bims-meract 2026-08-09 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–08–09
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.
Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple-Negative Breast Cancer.
Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.
TMEM135 deficiency prevents intestinal lipid accumulation by coordinating lipid uptake and oxidation through ELOVL6-mediated PPARα activation.
Mechanistic role of glycolytic pathways in the tumor microenvironment in driving chemoresistance.
Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.
FGD5 regulates PGK1 ubiquitination to synergize with 2-deoxy-D-glucose in pancreatic ductal adenocarcinoma.
Mannose supports lung cancer metabolism during glycolytic limitation.
Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.
IL-6 trans-signalling in cancer metabolism, multidrug resistance and chronic inflammation.
Succinylation of TAGLN2 at K40 drives lipid oxidative stress resistance and TMZ chemoresistance via redox reprogramming in Glioblastoma.
AKAP13 regulates GLI1/ULK1 axis and drive tumor resistance to next-generation HER2-targeted therapies.

Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

  Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.106492
Drug Resist Updat. 2026 Aug 02. pii: S1368-7646(26)00113-5. [Epub ahead of print]89 101462

Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.

Simona Fontana, Dimas Carolina Belisario, Claudia Giannotta, Luca Alessandri, Sabrina Digiovanni, Angelo Meoli, Francesco Passiglia, Alessandra Merlini, Giulianmichela Di Palma, Martina Perin, Francesca Napoli, Maddalena Arigoni, Muhlis Akman, Elisa Balmas, Costanzo Costamagna, Iris Chiara Salaroglio, Joanna Kopecka, Alessandro Bertero, Luisella Righi, Massimo Massaia, Raffaele Calogero, Silvia Novello, Giorgio Vittorio Scagliotti, Yehuda G Assaraf, Chiara Riganti.

   AIMS: Non-small cell lung cancer (NSCLC) patients treated with platinum drugs develop chemoresistance. C/EBPβ has alternative translational LAP and LIP isoforms which impact cancer chemoresistance by modulating ABC efflux transporter expression and activity. Differential alternative translation of LAP:LIP reprograms metabolism in murine embryonic fibroblasts; however, little is known in cancer. To target possible metabolic vulnerabilities, we herein investigated whether LAP/LIP rewires NSCLC cell metabolism towards a chemoresistant phenotype.
METHODS: LAP- or LIP-overexpressing NSCLC cells were screened for anticancer drug sensitivity, DNA damage and ABC exporter expression and function. Metabolome/lipidome analyses and functional metabolic assays were performed to identify possible chemosensitizing agents. Tumor growth, mass spectrometry imaging and single-cell RNA-sequencing were determined in Hu-CD34+NSG xenografts.
RESULTS: LAP induced chemoresistance by increasing ABCB1/ABCC1/ABCC2 levels, activity and oxidative DNA damage. Furthermore, LAP altered metabolome and lipidome composition of plasma membrane and mitochondria, and upregulated HADHA and CPT1A, key enzymes in fatty acid oxidation (FAO). The high metabolic flux through FAO and oxidative phosphorylation increased mitochondrial ATP levels, thereby fueling these ATP-driven multidrug efflux pumps. Conversely, LIP displayed the opposite effect. CPT1A knock-out or catalytically-inactive mutant, FAO inhibition with etomoxir or trimetazidine, surmounted chemoresistance. In LAPhigh chemoresistant immune-xenografts, etomoxir redistributed fatty acids within tumor immune-microenvironment (TIME), metabolically reprogrammed NK cells and enhanced their anti-tumor activity.
CONCLUSION: Increased LAP:LIP ratio induced chemoresistance in NSCLC tumors by instigating a FAO-dependence, unveiling a metabolic vulnerability. FAO inhibition emerges as a novel chemosensitization strategy operating via rewiring tumor and TIME metabolism.

Keywords:  C/EBP-β; Cisplatin resistance; Fatty acid oxidation; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.drup.2026.101462
Nat Metab. 2026 Aug 05.

Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.

Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

DOI: https://doi.org/10.1038/s42255-026-01582-0
Adv Sci (Weinh). 2026 Aug 07. e77030

circZNF148 Drives Glucose Metabolism Reprogramming to Enhance Metastasis and Immune Evasion via HK1 Stabilization in Triple-Negative Breast Cancer.

Yuhan Jin, Wenjing Zhao, Lei Wang, Jianing Wang, Keying Zhao, Dan Luo, Yifei Wang, Yuxia Yang, Jingze Yang, Yaming Li, Tong Chen, Dianwen Han, Zekun Wang, Xiaoyan Li, Bing Chen, Lijuan Wang, Yiran Liang, Qifeng Yang.

