bims-meract 2026-09-06 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–09–06
twelve papers selected by
Andrea Morandi, Università degli Studi di Firenze

YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer.
DHCR24+ tumor epithelial cells drive cisplatin resistance in bladder cancer by enhancing cholesterol metabolism to activate lipid raft-associated MAPK signaling.
PPARα activation overcomes fibroinflammatory liver microenvironment-associated anti-PD-1 resistance in hepatocellular carcinoma by mediating GSDME-dependent pyroptosis.
Targeting PGAM1 Y119 Phosphorylation Resensitizes Non-Small Cell Lung Cancer to Cisplatin Therapy by Promoting Oxidative Stress and DNA Damage.
p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma.
Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
PRMT7-mediated arginine methylation of FOXK activates Wnt/β-catenin signalling to drive doxorubicin resistance in diffuse large B-cell lymphoma.
Atractylenolide I stabilizes HMOX1 to induce ferroptosis and enhance lenvatinib efficacy in hepatocellular carcinoma.
L-Glutamine's potential to enhance chemotherapy efficacy in advanced pancreatic cancer.
Metabolic Reprogramming Drives Platinum Resistance in Gastric Cancer: From ENO1/PDK3 to ATF4-Autophagy Compensation.
Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.
EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.

Adv Sci (Weinh). 2026 Aug 30. e77492

YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer.

Zheng-Hao Lai, Yi Wang, Na-Na Li, Ling Zeng, Renzhong Liu, Xue Li, Cheukfai Li, Xin-Yu Ma, Wenkui Fu, Yingsen Tang, Jinjin Chen, Ning Liao, Man-Li Luo.

  Developing effective therapies for triple-negative breast cancer (TNBC) requires the identification of key molecular regulators. Here, among the major m6A modulators, we find that only the reader YTHDC1 is specifically overexpressed in TNBC and correlates to unfavorable prognosis. Mechanistically, YTHDC1 orchestrates glucose and glutamine metabolism in an m6A-dependent manner to confer robust adaptability to lethal metabolic stress in TNBC cells. It not only stabilizes GLUT3 mRNA to sustain glucose uptake and NADPH production, but also reduces the mRNA stability of ATF4, thereby suppressing the overexpression of the cystine/glutamate antiporter SLC7A11 to prevent excessive cystine uptake and glutamate export. YTHDC1 knockdown simultaneously disrupts glucose metabolism and upregulates SLC7A11, triggering disulfidptosis in TNBC cells in vitro and in vivo. Leveraging this YTHDC1 knockdown-induced metabolic vulnerability, we develop an ATF4 mRNA-targeted nanotherapy, which delivers mRNA directly to the cytoplasm and bypasses m6A-mediated destabilization by YTHDC1 in the nucleus. By promoting SLC7A11 expression, therapeutic overexpression of ATF4 sensitizes TNBC cells to disulfidptosis upon GLUT inhibitor BAY-876 treatment, and to glutamate deprivation-induced cell death upon GLS inhibitor CB-839 treatment. Collectively, this work reveals YTHDC1 as a pivotal coordinator of the glucose-glutamine-cystine metabolic network and provides ATF4 mRNA nanomedicine-based combination strategies to improve TNBC therapeutic efficacy.

Keywords:  YTHDC1; disulfidptosis; m6A; metabolism; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.77492
Oncogene. 2026 Aug 29.

DHCR24+ tumor epithelial cells drive cisplatin resistance in bladder cancer by enhancing cholesterol metabolism to activate lipid raft-associated MAPK signaling.

Yuanqiao Zhao, Zhuo Xing, Mengmeng Wang, Liangmin Fu, Ruilin Liu, Zexian Ding, Yuan Li, Yinhuai Wang, Bin Yan, Xueqiang Zhu.

