bims-matara Biomed News
on MTOR
Issue of 2026–09–13
fifteen papers selected by
Lucas van Endert, Institut du Cerveau
  1. D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
  2. Long-term seizure outcomes and factors associated with response to adjunctive everolimus in TSC-associated epilepsy.
  3. Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
  4. Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.
  5. 18 β-Glycyrrhetinic Acid Inhibits Malignant Progression of Prostate Cancer via Regulation of Autophagy and EMT Induced by PTEN/PI3K/mTOR Pathway.
  6. Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
  7. Copper and iron engage distinct metabolic programs for cellular survival.
  8. Knockdown of CDC20 attenuates pulmonary fibrosis by repressing fibroblast activation via the TSC1-mediated mTOR pathway.
  9. NFS1 activates PI3K/AKT/mTOR signaling to upregulate GPX4 expression and enhance ferroptosis resistance in osteosarcoma.
  10. Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.
  11. Convergent and Divergent Molecular Pathways in FMR1-, TSC2- and FMR1/TSC2 Knockout Neurons.
  12. Terazosin Alleviates Apoptosis and Neuroinflammation in Cerebral Ischemia-reperfusion Injury via Activating the PI3K/AKT/mTOR Signaling Pathway.
  13. A novel mTORC1-NPC2 axis suppresses lipophagy and drives atherosclerotic plaque progression.
  14. Autophagy in tuberculosis: advances, translational gaps, and the promise of host-directed therapies.
  15. GPCR-Driven Muscarinic M1 and Histamine H1 Receptor Signaling Converging on the PI3K/Akt/mTOR Pathway: Functional Integration in Neuroinflammation and Myelin Repair in Multiple Sclerosis.
  1. Mol Ther. 2026 Sep 11. pii: S1525-0016(26)00777-X. [Epub ahead of print]
    D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
    Jae Ho Shim, Ji Yeon Lee, Byung Kook Ahn, Sang Woo Woo, Jihye Han, Hyeon Soo Kim.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation. Three orthogonal biophysical methods demonstrate that DLMEH directly binds Sestrin2 (Kd 28.3 μM), equivalent to L-leucine. Sestrin2 siRNA knockdown and rapamycin co-treatment confirm Sestrin2-dependent, mTORC1-specific activation. In human primary myotubes, DLMEH (100 μM) restores dexamethasone-suppressed protein synthesis by 58.2%, significantly exceeding L-leucine (800 μM, 28.5%). In a rat dexamethasone-induced atrophy model, intravenous DLMEH (100 mg/kg/day, 14 days) preserves gastrocnemius mass (19.3% rescue), grip strength (90% of normal), and treadmill endurance (85% of normal), all superior to oral L-leucine. RNA-seq reveals 41.7% reversal of dexamethasone-induced transcriptomic changes with enrichment in mTOR signaling, ribosome biogenesis, and oxidative phosphorylation. Safety profiling establishes NOAEL at 2000 mg/kg with therapeutic index greater than 30. DLMEH represents a first-in-class Sestrin2-targeting mTORC1 activator for sarcopenia.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.09.007
  2. J Formos Med Assoc. 2026 Sep 09. pii: S0929-6646(26)00870-3. [Epub ahead of print]
    Long-term seizure outcomes and factors associated with response to adjunctive everolimus in TSC-associated epilepsy.
    Tzu-Hsuan Su, Pei-Lung Chen, Steven Shinn-Forng Peng, Chi-Yung Shang, Chia-Wei Lin, Pi-Chuan Fan.
       BACKGROUND: Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, is increasingly used in tuberous sclerosis complex (TSC)-associated epilepsy; however, long-term real-world outcomes and factors associated with favorable response remain unclear. This study aimed to evaluate the long-term seizure outcomes of adjunctive everolimus and explore clinical factors associated with treatment response.
    METHODS: We retrospectively recruited 21 patients with active TSC-associated epilepsy receiving adjunctive everolimus and assessed seizure outcomes during follow-up. Clinical characteristics were compared between responders and non-responders at 1 year after treatment initiation.