  Breast cancer is the leading malignancy among women worldwide, with triple-negative breast cancer (TNBC) representing the most aggressive subtype. Accumulating evidence highlights glucose metabolism reprogramming as a critical driver of TNBC progression and immune evasion, yet the underlying molecular mechanism remains poorly defined. Using circRNA sequencing in both glucose metabolism-stressed TNBC cells and lung metastasis models, we identified circZNF148 as a consistently upregulated circular RNA that promotes tumor progression and immune evasion by enhancing glycolysis. Mechanistically, circZNF148 scaffolds the interaction between hexokinase 1 (HK1) and the deubiquitinase adaptor ADRM1, suppressing K11-linked ubiquitination and proteasomal degradation of HK1, thereby stabilizing the enzyme and sustaining glycolytic flux. Elevated lactate production subsequently impairs CD8+ T cell function, reducing IFN-γ and TNF-α secretion, diminishing cytotoxicity, and promoting exhaustion. Concurrently, increased intracellular lactate drives lysine lactylation of PD-L1, which enhances its protein stability and membrane localization, thus linking metabolic state to immune checkpoint regulation. Clinically, circZNF148 is significantly upregulated in TNBC tissues, correlating with advanced stage and poor prognosis. Collectively, our findings establish the circZNF148-HK1-lactate axis as a critical mediator of metabolic adaptation and immune evasion in TNBC. Targeting this pathway offers a promising strategy to overcome therapeutic resistance and improve outcomes in TNBC.

Keywords:  circZNF148; glycolysis; immune evasion; lactylation; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.77030
Clin Cancer Res. 2026 Aug 03.

Inhibition of Acetyl-CoA-carboxylase induces endoplasmic reticulum stress and augments the efficacy of anti-cancer therapies.

Naing Lin Shan, Henriette Balinda, Jiawei Dai, Yueyue Wang, Hao-Kuen Lin, Michal Marczyk, Gerson Espinoza Campos, Sheila Umlauf, Martina S J McDermott, Iriana Colorado, Sabine M Lang, Yulia V Surovtseva, Rena Feinman, Dennis J Slamon, Kim R M Blenman, Qin Yan, Viswanathan Muthusamy, Andrew J Brenner, Lajos Pusztai.

PURPOSE: Increased dependence on de novo fatty acid synthesis is a key feature of metabolic rewiring in cancer cells. Acetyl-CoA-carboxylase (ACC) is the rate limiting enzyme of de novo fatty acid synthesis. We examined the anti-cancer activity of the ACC inhibitor, PF-05175157, alone and in combination with approved anticancer therapies.
EXPERIMENTAL DESIGN: PF-05175157 activity was assessed in high throughput cell line screen and in mouse xenograft experiments. Drug-drug interactions were tested with 166 FDA-approved agents. Mechanistic studies included lipid profiling and evaluation of endoplasmic reticulum (ER) stress and unfolded protein response markers and downstream effects on cellular metabolism and viability.
RESULTS: PF-05175157 showed broad anti-cancer activity including in cells resistant to targeted therapies and inhibited tumor growth in xenograft experiments. Combination studies demonstrated enhanced efficacy with multiple FDA-approved anti-cancer drugs, including tyrosine kinase inhibitors and chemotherapy agents. Lipid profiling showed increase in cholesterol esters and unsaturated long-chain fatty acids that alter membrane fluidity. These changes were associated with evidence of ER stress and unfolded protein response followed by metabolic arrest leading to cell death.
CONCLUSIONS: ACC inhibition with PF-05175157 has a potential for clinical application as an anti-cancer agent and due to its unique mechanism of action and broad synergy with existing anti-cancer therapies.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-1028
Exp Mol Med. 2026 Aug 05.

TMEM135 deficiency prevents intestinal lipid accumulation by coordinating lipid uptake and oxidation through ELOVL6-mediated PPARα activation.

Hyunsoo Kim, Channy Park, Xiaofan Wei, Arun Chhetri, Laxman Manandhar, Jiwon Seo, Yoonkyung Park, Sang-Wook Lee, Raekil Park.