Cisplatin-based combination therapy remains the primary treatment modality for patients with advanced bladder cancer (BCa); however, the emergence of drug resistance severely restricts clinical benefits. The molecular mechanisms underlying chemoresistance remain incompletely understood. By integrating single-cell transcriptomics with in vitro and in vivo experiments, we revealed that cholesterol metabolism was significantly hyperactivated in cisplatin-resistant BCa tissues. Further subpopulation re-clustering identified a specific chemoresistant epithelial cell subset (C3) characterized by robust cholesterol metabolism, in which the cholesterol metabolic enzyme DHCR24 was significantly upregulated and played a pivotal role in mediating cisplatin resistance in BCa. Mechanistically, the elevated expression of TFDP1 in cisplatin-resistant BCa epithelial cells upregulated DHCR24 via the formation of the TFDP1-E2F1 transcriptional complex, thereby promoting cholesterol biosynthesis. The enriched intracellular cholesterol facilitated the formation of cell membrane lipid rafts and enhanced the phosphorylation of Src, which in turn hyperactivated the downstream MAPK signaling pathway, ultimately conferring cisplatin resistance. Furthermore, the accumulated cholesterol enhanced PD-L1 protein stability, thereby impairing the efficacy of immunotherapy in BCa. Taken together, our study characterizes a specific DHCR24+ tumor epithelial subpopulation that orchestrates cisplatin resistance via the "cholesterol-lipid raft-MAPK" axis. These findings establish a clear mechanistic link between cholesterol metabolism and cisplatin sensitivity.

DOI: https://doi.org/10.1038/s41388-026-03967-7
Nat Commun. 2026 Aug 06. pii: 9474. [Epub ahead of print]17(1):

PPARα activation overcomes fibroinflammatory liver microenvironment-associated anti-PD-1 resistance in hepatocellular carcinoma by mediating GSDME-dependent pyroptosis.

Peng Chen, Kai Xiong, Kuiyuan Huang, Zheyu Dong, Junjie Liang, Xiaoning Gan, Tengzhen Li, Morang Zhang, Shunzi Jing, Xinwen Xu, Yalu Zheng, Zhangyun Li, Weicong Chen, Dandan Zheng, Yuanyuan Zhong, Guanqi Dai, Qiang Li, Jiaojiao Chu, Mingrong Cao, Jian Sun, Zhilong Liu, Jiexin Li, Shangxiang Chen, Yuanbo Zhao, Qin Juan, Xueqin Li, Zhili Wen, Yongyin Li, Huajin Pang, Duo Wang, Yuchuan Jiang.

The fibroinflammatory liver microenvironment (FILM), characterized by collagen-rich stroma and immunosuppressive inflammation, is prevalent in hepatocellular carcinoma (HCC) and correlates with poor response to programmed cell death protein 1 (PD-1) blockade. Here, we show that FILM suppresses gasdermin E (GSDME)-dependent pyroptosis and promotes immune suppression and anti-PD-1 resistance. Mechanistically, FILM-associated cancer-associated fibroblasts recruit and polarize macrophages toward a nitric oxide synthase 2 (NOS2)⁺ inflammatory phenotype. NOS2+ macrophage-derived nitric oxide induces SP1 S-nitrosylation, impairs SP1 binding to the peroxisome proliferator-activated receptor alpha (PPARA) promoter and transcriptionally represses PPARA in HCC cells. PPARα downregulation reduces pyruvate dehydrogenase kinase 4 (PDK4) expression, mitochondrial reactive oxygen species production, caspase-3 activation and GSDME cleavage. Conversely, ligand activation of tumor intrinsic PPARα restores the PDK4-ROS-caspase-3-GSDME axis, enhances dendritic cell and CD8⁺ T cell activation, and sensitizes HCC to anti-PD-1 therapy. The clinically approved PPARα agonist fenofibrate enhances anti-PD-1 efficacy in HCC models in male mice and is associated with improved clinical benefit in a retrospective cohort of patients with HCC. We propose a FILM-NOS2-SP1-PPARα-PDK4 axis that controls pyroptotic immunogenicity and immunotherapy response, supporting PPARα activation as a strategy to overcome FILM-associated immune resistance in HCC.

DOI: https://doi.org/10.1038/s41467-026-75770-7
J Biol Chem. 2026 Sep 01. pii: S0021-9258(26)02378-1. [Epub ahead of print] 113506

Targeting PGAM1 Y119 Phosphorylation Resensitizes Non-Small Cell Lung Cancer to Cisplatin Therapy by Promoting Oxidative Stress and DNA Damage.

Wenxia Zhang, Yanzhao Qu, Xin Wang, Lihua Wang, Xin Jin, Jiahui Kuang, Qian Wang, Shunxin Han, Min Wei, Yang Wang, Jia Liu.