    RESULTS: Over a median treatment duration of 72 months, responder rates ranged from 53.8% to 64.7%, and seizure-free rates ranged from 33.3% to 41.2%. Responders had fewer involved organ systems at baseline (median 3 vs. 4, p = 0.020) and lower anti-seizure medication burden (median 2 vs. 4, p = 0.045). Younger age at treatment initiation showed a trend toward improved response.
    CONCLUSION: Adjunctive everolimus was associated with sustained long-term seizure reduction in this real-world cohort. In exploratory analyses, fewer involved organ systems and fewer baseline ASMs were associated with favorable treatment response. These findings require validation in larger prospective cohorts.
    Keywords:  Epilepsy; Everolimus; Mechanistic target of rapamycin; Tuberous sclerosis complex; mTOR inhibitor
    DOI:  https://doi.org/10.1016/j.jfma.2026.09.003
  3. JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]
    Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
    Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.
      Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
    Keywords:  Endocrinology; Muscle biology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.210523
  4. Front Immunol. 2026 ;17 1914506
    Immunometabolism drives metabolic and infectious disease progression through bidirectional metabolic reprogramming and epigenetic remodeling.
    Wenbin Tan.
      Immunometabolism has become a central mechanism governing innate and adaptive immune responses. The field has moved from cataloguing metabolic shifts during immune activation to understanding how specific pathways control immune cell fate and function. This review brings together current knowledge on immunometabolic regulation in metabolic and infectious diseases, emphasizing bidirectional crosstalk between these domains. We address controversies over whether inflammation causes insulin resistance or follows from it, examine the distinct metabolic programs of different immune cell types, and explore trained immunity as a link between innate immune memory and metabolic disease. The review also covers pathogen-specific metabolic strategies and host countermeasures, surveys emerging immunometabolic therapies, and flags unresolved questions for future work. Among promising strategies, mechanistic target of rapamycin (mTOR) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have advanced to clinical trials for immunometabolic indications, whereas epigenetic reprogramming and nanoparticle-based metabolic delivery remain in preclinical development.
    Keywords:  epigenetic remodeling; immunometabolism; infection; inflammation; innate immune memory; metabolic diseases; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1914506
  5. Clin Exp Pharmacol Physiol. 2026 Sep;53(9): e70156
    18 β-Glycyrrhetinic Acid Inhibits Malignant Progression of Prostate Cancer via Regulation of Autophagy and EMT Induced by PTEN/PI3K/mTOR Pathway.
    Dawei Xiong, Hongfeng Dai.
       BACKGROUND: Prostate cancer (PCa) is one of the most common malignancies in men, and its progression is closely related to epithelial-mesenchymal transition (EMT) and autophagy imbalance. 18β-Glycyrrhetinic acid (18β-GA) has been reported to exhibit various anti-tumour activities. This study aims to systematically evaluate the impact of 18β-GA on the malignant biological behaviours of PCa and explore its potential molecular mechanisms.
    METHODS: The human PCa cell lines LNCaP and PC-3 were used to evaluate the inhibitory effects of 18β-GA on malignant progression. The potential mechanisms were further explored by assessing EMT markers, autophagy-related proteins and angiogenesis. The role of the PTEN/PI3K/mTOR pathway in 18β-GA's effects was explored through siRNA-mediated PTEN knockdown and Western blot analysis. A PCa xenograft model was established in vivo to assess the impact of 18β-GA on tumour growth.
    RESULTS: 18β-GA significantly inhibited the viability, proliferation, migration and invasion of LNCaP and PC-3 cells, while promoting apoptosis, with no significant toxicity to RWPE-1 cells. 18β-GA upregulated E-cadherin and Claudin-1, while downregulating N-cadherin, Vimentin, Snail and MMP2/9, thus inhibiting the EMT process and reducing the angiogenesis capacity and VEGF expression in HUVECs. Additionally, 18β-GA increased the LC3-II/LC3-I ratio, upregulated Beclin1 and ATG7 and downregulated p62, indicating activation of autophagic flux. Mechanistic studies revealed that 18β-GA upregulated PTEN expression and inhibited PI3K and mTOR phosphorylation. PTEN knockdown partially reversed its effects on autophagy, EMT and malignant phenotypes. In vivo experiments further confirmed that 18β-GA significantly suppressed xenograft tumour growth and exhibited anti-tumour effects.
