bims-stacyt 2026-05-10 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–05–10
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Structure-guided identification of small molecules potentially able to modulate GDF15 activity.
RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.
Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis.
Cancer cachexia induces senescent reprogramming of brown adipose tissue and pro-cachectic S100A9 secretion by adipocytes.
Fasting opens a metabolic window that favors anti-tumor immunity.
A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.
A nutrient-responsive AMPK/TBK1 circuit restricts adipocyte catabolism.
Arginine Deprivation of ASS1-Deficient Cancers Drives Mistranslation and Shared Neoepitope Production.

Sci Rep. 2026 May 07.

Structure-guided identification of small molecules potentially able to modulate GDF15 activity.

Antonio Chiariello, Lorenzo Lenti, Lorenzo Trofarello, Manuela Sollazzo, Mattia Lauriola, Alberto Del Rio, Stefano Salvioli, Marco Daniele Parenti, Maria Conte.

  Growth Differentiation Factor 15 (GDF15) has been associated with different pathological conditions, including cancer cachexia. Various strategies, such as monoclonal antibodies and peptide antagonists, have been developed to inhibit GDF15 activity; however, it is currently unknown whether using small organic molecules (SOMs) can effectively target GDF15. Here, we implemented a structure-based in silico screening workflow using a curated compound library to identify SOMs with potential binding affinity for GDF15. The top-ranking SOMs predicted to interact with either the monomeric or dimeric forms of GDF15 were then tested in vitro in acellular systems, as well as in normal (dermal fibroblasts, DFs) and cancer (ovarian, OV90) cells characterized by low or high GDF15 expression levels, respectively. Among the tested SOMs, dioxoimidazolidin derivative (named SOM D) emerged as particularly promising, as resulted capable of disturbing GDF15 dimer stability and GDF15-GFRAL interaction. Furthermore, SOM D significantly modulated genes and proteins recognized as downstream of GDF15 signaling, such as IL-6 and NF-κB, particularly in OV90 cells, but not in DFs. Overall, these results support the idea that GDF15 activity could be modulated through SOMs and warrant further structure-activity optimization and quantitative target-engagement studies to assess the therapeutic potential of these scaffolds as GDF15 inhibitors.

Keywords:  GDF15; Ovarian cancer cells; Small organic molecules; Virtual screening

DOI:  https://doi.org/10.1038/s41598-026-51932-x
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70302

RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.

Sara Chiappalupi, Giulia Gentili, Laura Salvadori, Martina Paiella, Marcello Manfredi, Vittoria Federica Borrini, Kaamashri Mangar, Ann Marie Schmidt, Maurizio Muscaritoli, Francesca Riuzzi, Guglielmo Sorci.