  Cisplatin resistance remains a primary challenge in the clinical management of non-small cell lung cancer (NSCLC), yet the regulatory targets underlying this resistance remain largely unknown. It is well established that cisplatin kills tumor cells through the induction of DNA damage and the accumulation of reactive oxygen species (ROS), which exacerbate DNA damage. Here, we identify the glycolytic metabolic enzyme PGAM1, and specifically its elevated activity in cisplatin-resistant tumors, as a pivotal metabolic driver of this resistance. Y119 phosphorylation, which reflects increased PGAM1 activity, is significantly elevated in NSCLC patient tissues and further amplified in cisplatin-resistant cell lines. Mutation of the PGAM1 Y119 phosphorylation site (Y119F) resensitizes resistant cells to cisplatin both in vitro and in vivo. Mechanistically, Y119-phosphorylated PGAM1 enhances flux through the pentose phosphate pathway (PPP) and the serine synthesis pathway (SSP). This metabolic reprogramming promotes nucleotide biosynthesis and NADPH generation, thereby alleviating cisplatin-induced DNA damage and oxidative stress. In vivo, a PGAM1-derived pY119-mimetic cell-permeable peptide (Y119E-TAT) that competitively disrupts PGAM1 binding to its histidine kinase, thereby inhibiting PGAM1 activity, potently inhibits cisplatin-resistant NSCLC tumor growth. Together, these findings reveal a novel mechanism by which PGAM1 Y119 phosphorylation drives chemoresistance and suggest that targeting this phosphorylation event represents a potential therapeutic strategy to overcome cisplatin resistance in NSCLC.

Keywords:  DNA damage; ROS; cisplatin resistance (CR); metabolic reprogramming; phosphoglycerate mutase 1 (PGAM1); phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2026.113506
Nat Commun. 2026 Aug 05. pii: 9415. [Epub ahead of print]17(1):

p38β-mediated BiP phosphorylation drives stemness and chemoresistance by suppressing UPR activation in hepatocellular carcinoma.

Liang Xu, Ianto Bosheng Huang, Minghe Zhang, Yunong Xie, Bing Li, Linglin Liu, Long Hin Ng, Yimiao He, Yan Liu, Tin-Lok Wong, Xiaoyun Lu, Terence Kin-Wah Lee, Jing-Ping Yun, Lei Jin, Stephanie Ma, Man Tong.

Tumor-initiating cells (TICs) promote tumor initiation and therapy resistance, yet the kinase regulators that sustain TICs remain incompletely defined. Here, we identify the stress kinase p38β (MAPK11) supports TIC maintenance and drug resistance in hepatocellular carcinoma (HCC). Integrated analysis of chemotherapy-enriched HCC spheroids, and DepMap data prioritized p38β as a kinase linked to stemness and chemoresistance. High p38β expression correlates with poor prognosis and aggressive clinicopathological features in HCC patients. Mechanistically, p38β phosphorylates the endoplasmic reticulum (ER) chaperone BiP at threonine 648, enhancing its association with the unfolded protein response (UPR) sensors PERK and IRE1-α. This modification suppresses UPR activation and reduces unfolded protein accumulation, thereby preserving ER proteostasis under chemotherapeutic stress. Functionally, p38β-driven BiP phosphorylation sustains TIC phenotypes and cisplatin resistance in vitro and in vivo. BiP inhibition with HA15 restores UPR signaling and sensitizes patient-derived xenograft and organoid models to cisplatin, revealing a targetable p38β-BiP axis in HCC.

DOI: https://doi.org/10.1038/s41467-026-76073-7
Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.

  High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy

DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
Clin Transl Med. 2026 Sep;16(9): e70802

PRMT7-mediated arginine methylation of FOXK activates Wnt/β-catenin signalling to drive doxorubicin resistance in diffuse large B-cell lymphoma.

Xiaoyan Zhao, Jiasi Zhang, Yao Teng, Yaqin Wang, Wen Yu, Yan Sun, Zhou Wu, Aiguo Liu.

   BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in diffuse large B‑cell lymphoma (DLBCL) treatment, yet its clinical efficacy is often compromised by drug resistance. Protein arginine methyltransferase 7 (PRMT7) is a methyltransferase implicated in tumourigenesis and cancer progression. However, its precise role and underlying mechanisms in DLBCL progression and doxorubicin resistance remain unclear.
METHODS: We analysed PRMT7 expression in DLBCL cell lines and patient specimens using bioinformatic databases, western blotting, reverse Transcription Polymerase Chain Reactionand immunohistochemistry. Functional studies were performed in DLBCL cell lines through CRISPR/Cas9‑mediated knockout and overexpression systems, combined with in vitro assays for proliferation, apoptosis and doxorubicin sensitivity, as well as in vivo xenograft models. Mechanistically, co‑immunoprecipitation, arginine methylation assays and immunofluorescence were employed to characterise the PRMT7-Forkhead box K (FOXK)1/2-Dishevelled Segment Polarity Protein 2 (DVL2) axis and its modulation of Wnt/ (beta) β‑catenin signalling. In addition, we designed and evaluated FOXK‑methylation‑competitive inhibitory peptides for their capacity to sensitise DLBCL cells to doxorubicin.
RESULTS: Our study revealed that PRMT7 is upregulated in DLBCL and promotes both tumour proliferation and doxorubicin resistance. Conversely, knockdown of PRMT7 inhibited DLBCL cell proliferation and enhanced sensitivity to doxorubicin. Mechanistically, PRMT7 catalyses arginine methylation of FOXK1 at arginine (R) 191 and FOXK2 at R144, which markedly increases their binding affinity for DVL2 and facilitates DVL2 nuclear translocation. This event leads to constitutive activation of the Wnt/β‑catenin signalling pathway. Importantly, we developed a FOXK‑derived peptide that competitively inhibits FOXK methylation, suppresses Wnt/β‑catenin signalling and significantly potentiates the antitumour efficacy of doxorubicin in DLBCL.
CONCLUSION: Our findings indicate that the PRMT7/FOXK/DVL2/Wnt-β-catenin axis serves as a novel driver of DLBCL progression and doxorubicin resistance. Targeting the PRMT7-FOXK methylation interface may offer a potential therapeutic approach for overcoming doxorubicin resistance in DLBCL, although further validation in clinical settings is warranted.
KEY POINTS: Upregulated PRMT7 drives DLBCL progression and doxorubicin resistance PRMT7 methylates FOXK1 at arginine 191 and FOXK2 at arginine 144 FOXK1/2 methylation enhances interaction with DVL2 and promotes nuclear translocation FOXK1/2 methylation dactivate Wnt/ß-catenin signaling through DVL2 nuclear entry A novel peptide inhibitory blocks FOXK1/2 methylation and restores doxorubicin sensitivity.

Keywords:  Forkhead box K; diffuse large B‐cell lymphoma; doxorubicin resistance; methylation; protein arginine methyltransferase 7

DOI:  https://doi.org/10.1002/ctm2.70802
iScience. 2026 Sep 18. 29(9): 117259

Atractylenolide I stabilizes HMOX1 to induce ferroptosis and enhance lenvatinib efficacy in hepatocellular carcinoma.

Yangyang Miao, Shengjie Jin, Rui Peng, Daoyuan Tu, Jiahao Zhang, Songsong Fan, Bingbing Su, Anyang Jiang, Jihu Zheng, Guoqing Jiang, Chi Zhang, Jun Cao, Dousheng Bai.

  Lenvatinib resistance limits the therapeutic efficacy of hepatocellular carcinoma (HCC), highlighting the need for effective strategies to enhance treatment response. Atractylenolide I (AT-1), a bioactive compound derived from Atractylodes macrocephala, exhibits antitumor activity, yet its mechanism in HCC remains unclear. Here, we demonstrate that AT-1 suppresses HCC growth by inducing ferroptosis and enhances Lenvatinib efficacy. AT-1 increases intracellular Fe2+ accumulation, lipid peroxidation, and reactive oxygen species, consistent with ferroptotic cell death. Mechanistically, AT-1 directly binds to heme oxygenase-1 (HMOX1) and stabilizes its protein expression by inhibiting ubiquitination at lysine residues K177 and K179, thereby preventing proteasomal degradation. Genetic or pharmacological inhibition of HMOX1 abrogates AT-1-induced ferroptosis and antitumor effects in vitro and in vivo. Notably, AT-1 synergistically enhances Lenvatinib-mediated tumor suppression in HCC models. These findings identify HMOX1 stabilization as a core ferroptosis-regulating mechanism and support AT-1 as a promising adjuvant strategy for HCC therapy.

