oct 12.

Comprehensive transcriptomic and proteomic profiling of mTOR-related epilepsy.

Kaiyuan Ji, Satoshi Miyashita, Keiya Iijima, Kaoru Yagita, Tomoo Owa, Kazumi Shimaoka, Nao K N Tabe, Minami Mizuno, Ayane Hosaka, Kayo Nishitani, Kumiko Murayama, Kanako Komatsu, Masaki Sone, Terunori Sano, Shinichiro Taya, Tomoki Nishioka, Kozo Kaibuchi, Masaki Takao, Masaki Iwasaki, Mikio Hoshino.

   OBJECTIVE: Malformations of cortical development (MCDs) are a major cause of drug-resistant epilepsy (DRE) in children. A subset of MCDs, including focal cortical dysplasia type II, tuberous sclerosis complex, and hemimegalencephaly, shares characteristic histopathological features and somatic mutations in genes within the Phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling cascade, and is collectively termed mTORopathies. However, mechanisms driving epileptogenesis and drug-resistant seizures remain poorly understood.
METHODS: We performed integrated genomic, transcriptomic, and proteomic analyses of 56 surgical brain specimens from 41 patients with MCDs and 15 with mesial temporal lobe epilepsy. Targeted genomic sequencing identified 19 somatic mutations in PI3K-AKT-mTOR pathway genes, including novel variants in AKT3 (L51H) and MTOR (A512T).
RESULTS: RNA sequencing with independent cohort comparison identified 160 consistently differentially expressed genes. Downregulated genes were enriched in oxidative phosphorylation (OXPHOS) and mitochondrial metabolic pathways, whereas upregulated genes were associated with developmental process. Proteomic analysis revealed directionally concordant reductions in several mitochondrial proteins, and pathway-level alterations in some biological cellular processes.
SIGNIFICANCE: This study provides a patient-matched, multi-omics dataset of human mTOR-related epilepsies from a single-institution cohort. Integrated transcriptomic and proteomic analyses suggested impaired OXPHOS as a molecular hallmark, potentially contributing to focal hypometabolism in mTOR-related epilepsy. These findings offer mechanistic insights into epileptogenesis and provide a resource for understanding molecular pathologies and developing mechanism-based therapies for mTOR-related epilepsy.

Keywords:  epilepsy; mTORopathy; oxidative phosphorylation; proteomics; transcriptomics

DOI:  https://doi.org/10.1002/epi.70514
Int J Mol Sci. 2026 Oct 07. pii: 8892. [Epub ahead of print]27(19):

Integrative Phosphoproteomic Characterization of ULK1 Phosphosites Reveals Co-Regulatory Networks in Autophagy and Metabolic Adaptation.

Furqaan Ahmed Basha, Sreeshma Ravindran Kammarambath, Leona Dcunha, Althaf Mahin, Athira Perunelly Gopalakrishnan, Alimath Sambreena, Inamul Hasan Madar, Rajesh Raju.

  Unc-51-like autophagy-activating kinase 1 (ULK1), a serine/threonine kinase, is the central regulator of autophagy initiation and plays a crucial role in cellular homeostasis, metabolic adaptation, and stress responses. We performed a large-scale phosphoproteomic data analysis of ULK1 by systematically integrating and analyzing 891 profiling and 245 differential human phosphoproteomic datasets. S450, S623, and S638 emerged as the predominant phosphosites in ULK1, with the highest frequency of detection across multiple cellular phosphoproteomics datasets. Conservation analysis showed that these phosphosites are conserved across mammalian species and human ULK1 and ULK2 (Unc-51-like autophagy-activating kinase 2). The co-regulatory networks associated with these phosphosites, including interacting proteins, upstream kinases, and downstream substrates, were systematically analyzed. The phosphosite co-regulated ULK1 interactome revealed a network of associations linking ubiquitin-dependent cargo recognition to autophagosome biogenesis, trafficking, and maturation, indicating that ULK1 phosphoregulation may extend beyond its established role in autophagy initiation and be associated with multiple stages of selective autophagy. Notably, ULK1 phosphosites were linked to key metabolic enzymes in glycogen, sphingolipid, phospholipid, and glycolytic pathways, as well as classical lipolysis. Protein-normalized analysis across 12 cancer cohorts showed significant upregulation of the predominant ULK1 phosphosites, most frequently at S450 and S623. Comparative analysis with an independent ULK1/2 knockout phosphoproteomic dataset further supported the relevance of these identified co-regulated protein phosphosites. Collectively, this study provides a phosphosite-resolved view of ULK1 regulation and identifies candidate phosphosites and associated proteins for future functional and mechanistic studies.