   BACKGROUND: Cancer cachexia (CC) is a highly debilitating syndrome characterized by loss of body and muscle weight affecting most advanced cancer patients. The receptor for advanced glycation end-products (RAGE) is expressed by several cell types and sustains the inflammatory response in acute and chronic diseases. Total ablation of RAGE (Ager-/- mice) translates into restrained CC and increased survival in tumour-bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re-expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown.
METHODS: Using an HSA/Cre-loxP system, we generated a tamoxifen-inducible conditional AgermKO mouse model in which RAGE is selectively ablated in myofibres. Tamoxifen-treated AgermKO, Agerflox and Ager-/- mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25 dpi, when histological, molecular and proteomic analyses were performed in tumour-bearing and control mice. Muscle samples of pre-cachectic and cachectic pancreatic cancer patients were analysed to validate the results.
RESULTS: Compared with LLC-Agerflox mice, LLC-AgermKO mice showed reduced (7.5% [p = 0.004] vs. 15.1% [p < 0.0001]) body weight loss, no significant reduction of hind-limb muscle mass and strength and myofibre cross-sectional areas, increased survival (69.2% vs. 42.9% mice alive at 25 dpi) and restrained muscle and serum pro-inflammatory factors. Mechanistically, AgermKO muscles resist cancer-induced atrophy by maintaining an active Akt-GSK-3β-PGC-1α pathway, and increasing the synthesis of myosin heavy chain (MyHC)-I and -IIa (71.8% [p = 0.008] and 73.9% [p = 0.002] increase, respectively) along with a 76.3% (p = 0.008) increase in hybrid MyHC-I/IIa myofibres. Distinct proteomic signatures characterize muscles of tumour-bearing mice in dependence on RAGE expression, supporting a protective effect of RAGE ablation in muscles. LLC/AgermKO muscles showed increased amounts of several enzymes involved in glycolysis and glucose catabolism, typical of Warburg metabolism. Noteworthy, muscles of pre-cachectic and cachectic cancer patients showed ~3-fold increase (p < 0.05) in RAGE amounts and reduced Akt-GSK-3β-PGC-1α pathway, compared with healthy control subjects.
CONCLUSIONS: Our data provide evidence that RAGE engagement at myofibre level drives loss of body and muscle weights and inflammation in cancer conditions. RAGE ablation in muscles confers resistance to CC through myofibre remodeling and glycolytic reprogramming. On the clinical side, the overexpression of RAGE is an early event in muscles of cancer patients, suggesting a role for RAGE in the onset of the cachectic syndrome. Thus, the molecular targeting of RAGE might be useful to counteract cachexia and prolong survival in cancer patients.

Keywords:  RAGE; animal models; cancer cachexia; muscle wasting; myofibre remodeling

DOI:  https://doi.org/10.1002/jcsm.70302
Free Radic Biol Med. 2026 May 06. pii: S0891-5849(26)00745-8. [Epub ahead of print]

Salubrinal-activated integrated stress response protects against doxorubicin-induced cardiotoxicity via activating transcription factor 4-mediated antioxidant defense and glutathione homeostasis.

Sheng-Fan Wang, Hsuan-Yu Chou, Pei-Hsun Liu, Hsing-Hui Su, Giun-Yi Hung, Chian-Ying Chou, Ling-Ming Tseng, Yuh-Chiang Shen, Jiin-Cherng Yen, Shiang-Suo Huang, Hsin-Chen Lee.

  Doxorubicin is an effective chemotherapeutic agent; however, its use is limited by cardiotoxicity. Mitochondrial dysfunction is a central driver of doxorubicin-mediated cardiotoxicity. The role of the integrated stress response (ISR), a mitochondria-to-nucleus signaling pathway and crucial cellular defense mechanism in doxorubicin-induced cardiotoxicity, remains unclear. We investigated the pharmacological ISR activator salubrinal, a selective inhibitor of eukaryotic initiation factor 2α dephosphorylation with potential cardioprotective properties, to elucidate the molecular mechanisms underlying ISR-mediated cardioprotection in H9c2 cardiomyocytes, C57BL/6 mice, and HL-1 cell models. Doxorubicin disrupts ISR signaling, whereas salubrinal alleviates cardiotoxicity by activating transcription factor 4 (ATF4, a central ISR hub)-dependent pathways that suppress doxorubicin-induced apoptosis and preserve mitochondrial metabolism. The cystine/glutamate antiporter xCT, essential for glutathione (GSH) homeostasis, and growth differentiation factor 15 (GDF15), a mitochondrial stress-induced mitokine and potential biomarker of doxorubicin cardiotoxicity, are both regulated by ATF4. Mechanistically, we found that salubrinal contributes to cardioprotection against doxorubicin by enhancing the GSH-based antioxidant capacity via the ATF4-dependent GDF15-xCT axis. Further analysis of ATF4-associated GSH regulatory pathways revealed that enzymes involved in serine metabolism and glutathione peroxidase 4, a critical enzyme in GSH utilization that is upregulated by ATF4-mediated heat shock 70 kDa protein 5 and cystathionine gamma-lyase, contribute to the cardioprotective effects of salubrinal against doxorubicin-induced oxidative stress. Our findings highlight the ISR as a vital survival mechanism in cardiomyocytes exposed to doxorubicin. Regulating antioxidant defenses through enhanced GSH homeostasis and ISR activation, particularly via pharmacological agents such as salubrinal, may offer a promising therapeutic strategy for mitigating doxorubicin-induced cardiotoxicity.