    CONCLUSION: 18β-GA inhibits the malignant progression of PCa cells and xenograft tumour growth by upregulating PTEN and inhibiting the PI3K/mTOR axis, synergistically activating autophagy and inhibiting EMT and angiogenesis. 18β-GA holds promise as a potential anti-PCa drug targeting the PTEN/PI3K/mTOR pathway, jointly regulating autophagy and EMT.
    Keywords:  18β‐glycyrrhetinic acid; PTEN/PI3K/mTOR pathway; autophagy; epithelial–mesenchymal transition; prostate cancer
    DOI:  https://doi.org/10.1111/1440-1681.70156
  6. Autophagy. 2026 Sep 07. 1-17
    Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
    Rubén Barrios, Rebeca Gracia-Domingo, Cristina Corral-Ramos, Élida Alechaga, Óscar J Pozo, José Ayté, Elena Hidalgo.
      TORC1 is a central regulator of cell growth whose inactivation under conditions of nutrient deprivation triggers adaptive responses, including macroautophagy/autophagy, amino acid uptake, and sexual differentiation. Autophagy-deficient fission yeast cells display mating defects and are unable to recover from amino acid starvation, even when external amino acids are available. Here, we investigate how TORC1 signaling and autophagy interact to control these processes. We show that both major phenotypes of autophagy-deficient cells - their inability to resume growth after amino acid starvation and their mating defects - stem from insufficient intracellular amino acid pools. Genetic or environmental enhancement of intracellular amino acid pools alleviates both defects. During leucine starvation, deletion of any1 rescues the growth defect of atg1Δ mutants by maintaining amino acid transporters at the plasma membrane, promoting amino acid uptake. Importantly, we uncover a previously unrecognized role for autophagy in the cell-cycle remodeling required for sexual differentiation. Nitrogen depletion-mediated TORC1 inactivation initiates these cell-cycle rearrangements required to start the mating/meiosis program, but autophagy is specifically required for the final G2-to-G1 arrest that precedes the program. This step correlates with the accumulation of the cyclin-dependent kinase inhibitor Rum1. Metabolomic analyses reveal that intracellular amino acid pools drop sharply during nitrogen starvation, especially in autophagy-deficient cells, and supplementation with trace amino acids restores their ability to complete the final G2-to-G1 transition. Together, our results reveal that autophagy sustains intracellular amino acid pools during prolonged stress, enabling TORC1 reactivation and cell-cycle remodeling necessary for successful mating and meiosis.Abbreviations: DNA: deoxyribonucleic acid; FACS: fluorescence-activated cell sorting; GATOR1: GAP activity toward Rags 1; GATOR2: GAP activity toward Rags 2; GFP: green fluorescent protein; MM: minimal medium; N: nitrogen; PCR: polymerase chain reaction; RNA: ribonucleic acid; S. cerevisiae: Saccharomyces cerevisiae; S. pombe: Schizosaccharomyces pombe; TOR: target of rapamycin; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; tRNA: transfer ribonucleic acid; YE5S: yeast extract 5 amino acid supplemented; WT: wild-type.
    Keywords:  Amino acid transporters; Eif21/eIf2α; Eliminate Gcn2; G1 arrest; Rum1; TORC1; leucine starvation
    DOI:  https://doi.org/10.1080/15548627.2026.2719430
  7. Geroscience. 2026 Sep 09.
    Copper and iron engage distinct metabolic programs for cellular survival.
    Arshia Naaz, Trishia Yi Ning Cheng, Jovian Jing Lin, Mingtong Gao, Rajkumar Dorajoo, Brian K Kennedy, Mohammad Alfatah.