Excessive lipid accumulation impairs digestion and gastrointestinal function. Transmembrane protein 135 (TMEM135) is involved in lipid metabolism of various tissues. Here, TMEM135 deficiency increased intestinal lipid absorption through ELOVL6-dependent oleoylethanolamide production and subsequent activation of peroxisome proliferator-activated receptor alpha (PPARα), which upregulated CD36 at the plasma membrane in the intestine of mice fed a high-fat diet or lard oil. Despite this enhanced lipid uptake, long-term lipid accumulation was suppressed by elevated peroxisomal and mitochondrial β-oxidation through increased fatty acid oxidation and oxidative phosphorylation activities without chylomicron secretion in TMEM135-depleted intestine. Inhibition of PPARα or ELOVL6 attenuated these effects. Furthermore, consistent results were observed in both TMEM135 KO and intestine-specific TMEM135iKO mice, confirming tissue-specific rather than systemic effects. Overall, these results provide insight into the role of TMEM135 as a regulatory node connecting intestinal lipid absorption and systemic energy expenditure, contributing to the coordination between lipid storage and oxidation during metabolic adaptation.

DOI: https://doi.org/10.1038/s12276-026-01795-z
Front Cell Dev Biol. 2026 ;14 1883537

Mechanistic role of glycolytic pathways in the tumor microenvironment in driving chemoresistance.

Zhongyi Tan, Lai Wen, Hewen Guan, Nabuqi Bao, Zijing Wu, Xu Ji, Lin Lin.

  Tumor glycolysis reprogramming, characterized by the "Warburg effect," has emerged as a critical hallmark of cancer progression and therapeutic resistance. Increasing evidence indicates that enhanced glycolytic activity not only supports rapid tumor growth by sustaining ATP production and biosynthetic demands, but also profoundly contributes to the development of chemoresistance. In resistant tumors, glycolysis-driven metabolic adaptation promotes energy homeostasis, maintains redox balance, enhances DNA damage repair, suppresses apoptosis, and supports cancer stemness, thereby reducing the cytotoxic efficacy of chemotherapeutic agents. Moreover, aberrant glycolytic metabolism extensively remodels the tumor microenvironment (TME) through lactate accumulation, extracellular acidification, hypoxia maintenance, immune suppression, and metabolic crosstalk with stromal cells, collectively facilitating tumor survival and therapeutic tolerance. Importantly, targeting glycolytic pathways has shown promising potential in restoring chemosensitivity and enhancing the efficacy of conventional chemotherapy in multiple malignancies. In this review, we systematically summarize the role of glycolytic reprogramming in maintaining resistant tumor cell metabolic homeostasis, regulating the chemoresistant TME, and driving molecular mechanisms underlying chemotherapy resistance. We further discuss current therapeutic strategies targeting glycolysis and their potential clinical applications for overcoming chemoresistance. A deeper understanding of glycolysis-mediated metabolic plasticity may provide novel insights into precision metabolic intervention and combination therapy in cancer treatment.

Keywords:  chemoresistance; glycolytic pathways; lactate; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2026.1883537
Oncogene. 2026 Aug 03.

Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5 destabilization in prostate cancer.

Jintao Hu, Cong Lai, Yunfei Xiao, Zi Yan, Yongmei Tan, Junjie Wang, Jiangping Qiu, Kuiqing Li, Hao Yu, Xutao Chen, Jinli Han, Xiaolin Cai, Tianlong Luo, Chunnuan Deng, Rong Na, Wang He, Kewei Xu, Cheng Liu.

Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.

DOI: https://doi.org/10.1038/s41388-026-03946-y
Oncogene. 2026 Aug 07.

FGD5 regulates PGK1 ubiquitination to synergize with 2-deoxy-D-glucose in pancreatic ductal adenocarcinoma.

Wenting Song, Jianong Luo, Kun Cai, Shiyu Chen, Suye Ran, Xueyi Jiang, Chao Yu, Chengyi Sun.