Keywords:  HMOX1; atractylenolide I; ferroptosis; heme oxygenase-1; hepatocellular carcinoma; lenvatinib; ubiquitination

DOI:  https://doi.org/10.1016/j.isci.2026.117259
Nat Cancer. 2026 Sep 01.

L-Glutamine's potential to enhance chemotherapy efficacy in advanced pancreatic cancer.

DOI: https://doi.org/10.1038/s43018-026-01231-1
J Gastroenterol Hepatol. 2026 Aug 31.

Metabolic Reprogramming Drives Platinum Resistance in Gastric Cancer: From ENO1/PDK3 to ATF4-Autophagy Compensation.

Wenqiang Luo, Lei Jiang, Xiao Hu.

DOI: https://doi.org/10.1111/jgh.70708
Blood Cancer Discov. 2026 Sep 02.

Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.

Qingyu Luo, Karley S Whalen, Xiaowei Wu, Amanda L Fortune, Jacqueline S Garcia, Kate Marinchev, Lin Zhang, Weiye Qian, Evangeline G Raulston, Yabing Nan, Christopher A G Booth, Kezhi Yan, David E Root, John G Doench, Andrew A Lane.

Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, whose depletion sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its ZC3H4-mediated nuclear mRNA degradation. KHSRP depletion therefore enhanced the synergistic cytotoxicity of vitamin C and uric acid, particularly in therapy-persistent leukemia cells. Re-expression of TET2 overrode the chemosensitizing effect of KHSRP depletion in TET2-mutant leukemia, suggesting that KHSRP-linked phenotypes were related to vitamin C and uric acid-mediated TET activation. These findings nominate targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0030
Exp Neurol. 2026 Aug 29. pii: S0014-4886(26)00366-3. [Epub ahead of print]407 116000

EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.

Lufei Chen, Ruying Lin, Yongpei Xu, Shiqi Lin, Jinyuan Fan, Huiyao Zhang, Ying Zhou, Qinyong Ye, Zucheng Ye.

  Glioblastoma (GBM) exhibits profound metabolic and redox adaptation that supports tumor progression and therapeutic resistance. Here, we identify the glutamate transporter EAAT1 (SLC1A3) as a critical regulator of glutamate-dependent redox homeostasis in GBM. Analysis of TCGA, GTEx, and CGGA datasets showed that EAAT1 expression is elevated in GBM and that higher EAAT1 expression is associated with poor patient survival. Using CRISPR/Cas9-mediated EAAT1 knockout together with biochemical, imaging, transcriptomic, and in vivo approaches, we found that loss of EAAT1 altered extracellular and intracellular glutamate homeostasis, reduced intracellular glutamate, glutamine, and glutathione levels, and increased reactive oxygen species (ROS) accumulation. EAAT1 deficiency also suppressed oxidative phosphorylation and ROS-related programs and attenuated the Keap1/Nrf2/HO-1 antioxidant axis, accompanied by reduced GPX4 expression and increased lipid peroxidation. Furthermore, EAAT1 ablation downregulated glutamine synthetase and glutaminase, suggesting impaired glutamine-dependent anaplerotic metabolism. Glutamate supplementation partially restored Keap1/Nrf2/HO-1 pathway protein expression in EAAT1-knockout cells. Functionally, EAAT1 loss inhibited GBM cell proliferation and migration, enhanced sensitivity to oxidative stress and temozolomide (TMZ), and reduced tumor growth in xenograft models. Collectively, our findings establish EAAT1 as a key metabolic regulator linking glutamate transport to antioxidant defense and therapeutic response in GBM. Targeting EAAT1 may therefore represent a metabolic vulnerability for overcoming metabolic and redox adaptation and improving TMZ responsiveness in GBM.

Keywords:  EAAT1; Glioblastoma; Glutamate; Oxidative stress

DOI:  https://doi.org/10.1016/j.expneurol.2026.116000