      Copper and iron are redox-active micronutrients with tightly coupled homeostasis, yet how copper modulates iron-dependent stress responses remains unclear. Using Saccharomyces cerevisiae under nutrient-limited conditions, we uncoupled proliferative growth from long-term survival to dissect metal-dependent adaptation. Copper selectively preserved survival without affecting growth, whereas iron showed similar effects. Iron chelation impaired growth and suppressed electron transport chain gene expression; copper partially rescued these defects but required iron availability for its pro-survival activity. Despite this interdependence, copper and iron engaged distinct signaling programs. Iron-dependent survival required a Target of Rapamycin complex 1 (TORC1)-permissive state and was attenuated by rapamycin, whereas copper remained active under TORC1 inhibition. In contrast, copper promoted survival through AMP-activated protein kinase (AMPK) and antioxidant pathways, while iron exhibited context-dependent AMPK reliance. Together, these findings reveal that copper and iron support cellular survival through distinct metabolic programs and suggest that the consequences of micronutrient availability are shaped by the underlying nutrient-sensing and metabolic state of the cell. This framework provides insight into how alterations in micronutrient homeostasis and metabolic signaling may influence cellular resilience during aging.
    Keywords:  AMPK; Cellular survival; Copper; Iron; Mitochondria; Nutrient limitation; Redox homeostasis; TORC1
    DOI:  https://doi.org/10.1007/s11357-026-02527-x
  8. Cell Signal. 2026 Sep 08. pii: S0898-6568(26)00545-0. [Epub ahead of print] 112886
    Knockdown of CDC20 attenuates pulmonary fibrosis by repressing fibroblast activation via the TSC1-mediated mTOR pathway.
    Yatao Guo, Mengchan Zhu, Ruyi Li, Jia Li, Jiming Si, Yuanhua Liu, Jingjing Mei, Yan Kang, Jianjun Jin.
      Idiopathic pulmonary fibrosis (IPF) is a fatal disease of the fibrous lungs that is closely associated with fibroblast activation. Cell division cycle protein 20 homolog (CDC20) regulates cell cycle progression, yet its role in lung fibrosis remains unclear. This study aimed to explore the function of CDC20 in IPF and investigate the potential mechanism of CDC20 to influence the progression of pulmonary fibrosis. Here, we found that the expression levels of CDC20 were upregulated in the lung tissue of mice with bleomycin (BLM)-induced pulmonary fibrosis, as well as in activated fibroblasts. Knockdown of CDC20 suppressed the activation of MRC-5 triggered by TGF-β1 via enhancing autophagy. Nevertheless, chloroquine (CQ)-mediated inhibition of autophagy abolished this regulatory effect on fibroblast activation. CDC20 knockdown also inhibited TGF-β1-induced migration and contraction of fibroblasts. CDC20 silencing had a protective effect against BLM-induced lung injury in mice, and CDC20 knockdown inhibited fibrosis in lung tissue and promoted autophagy. The interacting protein TSC1 with CDC20 was screened by IP/LC-MS, and Co-IP analysis showed that TSC1 interacted with CDC20, and CDC20 promoted the ubiquitination degradation of TSC1. Mechanistically, CDC20 boosted the ubiquitination and degradation of TSC1, and the reduction of TSC1 promoted the activation of the mTOR pathway to inhibit fibroblast autophagy, thereby facilitating fibroblast activation. Overall, CDC20 exacerbated pulmonary fibrosis by inhibiting fibroblast autophagy via blocking the mTOR signaling pathway, which suggested that targeting CDC20 might hold putative therapeutic effect in IPF.
    Keywords:  Autophagy; CDC20; Fibroblast; IPF; TSC1; mTOR
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112886
  9. Funct Integr Genomics. 2026 Sep 07. pii: 252. [Epub ahead of print]26(1):
    NFS1 activates PI3K/AKT/mTOR signaling to upregulate GPX4 expression and enhance ferroptosis resistance in osteosarcoma.
    Yu-Nan Man, Jing-Tang Li, Tao Zhang, Ying-Peng Xu, Ya-Yun Liu.