Keywords:  ULK1; autophagy; lipolysis; metabolic enzymes; phospho-regulatory network

DOI:  https://doi.org/10.3390/ijms27198892
Placenta. 2026 Oct 12. pii: S0143-4004(26)00720-4. [Epub ahead of print]186 148-159

The AMPK/mTOR axis is linked to placental ferroptosis in human gestational diabetes mellitus.

Qian Li, Xiaoyi Yin, Ziyi Guo, Haobin Zhao, Niannian Li, Yuchun Zhu, Guanglei Wang.

   BACKGROUND: Ferroptosis has been closely implicated in placenta-related complications. Nevertheless, its specific role in the placenta of gestational diabetes mellitus (GDM) remains poorly understood. We hypothesized that ferroptosis contributes to impaired placental cell function in GDM and that the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis acts as an potential regulator of ferroptosis.
METHODS: Term placental tissues from pregnant women with GDM and healthy controls were analyzed, and the human chorionic trophoblast line (HTR8/SVneo) was used in the in vitro experiments.
RESULTS: Altered levels of ferroptosis markers-transferrin receptor 1 (TfR1), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferrous iron and malondialdehyde (MDA), and potential ferroptosis mediators-reactive oxygen species (ROS), AMPK, and mTOR were observed in GDM placentas compared to control. AMPK inhibitor, AMPK activator, and mTOR inhibitor were applied to modulate the AMPK/mTOR signaling axis in in vitro experiments. Our in vitro data revealed that modulation of AMPK or mTOR activation directly affects the induction of ferroptosis as well as trophoblast cell proliferation and migration.
CONCLUSIONS: Our study suggests that AMPK/mTOR axis is closely associated with placental ferroptosis which may represent a promising therapeutic target for mitigating GDM-related placental complications following further validation in animal models.

Keywords:  AMPK; Ferroptosis; GDM; Oxidative stress; Placenta; mTOR

DOI:  https://doi.org/10.1016/j.placenta.2026.10.003
Naunyn Schmiedebergs Arch Pharmacol. 2026 Oct 17.

The dual role of the PI3K/AKT/mTOR axis in glial cell survival and neuroinflammation.

Nourelhouda Neili, Aroua Jlassi, Sarra Hjaij, Ines Elbini.

  Multiple sclerosis is characterized by a triad of inflammation, demyelination, and neurodegeneration, yet current disease-modifying therapies are limited in their ability to halt progressive neurodegeneration or promote remyelination. The PI3K/AKT/mTOR signaling pathway is a master regulator of these divergent cellular processes and therefore represents a biological paradox in multiple sclerosis. In the pathogenic facet of the disease, activation of this axis supports the differentiation and effector functions of pro-inflammatory T- and B-cells and contributes to inflammatory programs in microglia and macrophages. In the regenerative facet, physiological PI3K/AKT/mTOR activity is required for oligodendrocyte precursor-cell survival, differentiation, myelin synthesis, and maintenance of myelin integrity. Astrocytic signaling adds another layer of context-dependence, with pathway activity influencing reactive gliosis and the inflammatory or reparative properties of the lesion environment. Consequently, systemic inhibition of the pathway may suppress neuroinflammation while simultaneously interfering with endogenous repair. This review therefore considers PI3K/AKT/mTOR axis according to these opposing pathogenic and protective functions, highlighting the importance of cell type, disease stage, and treatment timing. Precision strategies capable of selectively suppressing inflammatory signaling while preserving or restoring pro-regenerative activity, potentially through cell-specific molecular targets, may provide a more rational therapeutic approach than generalized pathway inhibition.

Keywords:  Autoimmune encephalomyelitis; Multiple sclerosis; PI3K/AKT/mTOR axis

DOI:  https://doi.org/10.1007/s00210-026-05986-3
Animal Model Exp Med. 2026 Oct 12.