Keywords:  cardiotoxicity; doxorubicin; glutathione; integrated stress response; mitochondria; salubrinal

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.281
Cell Death Dis. 2026 May 02.

Cancer cachexia induces senescent reprogramming of brown adipose tissue and pro-cachectic S100A9 secretion by adipocytes.

Claudia Di Biagio, Flavia Tortolici, Francesco Gaudioso, Andrea Ninni, Francesca Giurdanella Annina, Chiara De Ranieri, Fabio Zaccaria, Francesca Sciarretta, Verteramo Luca, Francesca Arciprete, Simone Carotti, Antoine Af de Vries, Sander Kooijman, Francesca Pacello, Andrea Battistoni, Daniele Lettieri-Barbato, Katia Aquilano.

Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by progressive loss of fat and lean mass, systemic inflammation, and poor therapeutic responsiveness. While brown adipose tissue (BAT) is traditionally considered a protective, energy-dissipating organ, its qualitative remodeling in CAC remains poorly characterized.Here, we demonstrate that CAC induces a senescent conversion of BAT, marked by thermogenic failure, fibrosis, inflammation, and acquisition of a senescence-associated secretory phenotype (SASP). Through integrative transcriptomic, proteomic, and secretomic analyses in a murine model of lung cancer-induced cachexia, we identify S100A9 as a key factor selectively upregulated and secreted by brown adipocytes. Functional assays reveal that the BAT secretome exerts deleterious paracrine effects on white adipocytes and skeletal myotubes, promoting lipolysis and atrophy, while also impairing brown adipocyte identity in an autocrine manner. Co-culture and gain-of-function experiments with S100A9 recapitulate these phenotypes in vitro in mouse and human brown adipocytes, whereas pharmacological blockade of S100A9 signaling partially restores thermogenic and metabolic features. Collectively, our findings reveal that BAT undergoes functional reprogramming into a senescent and secretory tissue in cancer cachexia, with adipocyte-derived S100A9 acting as a novel pro-cachectic mediator. This work redefines the role of BAT in CAC and identifies S100A9 as a potential therapeutic target within the adipose-muscle crosstalk.

DOI: https://doi.org/10.1038/s41419-026-08806-x
Cell Metab. 2026 May 05. pii: S1550-4131(26)00109-9. [Epub ahead of print]38(5): 833-834

Fasting opens a metabolic window that favors anti-tumor immunity.

Ling Cai, Tao Dai.

Short-term fasting reshapes the metabolic landscape of the tumor microenvironment, creating a transient window of altered nutrient availability that cytotoxic CD8⁺ T cells can exploit. Chen and colleagues report that intratumoral isoleucine accumulation during fasting supports T cell effector programs, enhancing responses to immune checkpoint blockade in mice and humans.

DOI: https://doi.org/10.1016/j.cmet.2026.03.015
Nat Commun. 2026 May 06.

A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.

Fiona Shilliday, Miguel Gancedo-Rodrigo, Ginto George, Shintaro Aibara, Santosh Adhikari, Syedah Neha Ashraf, Evelyne J Barrey, Paolo A Centrella, Damian Crowther, Paige Dickson, Diana Gikunju, Marie-Aude Guié, John P Guilinger, Anders Gunnarsson, Heather P Harding, Christopher D Hupp, Rachael Jetson, Anthony D Keefe, JeeSoo Monica Kim, Richard J Lewis, Taiana Maia de Oliveira, Jennifer Le-Marshall, Usha Narayanan, Katherine A Nugai, Dušan Petrović, Emma Rivers, David Ron, Daisy Stringfellow, Karl Syson, Lewis Ward, John T S Yeoman, Yan Yu, Ying Zhang, Alisa Zyryanova, David J Baker, Perla Breccia, John E Linley.

Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that stabilises the inactive state of eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B reveals a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity is sensitive to eIF2's phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings establish the feasibility of targeting eIF2B with a drug-like allosteric inhibitor, that serves as an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation.

DOI: https://doi.org/10.1038/s41467-026-72688-y
JCI Insight. 2026 May 08. pii: e200168. [Epub ahead of print]11(9):

A nutrient-responsive AMPK/TBK1 circuit restricts adipocyte catabolism.

Churaibhon Wisessaowapak, Yuliya Skorobogatko, Hyeonhui Kim, Xue Feng, Seunghwan Son, Haipeng Fu, Sitao Zhang, Pichaya Lertvilai, Lina Chang, Annie Hoang, Hetty Chen, Sarah Bedsted, Joseph Valentine, Jin Young Huh, Peng Zhao, Shannon M Reilly, Piyajit Watcharasit, Maryam Ahmadian, Alan R Saltiel.

  Metabolic adaptation to both caloric excess and restriction promotes energy conservation by suppressing catabolic pathways via feedback mechanisms that remain incompletely defined. We identified TANK binding kinase 1 (TBK1) as a nutrient- and inflammation-responsive brake on AMPK signaling in adipocytes. Fasting or pharmacological AMPK activation induced Tbk1 transcription via a PGC1α/nuclear respiratory factor 1 axis, which, in turn, limited AMPK activity through a phosphorylation cascade to conserve energy. In obesity, this AMPK/TBK1 axis was disrupted due to chronically elevated basal TBK1, thereby restricting energy expenditure during fasting. Adipocyte-specific TBK1 deletion enhanced fasting-induced AMPK activation, mitochondrial function, and lipolytic gene expression in both lean and obese mice. Pharmacological TBK1 inhibition with amlexanox recapitulated these effects. Combined treatment of mice with amlexanox and the AMPK activator AICAR enhanced weight loss, improved glucose tolerance and insulin sensitivity, and suppressed inflammatory and lipogenic programs in adipose tissue, as well as fibrotic gene expression in the liver. Building on prior clinical observations linking TBK1 inhibition to metabolic health, these findings defined a nutrient-sensitive AMPK/TBK1 feedback loop that limited adipocyte catabolism and suggested that dual targeting of TBK1 and AMPK may help counteract metabolic adaptation and enhance the durability of obesity therapies.

Keywords:  Adipose tissue; Endocrinology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/jci.insight.200168
Cancer Res. 2026 May 07.

Arginine Deprivation of ASS1-Deficient Cancers Drives Mistranslation and Shared Neoepitope Production.

Remco Nagel, Adva Kochavi, Karine Flem-Karlsen, Mrittika Adhikary, Yali Gal-On, Maria G Klaoudatou, Julien Champagne, Lorenzo Valcanover, Heyilimu Palashati, Morten M Nielsen, Xiaodong Feng, Pierre-Rene Körner, Lisanne Giebel, Weiwen Yang, Arno Velds, Liesbeth Hoekman, Onno B Bleijerveld, Olaf van Tellingen, Johanna Olweus, Reuven Agami.

Arginine biosynthesis is frequently suppressed in cancer due to loss of ASS1 expression, rendering cancer cells reliant on extracellular arginine. This feature has driven the development of systemic arginine-depleting strategies, which are clinically safe but offer limited clinical benefit. Here, we demonstrated that under arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation, characterized by ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon preference was caused by a selective decrease in tRNAArg(UCU) levels following arginine deprivation, linked to METTL1-mediated tRNA modification. Proteomics and immunopeptidomics analyses validated that arginine shortage induced aberrant protein production at the endogenous level. T cell receptor (TCR) T cells that specifically recognize these HLA-presented mistranslated peptides efficiently killed cancer cells after arginine deprivation. These results lay the foundation for improved cancer therapies by combining systemic arginine-depleting strategies with TCR-based targeting of non-classical neoantigens.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4773