      Osteosarcoma continues to exhibit poor survival outcomes due to chemoresistance and metastasis, with metabolic reprogramming and ferroptosis resistance being key features of tumor heterogeneity, yet their upstream regulators remain poorly defined. NFS1, a cysteine desulfurase essential for iron-sulfur cluster biogenesis, protects multiple cancers from ferroptosis, but its role in osteosarcoma is unknown. In this study, we performed a transcriptomic meta-analysis and found that NFS1 expression was significantly upregulated in osteosarcoma tissues, with further elevation in metastatic lesions, and high NFS1 expression correlated with poor overall survival. Genome‑wide CRISPR screening data revealed a marked NFS1 dependency in osteosarcoma cell lines. Functionally, NFS1 promoted cell proliferation, migration, and invasion, whereas its knockdown suppressed these phenotypes. Using single‑cell RNA sequencing data from 27 osteosarcoma specimens, we applied a multi‑algorithm glycolytic scoring framework and observed NFS1 enrichment in highly glycolytic malignant cells, along with an association with PI3K/AKT/mTOR pathway activation. Mechanistically, NFS1 selectively enhanced PI3K, AKT, and mTOR phosphorylation without altering total protein levels, and upregulated GPX4, a central ferroptosis suppressor, leading to elevated ferroptosis resistance scores in NFS1‑high malignant cells. Collectively, these findings identify a previously unrecognized NFS1-PI3K/AKT/mTOR-GPX4 regulatory axis in osteosarcoma, linking metabolic reprogramming to ferroptosis resistance, and suggest that NFS1 functions as an oncogenic driver, as well as a promising prognostic biomarker and therapeutic target in osteosarcoma.
    Keywords:  Ferroptosis; GPX4; NFS1; Osteosarcoma; PI3K/AKT/mTOR signaling pathway
    DOI:  https://doi.org/10.1007/s10142-026-02040-6
  10. Int J Gynecol Cancer. 2026 Aug 09. pii: S1048-891X(26)00488-3. [Epub ahead of print] 104957
    Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.
    Anna Passarelli, Michele Bartoletti, Alberto Farolfi, Maria Lucia Iacovino, Francesco Perrone, Clorinda Schettino, Laura Arenare, Marcella Montico, Gustavo Baldassarre, Daniela Califano, Carmela Pisano, Valeria Andretta, Grazia Artioli, Alice Bergamini, Roberto Bianco, Alessandra Bologna, Domenica Lorusso, Anna Fagotti, Marica Gentile, Stefania Napolitano, Elena Poletto, Antonella Savarese, Giuseppa Scandurra, Giorgio Valabrega, Claudio Zamagni, Yvonne G Lin, Layal Maatouk, Sandro Pignata.
       BACKGROUND: The phosphatase and tensin homolog-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway is frequently altered in gynecological tumors, notably in endometrial cancer where PIK3CA mutations are found in nearly half of patients. Despite this, evidence of clinical activity of PI3K inhibitors in endometrial cancer is poor and limited. Alpelisib, an oral PI3K alpha-selective inhibitor, showed encouraging preliminary activity in advanced gynecological tumors harboring PIK3CA alterations. Inavolisib is a highly potent and selective PI3K inhibitor.
    PRIMARY OBJECTIVE(S): The MITO END-4 trial aims to assess the efficacy and safety of inavolisib in patients with endometrial cancer who have received platinum-based chemotherapy and immunotherapy. The primary objective is to determine the anti-tumor activity (assessed by objective response rate) of inavolisib in patients with advanced endometrial cancer with PIK3CA mutated tumors.
    STUDY HYPOTHESIS: The study tests the hypothesis that inavolisib has superior anti-tumor activity compared to historically available standard therapies in previously treated patients with advanced endometrial cancer harboring a PIK3CA mutation.
    TRIAL DESIGN: This is a phase II, single-arm, multicenter trial in which advanced endometrial cancer patients whose tumors harbor a pathogenic PIK3CA mutation will receive inavolisib.
    MAJOR INCLUSION/EXCLUSION CRITERIA: Patients aged 18 years and older with documented evidence of PIK3CA mutated advanced endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma or mixed histology) will be enrolled. Patients have previously received at least 1 platinum-based chemotherapy in any setting (adjuvant or advanced) with or without immune checkpoint inhibitor, alone or in combination. Not more than 4 lines of therapy are allowed. Key exclusion criteria include uterine sarcoma and prior treatment with any PI3K, AKT, or mechanistic target of rapamycin (mTOR) inhibitor.
    PRIMARY ENDPOINT(S): Objective response rate defined as a complete response or partial response by the Investigator using RECIST v1.1 criteria over the whole treatment period.
    SAMPLE SIZE: 48 patients.
    ESTIMATED DATES FOR COMPLETING ACCRUAL: May 2028.