Baihe Zhimu Decoction ameliorates anxious depression via PI3K/AKT/mTOR pathway-mediated neuroprotection and inhibition of hippocampal neuronal apoptosis.

Yuanshan Han, Kexin He, Haolan Yang, Jiacheng Dai, Ronglin Chen, Yang Liu, Yuhong Wang, Lin Tang, Hongqing Zhao.

   BACKGROUND: Anxious depression involves severe emotional dysregulation with a high risk of relapse and suicide. Although the classical Traditional Chinese Medicine formula Baihe Zhimu Decoction (BZD) is widely used for affective disorders, its underlying mechanisms remain poorly understood.
METHODS: In this study, the chemical constituents of BZD were first identified using UPLC-Q-TOF-MS/MS, followed by a maximum-dose safety evaluation. The therapeutic effects of BZD were then investigated in an anxious-depression mouse model induced by chronic restraint stress (CRS) combined with corticosterone (CORT) administration. Behavioral assessments, including the open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and forced swim test (FST), were performed, together with histopathological examination of hippocampal tissues. Network pharmacology was employed to analyze the relationships between active compounds and potential targets and to predict related signaling pathways. Subsequently, western blot analysis, immunofluorescence staining, Hoechst staining, and flow cytometry, combined with pathway-specific inhibitors, were used to examine the involvement of the signaling pathway in hippocampal tissues and primary hippocampal neurons.
RESULTS: Forty-one constituents were identified in BZD. In vivo results showed that BZD significantly alleviated hippocampal pathological injury and improved anxiety- and depression-like behaviors in stressed mice. Network pharmacology analysis identified 19 active compounds and 622 potential targets, highlighting the PI3K/AKT/mTOR signaling pathway. Mechanistically, BZD activated this pathway and protected against neuronal injury, while these effects were attenuated by the PI3K inhibitor LY294002.
CONCLUSIONS: BZD exerts potent neuroprotective and therapeutic effects against anxious depression, primarily driven by activating the PI3K/AKT/mTOR pathway and preserving hippocampal neuronal integrity.

Keywords:  Baihe Zhimu Decoction; PI3K/AKT/mTOR signaling pathway; anxious depression; network pharmacology; neuronal apoptosis

DOI:  https://doi.org/10.1002/ame2.70295
Cell Biochem Biophys. 2026 Oct 12.

Dysregulation of the miR-1825/TSC2/mTOR Axis Contributes to Prostate Cancer Aggressiveness.

Ozel Capik.

  Prostate cancer (PCa) is the second most widespread cancer affecting solid tumor in men and the fifth most widespread cause of cancer-associated mortality in men. Research into the underlying molecular mechanisms of PCa is an urgent need to develop better therapeutic strategies and reveal new molecular targets for therapeutic intervention. In this study, we proposed to investigate the functional significance of miR-1825 in driving the malignant characteristics of PCa cells in relation to the TSC2/mTOR axis. We primitively examined the effects of miR-1825 mimic/inhibitor on cell viability, cell motility, and clonogenic ability of DU145, LNCaP, and PC3 PCa cells. Subsequently, we investigated the relationship between miR-1825 expression and the TSC2/mTOR signaling pathway through integrated in vitro and in silico approaches. Overexpression of miR-1825 increasingly suppressed TSC2 expression at both the mRNA and protein levels, while concomitantly increasing mTOR expression. In contrast, inhibition of miR-1825 led to the upregulation of TSC2 and a corresponding decrease in mTOR levels. These outcomes support that TSC2 is a putative target of miR-1825 and further confirm the inverse regulatory relationship between TSC2 and mTOR. Moreover, dysregulation of miR-1825 significantly enhanced cell viability, clonogenic ability, and cell motility in PCa cells. Collectively, these data indicate that miR-1825 promotes tumorigenic phenotypes through the dysregulation of the TSC2/mTOR signaling axis in PCa. In summary, our findings demonstrate that miR-1825 acts as an oncogenic regulator in PCa by targeting TSC2 and modulating the mTOR pathway. The miR-1825/TSC2/mTOR axis may represent a promising therapeutic target for the treatment of PCa.

Keywords:  Prostate cancer; TSC2; Tumor progression; mTOR; miR-1825

DOI:  https://doi.org/10.1007/s12013-026-02201-1