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic plasticity that underlies its aggressive growth and therapeutic resistance. However, genetic determinants that modulate PDAC sensitivity to glycolytic inhibition remain incompletely defined. Here, we performed a pooled genome-wide CRISPR-Cas9 dropout screen in PDAC cells under 2-deoxy-D-glucose (2-DG) selection and identified FGD5 as a key regulator of glycolytic dependency. Loss of FGD5 sensitized PDAC cells to 2-DG, reduced clonogenic growth and stem-like properties, and was associated with a shift from glycolysis toward oxidative phosphorylation. Clinically, FGD5 expression was elevated in PDAC tissues and correlated with unfavorable patient outcomes. Mechanistically, FGD5 interacted with and stabilized PGK1 by limiting STUB1-mediated ubiquitination and proteasomal degradation. Pharmacological perturbation with CB-5083, a compound prioritized through structure-guided screening, modulated FGD5-PGK1-associated proteostasis readouts, increased PGK1 ubiquitination, reduced PGK1 abundance, and cooperated with 2-DG to suppress PDAC growth in vitro and in vivo. Moreover, lactate-associated H3K18 histone lactylation was linked to increased FGD5 transcription, consistent with a feed-forward regulatory connection between glycolysis, epigenetic modification, and metabolic adaptation. Collectively, our findings position FGD5 as a metabolic vulnerability in PDAC and provide a mechanistic framework supporting combinatorial strategies that couple glycolysis inhibition with perturbation of FGD5-PGK1-associated proteostasis. A genome-wide CRISPR-Cas9 screen identified FGD5 as a metabolic vulnerability that increases PDAC sensitivity to the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). In PDAC cells, FGD5 interacts with PGK1 and supports PGK1 stability by limiting STUB1-dependent ubiquitination and proteasomal degradation, thereby sustaining aerobic glycolysis and lactate production. Glycolysis-derived lactate is associated with increased H3K18 histone lactylation (H3K18la) at the FGD5 promoter, accompanied by elevated FGD5 transcription, consistent with a metabolic-epigenetic regulatory link. Pharmacological perturbation with CB-5083 attenuates FGD5-PGK1-associated proteostasis readouts, whereas 2-DG inhibits glycolytic flux and lactate-associated H3K18la. Together, CB-5083 and 2-DG cooperate to suppress PDAC growth by coupling perturbation of the FGD5-PGK1-associated proteostasis axis with glycolytic inhibition.

DOI: https://doi.org/10.1038/s41388-026-03943-1
EMBO Rep. 2026 Aug 07.

Mannose supports lung cancer metabolism during glycolytic limitation.

Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.

Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.

DOI: https://doi.org/10.1038/s44319-026-00874-6
Cell Rep Med. 2026 Aug 06. pii: S2666-3791(26)00393-9. [Epub ahead of print] 102976

Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.

Jiatong Li, Ao Gu, Ziheng Jia, Mengyao Li, Jinlu Zuo, Ziyi Wang, Xuechuan Li, Jiayi Feng, Tong Xue, Shuyang Zhai, Zhuying Yue, Yang An, Siyuan Kang, Zhiqing Yuan, Shimei Qiu, Yadong Xue, Liguo Liu, Nannan Tang, Yingbin Liu.

  Approximately 90% of patients with pancreatic cancer harbor KRAS mutations, predominantly the KRASG12D subtype. HRS-4642, a non-covalent inhibitor targeting KRASG12D, demonstrates potent antitumor efficacy but may ultimately lead to resistance. This study investigates the mechanisms underlying KRASG12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRASG12D inhibitor resistance in pancreatic ductal adenocarcinoma (PDAC) but also achieves remission with prolonging survival. Mechanistically, KRASG12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D mutant PDAC.

Keywords:  ANXA1; KRAS-G12D inhibitors; PDAC; drug resistance; glutamine

DOI:  https://doi.org/10.1016/j.xcrm.2026.102976
J Biol Chem. 2026 Aug 03. pii: S0021-9258(26)02255-6. [Epub ahead of print] 113383

IL-6 trans-signalling in cancer metabolism, multidrug resistance and chronic inflammation.

Federica Melisi, Lucia Stefania Pasquale, Teresa Peluso, Cinzia Graziano, Clara Iannarone, Margherita Vicario, Maria Roberta De Iesu, Martina Izzo, Rosalba Ricciardi, Marco Bocchetti, Alessia Maria Cossu, Giuseppe Matarese, Marianna Scrima, Michele Caraglia.

  Interleukin-6 (IL-6) trans-signalling plays a pivotal role in cancer progression and the regulation of metabolic pathways, exhibiting significant tissue specificity. IL-6, a pleiotropic cytokine, mediates cellular communication and inflammatory responses through distinct pathways with both beneficial and detrimental effects. Trans-signalling occurs when IL-6 binds to its soluble receptor (sIL-6Rɑ), forming a complex with the signal transducer gp130. This pathway is associated with a pro-inflammatory phenotype and not by chance, IL-6 trans-signalling also contributes to tumorigenesis promoting angiogenesis, resistance to apoptosis and metastasis. This review highlights the significance and tissue-specificity of IL-6 trans-signalling activation in cancer biology, metabolism, and drug resistance, underscoring its potential as a therapeutic target. Indeed, IL-6 trans-signalling influences metabolic processes by altering glucose and lipid metabolism, thereby supporting energy demands from rapidly proliferating cancer cells. Through metabolic reprogramming IL-6 trans-signalling not only fuels cancer cell growth but also contributes to development of a tumour-friendly microenvironment that is IL-6-dependent and self-sustaining. These events contribute also to development of multidrug resistance during cancer progression. In depth understanding of the molecular mechanisms underlying IL-6 trans-signalling will offer novel insights into precision medicine for cancer treatment and for the sensitisation of cancer cells to anti-tumour weapons.