    TRIAL REGISTRATION: MITO END-4; EU-CT NUMBER: 2025-522981-61-00; NCT07522697.
    Keywords:  Endometrial cancer; Inavolisib; MITO END-4; PIK3CA mutation; The Cancer Genome Atlas
    DOI:  https://doi.org/10.1016/j.ijgc.2026.104957
  11. Mol Neurobiol. 2026 Sep 08. pii: 883. [Epub ahead of print]63(1):
    Convergent and Divergent Molecular Pathways in FMR1-, TSC2- and FMR1/TSC2 Knockout Neurons.
    Kagistia Hana Utami, Nur Amirah Binte Muhammed Yusof, Yazhini Ramaswamy, Stacey Kiat Hong Tay, Ramkumar Aishworiya, Nevin Tham, Sarah R Langley, Mahmoud A Pouladi, Velda X Han.
      Fragile X syndrome (FXS) and tuberous sclerosis complex (TSC) are common monogenic causes of autism spectrum disorder (ASD). FXS arises from FMR1 silencing, while TSC results from mutations in TSC1 or TSC2, both converging on dysregulated ERK and mTORC1 signaling. Animal knockout models suggest opposing effects on synaptic plasticity, with reciprocal compensation in double knockouts (dKO). However, clinical case with dual mutations shows severe neurodevelopmental deficits; here, we explored a human cellular model to dissect the shared and divergent mechanisms. We generated isogenic human pluripotent stem cell (hPSC)-derived models of FMR1KO, TSC2KO, and FMR1/TSC2 dKO neurons. Neuronal transcriptomes were profiled by RNA-seq, integrating ERK, mTOR, FMRP targets, and ASD risk genes. Validation via qPCR of key genes, protein synthesis, proliferation assays, and microelectrode array was performed. The FMR1/TSC2 dKO neural progenitor cells (NPCs) demonstrated high DNA damage response but normalized proliferation. Convergent transcriptomic pathways across FMR1KO, TSC2KO, and dKO neurons included upregulated extracellular matrix and stress responses, and downregulated synaptic and neurotransmission-related pathways. TSC2KO and dKO neurons showed greater similarity transcriptionally and functionally. Translational pathways and global protein synthesis were oppositely regulated in TSC2KO and dKO versus FMR1KO neurons. The dKO neurons showed hyperexcitable network activity, mTOR hyperactivation, with distinct dysregulated FMRP targets and ASD risk gene expression. Unlike mouse models, FMR1/TSC2 dKO hPSC-derived neurons did not show rescue of synaptic gene expression. Rather, dKO neurons predominantly resembled TSC2KO neurons with translational, synaptic, and neurotransmission abnormalities. These findings highlight complex interplay between FMRP and TSC, providing a foundation for future studies of ASD-relevant mechanisms.
    Keywords:  Autism spectrum disorder; Fragile X syndrome; Transcriptomics; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1007/s12035-026-06166-3
  12. Curr Neuropharmacol. 2026 Aug 31.
    Terazosin Alleviates Apoptosis and Neuroinflammation in Cerebral Ischemia-reperfusion Injury via Activating the PI3K/AKT/mTOR Signaling Pathway.
    Linlin Xie, Yukun Ping, Jie Zhao, Qiong Wu, Yuwei Huang, Mingming Shang, Ludong Hu, Xiaobo Li.
       BACKGROUND: Ischemic stroke remains a major cause of disability and death worldwide, and effective neuroprotective treatments are urgently needed. This study investigated whether Terazosin (TZ), a clinically approved drug with neuroprotective potential, ameliorated Cerebral Ischemia-Reperfusion Injury (CIRI) and explored the underlying mechanisms.
    METHODS: This study integrated network pharmacology analysis with in vivo experimental validation to investigate the neuroprotective effects of TZ against CIRI. Neurological deficits, infarct volume, and brain edema were evaluated in mice. TTC, TUNEL, and Nissl staining, as well as Western blotting, immunofluorescence staining, and quantitative real-time PCR (qPCR), were used to evaluate cell apoptosis, inflammation, and the activity of the PI3K/AKT/mTOR signaling pathway. Potential targets associated with TZ and CIRI were obtained from public databases, followed by GO and KEGG enrichment analyses of the overlapping targets. Statistical analyses were performed using GraphPad Prism 10.1, and P < 0.05 was considered statistically significant.
    RESULTS: TZ treatment significantly reduced cerebral infarct volume and improved neurological function in a mouse MCAO/R model. It attenuated neuronal apoptosis, as evidenced by increased Bcl-2 expression and decreased Bax expression, and suppressed neuroinflammation, as indicated by reduced levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and decreased microglial activation. Bioinformatics analysis identified 140 overlapping targets between TZ and CIRI, with PIK3CA, MTOR, and several other genes emerging as key hub genes. KEGG enrichment analysis revealed significant enrichment of the PI3K/AKT signaling pathway. Further mechanistic investigations revealed that TZ activated the PI3K/AKT/mTOR signaling pathway. Importantly, the neuroprotective effects of TZ were abolished by the PI3K inhibitor LY294002, supporting an essential role of this pathway in mediating the protective effects of TZ against CIRI.
    DISCUSSION: These findings indicate that TZ may protect against CIRI by suppressing apoptosis and neuroinflammation through activation of the PI3K/AKT/mTOR signaling pathway, thereby providing preclinical evidence for its potential repurposing as a treatment for ischemic stroke.
    CONCLUSION: In summary, this study demonstrates that TZ exerts neuroprotective effects against CIRI by activating the PI3K/AKT/mTOR signaling pathway. These results provide a preclinical basis for repurposing TZ as a treatment for ischemic stroke and highlight the PI3K/AKT/mTOR axis as a potential neuroprotective target.
    Keywords:  PI3K/AKT/Mtor signaling pathway; Terazosin; apoptosis; cerebral ischemia-reperfusion injury; inflammatory response; neuron
    DOI:  https://doi.org/10.2174/011570159X477062260820053528
  13. Biochim Biophys Acta Mol Basis Dis. 2026 Sep 09. pii: S0925-4439(26)00305-4. [Epub ahead of print] 168439
    A novel mTORC1-NPC2 axis suppresses lipophagy and drives atherosclerotic plaque progression.
    Legao Chen, Weiqin Lu, Long Piao, Jing Sun, Wenjie Zheng, Kui Mao, Jianliang Pang, Yan Efrãta Sembiring, Jinsong Jiang.
       BACKGROUND: Endothelial dysfunction is a critical initiating factor in atherosclerosis (AS), with NPC2 and mTORC1 playing key roles in the regulation of endothelial lipophagy.
    OBJECTIVE: To reveal that hypercholesterolemia disrupts endothelial lipophagy via the mTORC1-NPC2 axis and to explore its role in atherosclerotic progression.
    METHODS: Thirty AS patients and 30 healthy controls were enrolled. Lipophagy markers in endothelial cells isolated from plaque and non-plaque regions were assessed. Exosomes were characterized and their effects on endothelial viability were evaluated. Multi-omics analyses identified key differentially expressed pathways, which were validated in a high-cholesterol diet mouse model and in human aortic endothelial cells (HAoECs) using pharmacological activation, knockout, and molecular interaction assays.
    RESULTS: AS patients showed significantly elevated serum cholesterol and suppressed lipophagy in plaque-derived endothelial cells. Plaque-derived exosomes inhibited endothelial cell viability and promoted injury marker expression. mTOR signaling was identified as a candidate activated pathway in plaque endothelium, and pharmacological activation of mTOR in HAoECs was associated with impaired lipophagy. Rapamycin attenuated HCD-induced mTOR activation and lipid accumulation in mice. GST pull-down and molecular docking supported a potential association between mTOR and NPC2, while NPC2 deficiency attenuated the rapamycin-associated restoration of lipophagy and lipid homeostasis.
    CONCLUSION: Hypercholesterolemia disrupts endothelial lipophagy through the mTORC1-NPC2 signaling axis, promoting lipid accumulation and accelerating atherosclerosis. Targeting this pathway may offer a novel therapeutic strategy for AS.
    Keywords:  Atherosclerosis; Cholesterol metabolism; Endothelial cells; Lipophagy; NPC2; mTORC1
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168439
  14. Front Cell Infect Microbiol. 2026 ;16 1896798
    Autophagy in tuberculosis: advances, translational gaps, and the promise of host-directed therapies.