Keywords:  IL-6; cancer; cancer metabolism; drug-resistance; inflammation; trans-signalling

DOI:  https://doi.org/10.1016/j.jbc.2026.113383
Free Radic Biol Med. 2026 Aug 01. pii: S0891-5849(26)00973-1. [Epub ahead of print]255 536-552

Succinylation of TAGLN2 at K40 drives lipid oxidative stress resistance and TMZ chemoresistance via redox reprogramming in Glioblastoma.

Wanyao Meng, Yayun Feng, Yuanyuan Huang, Xinxiang Zhang, Dequan Shen, Yichen Zhong, Hui Xu, Yating Liu, Jiahong Wang, Di Fan, Yanting Gu.

  Temozolomide (TMZ) resistance constitutes a primary cause of clinical treatment failure in glioblastoma (GBM). Targeting oxidative cell death to reverse glioma chemoresistance has emerged as a promising novel therapeutic strategy, whereas the core molecular mechanisms linking this oxidative cell death process to TMZ resistance remain poorly defined. Here, we identify that lysine 40 succinylation of TAGLN2 serves as a core driver enabling glioma cells to evade oxidative cell death and acquire TMZ resistance. Notably, this succinylation shows a correlation with CPT1A expression, which may regulate the succinyl-CoA metabolic environment to indirectly influence TAGLN2 succinylation. Mechanistically, TAGLN2-K40 succinylation blocks MARCH1-mediated ubiquitin-proteasome degradation to sustain TAGLN2 protein stability. It further inhibits PP2A activity to trigger the activation of PI3K/AKT/GSK-3β signaling, which subsequently promotes downstream activation of β-catenin and NRF2, upregulates GPX4 expression, and ultimately restrains oxidative cell death and reinforces TMZ resistance. Moreover, we constructed a cell-penetrating peptide targeting TAGLN2-K40 succinylation, which inhibits glioma growth. This work provides novel therapeutic targets and combinatorial regimens to overcome GBM chemoresistance.

Keywords:  Cell-penetrating peptide (CPP); GPX4; Glioma; Oxidative lipotoxicity; Succinylation; TAGLN2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.046
Oncogene. 2026 Aug 06.

AKAP13 regulates GLI1/ULK1 axis and drive tumor resistance to next-generation HER2-targeted therapies.

Qing Guo, Xinyu Chen, Linfeng Wu, Changhao Ren, Yourong Jian, Mingxi Lin, Yizi Jin, Cheng Zeng, Teng Zhou, Yuxin Yan, Yuanyuan Ruan, Jian Zhang.

Next-generation HER2-targeted therapies including tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) improve survival of HER2-positive cancer patients. However, mechanisms of primary and acquired resistance remain unclear. Here, we reported that primary HER2-specific targeted therapy (tucatinib) resistant or sensitive breast cancers derived from clinical trial patients exhibited differential protein profiles. Prolonged tucatinib exposure induced autophagy pathway enrichment in HER2-positive breast cancer cells. Integrated high-throughput analyses identified A-kinase anchoring protein (AKAP)13 as a critical molecule involved in both primary and acquired resistance and an independent predictor of poor prognosis. Silencing of AKAP13 significantly diminished novel HER2-targeted therapies resistance. Mechanistically, AKAP13 inhibits autophagosome formation by suppressing the expression of ULK1, a kinase essential for autophagy initiation. ULK1 transcription is driven by GLI1, which binds to the ULK1 promoter via its arginine-592 residue. We further elucidated that the RhoGEF domain of AKAP13 activates RhoA, which subsequently triggers the activation of PKA anchored to AKAP13. The activated PKA then inhibits the nuclear translocation of GLI1, thereby repressing its transcriptional activity on ULK1. In vivo and in vitro experiments demonstrated the synergistic efficacy of tucatinib and AKAP13 inhibitor A13. In the validation phase, organoids were constructed using tissue obtained via puncture from patients resistant to trastuzumab deruxtecan, confirming upregulation of AKAP13 and A13-mediated reversal of resistance to novel HER2-targeted therapies. Collectively, these findings highlight the role of AKAP13 in drug resistance and propose A13 as a promising therapeutic strategy for HER2-positive breast cancer. Model diagram of this study and proposed molecular mechanisms.

DOI: https://doi.org/10.1038/s41388-026-03931-5