    Manjunath Challa, Jessy Padma B, Sivakumar Shanmugam.
      Tuberculosis (TB) is still a major global health threat, worsened by the advancement of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb). Autophagy is a natural degradation and immune process that plays a critical role in the defence against intracellular pathogens, including Mtb. However, Mtb has developed complex mechanisms to evade autophagy by modulating phagosome-lysosome fusion, inhibiting xenophagy, and modifying host signaling pathways, including mTORC1 and AMPK, thereby suppressing epigenetically autophagy-related genes. These immune evasion strategies identify autophagy as a highly attractive target for host-directed therapies (HDTs). In many experimental models, several pharmacological and repurposed compounds, such as mTOR inhibitors, AMPK activators, lysosomal modulators, peptides, and small-molecule inhibitors, are promising factors in restoring autophagy, promoting bacterial clearance, and ameliorating inflammation. Despite the bright prospects of these preclinical studies, the intricacies of cellular pathways, the lack of selective autophagy modulators, the limited biomarkers, and the still inadequate models for translational research remain problematic. In this review, we summarise current insights into Mtb-mediated disruption of autophagy, evaluate emerging autophagy-enhancing HDTs, and highlight key biological and translational gaps. Further development of selective, system-level autophagy modulators may offer powerful adjunct therapies to improve TB treatment outcomes, especially in the era of escalating drug resistance.
    Keywords:  Mycobaterium tuberculosis; TB treatment; autophagy; host-directed therapies; tuberculosis
    DOI:  https://doi.org/10.3389/fcimb.2026.1896798
  15. Mol Neurobiol. 2026 Sep 09. pii: 886. [Epub ahead of print]63(1):
    GPCR-Driven Muscarinic M1 and Histamine H1 Receptor Signaling Converging on the PI3K/Akt/mTOR Pathway: Functional Integration in Neuroinflammation and Myelin Repair in Multiple Sclerosis.
    Rohit Kumar Singh, Janvi Verma, Sidharth Mehan, Divya Choudhary, Zuber Khan, Rajaram Samant, Manoj Tongra.
      Multiple sclerosis is a chronic immune-mediated neurodegenerative disorder characterized by inflammation, demyelination, axonal injury, and progressive neurological disability. Although current disease-modifying therapies effectively reduce relapse frequency and peripheral immune activation, they provide limited protection against long-term neurodegeneration and remyelination failure. Emerging evidence suggests that neurotransmitter receptor-linked intracellular signaling pathways play crucial roles in regulating neuroinflammation, glial function, and neuronal survival. This review comprehensively examines the interconnected roles of the CHRM1, H1R, and the PI3K/Akt/mTOR signaling pathway in MS pathophysiology. CHRM1 and H1R both G protein-coupled receptors widely expressed in neurons, glial cells, and immune cells, modulate intracellular calcium signaling, cytokine production, blood-brain barrier integrity, and oligodendrocyte precursor cell dynamics. Dysregulated activation of these receptors contributes to persistent neuroinflammation, impaired remyelination, and synaptic dysfunction. Downstream, the PI3K/Akt/mTOR axis functions as a critical integrative hub controlling cell survival, metabolism, autophagy, and myelin protein synthesis. Balanced activation of this pathway promotes neuronal protection and oligodendrocyte maturation, whereas its chronic dysregulation exacerbates mitochondrial dysfunction, oxidative stress, and axonal degeneration. By synthesizing current experimental and mechanistic evidence, this review highlights the functional cross-talk between cholinergic and histaminergic signaling and their convergence on PI3K/Akt/mTOR-mediated cellular responses. Understanding these interconnected molecular networks provides a foundation for developing multi-target therapeutic strategies aimed at simultaneously reducing neuroinflammation, enhancing neuroprotection, and promoting remyelination in progressive MS.
    Keywords:  CHRM1 (Muscarinic acetylcholine receptor M1); Histamine H1 receptor (H1R); Multiple sclerosis; Neuroinflammation; PI3K/Akt/mTOR signaling pathway; Remyelination
    DOI:  https://doi.org/10.1007/s12035-026-06190-3
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