bims-stacyt 2026-04-05 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–04–05
twelve papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.
Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
Association of growth differentiation factor-15 with muscle wasting and anemia in chronic kidney disease.
Antagonistic SMAD2/3 control of TIMP-1, VEGF-A, and hypoxia signaling in myofibroblasts shapes histotype-specific angiogenesis in lung cancer.
Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.
Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.
Aromatic amino acid metabolism shapes autophagy-mediated adaptation to iron deprivation in glioblastoma cells.
REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.
ATF6 ameliorates renal warm ischemia-reperfusion injury through FHL2-mediated NF-κB signaling pathway.
Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis.
ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Front Endocrinol (Lausanne). 2026 ;17 1797525

Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.

Kristoffer J Kolnes, Pauline M Møller, Rikke Kruse, Mette Marie H Christensen, Rasmus Kjøbsted, Martin Hey-Mogensen, Birgitte Andersen, Aase Handberg, Kurt Højlund.

   Background: Metformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear.
Objective: We examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro.
Methods: In a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3-3H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2).
Results: Metformin increased glucose utilization (p=8.9x10-13) due to increased glycolysis (p=7.6x10-13) in vivo. This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro, metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro.
Conclusions: The metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro. These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action.
Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01400191.

Keywords:  FGF21; GDF15; glycolysis; intestine; metformin; mitochondrial respiration

DOI:  https://doi.org/10.3389/fendo.2026.1797525
Sci Immunol. 2026 Apr 03. 11(118): eaeb6484

Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.

Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J Van den Eynde, Xin Lu, Mads Gyrd-Hansen.

Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5' untranslated region of TNFRSF1A and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.

DOI: https://doi.org/10.1126/sciimmunol.aeb6484
J Nutr Health Aging. 2026 Apr 02. pii: S1279-7707(26)00066-7. [Epub ahead of print]30(5): 100835

Association of growth differentiation factor-15 with muscle wasting and anemia in chronic kidney disease.

Ting-Yun Lin, Yung-Chieh Chen, Szu-Chun Hung.

   BACKGROUND: Cachexia, characterized by muscle wasting and anemia, is a major complication of chronic kidney disease (CKD). Growth differentiation factor-15 (GDF-15), a stress-responsive cytokine implicated in cancer cachexia, is markedly elevated in CKD and linked to disease progression. However, the role of GDF-15 in CKD-related cachexia remains unclear.
METHODS: We conducted a cross-sectional study of 268 patients with stage 3-5 CKD not yet on dialysis. Plasma GDF-15 concentrations were measured using immunoassays. Lean body mass was assessed by multifrequency bioimpedance spectroscopy with the Body Composition Monitor (BCM), and appendicular skeletal muscle mass (ASM) was estimated using a validated BCM-derived equation. Muscle wasting was defined as ASM index <7.0 kg/m² in men or <5.7 kg/m² in women, according to Asian Working Group for Sarcopenia criteria. Anemia was defined as hemoglobin <13 g/dL in men or <12 g/dL in women, based on KDIGO criteria. Associations of GDF-15 with muscle wasting and anemia, two core features of CKD cachexia, were examined using multivariable regression models.
MAIN FINDINGS: Median plasma GDF-15 concentration was 2674 (range 550-12466) pg/mL. Higher GDF-15 was independently associated with lower lean tissue index and lower hemoglobin (both P < 0.001). Additional independent determinants of GDF-15 included age, male sex, diabetes, smoking status, eGFR, proteinuria, ferritin, and NT-proBNP. In multivariable logistic regression, each natural log increase in GDF-15 was associated with greater odds of both muscle wasting (OR 2.93, 95% CI 1.23-6.97, P = 0.015) and anemia (OR 3.45, 95% CI 1.09-10.91, P = 0.035).
CONCLUSION: Elevated GDF-15 is associated with muscle wasting and anemia in CKD independent of age, sex, comorbidities, and kidney function, mirroring its role in cancer cachexia. These findings suggest that GDF-15 may reflect pathophysiological processes linked to cachexia-related phenotypes and warrants further investigation as a potential therapeutic target in CKD.

Keywords:  Anemia; Cachexia; Chronic kidney disease; Growth differentiation factor-15; Muscle wasting

DOI:  https://doi.org/10.1016/j.jnha.2026.100835
Cell Death Dis. 2026 Mar 30.

Antagonistic SMAD2/3 control of TIMP-1, VEGF-A, and hypoxia signaling in myofibroblasts shapes histotype-specific angiogenesis in lung cancer.

Natalia Díaz-Valdivia, Paula Duch, Rafael Ikemori, Amelia L Parker, Marselina Arshakyan, Alejandro Llorente, Alejandro Bernardo, José Rodríguez-Rojas, Josep Lluis Carrasco, Danielle Park, Erik Sahai, Cristina Fillat, Manel Juan, Ernest Nadal, Noemí Reguart, Derek C Radisky, Oriol Casanovas, Jordi Alcaraz.

Non-small cell lung cancer (NSCLC) exhibits disparate responses to anti-angiogenic therapies between its two major histologic subtypes, lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), suggesting a histotype-dependent angiogenesis regulation. Tumor-associated fibroblasts (TAFs) exhibit an activated/myofibroblast-like phenotype in NSCLC, and are emerging as major regulators of tumor progression; yet, their role in controlling angiogenesis in NSCLC remains undefined. Here we analyzed angiogenesis/hypoxia markers in NSCLC, and combined transcriptomics (bulk RNA-seq, scRNA-seq), angiogenesis arrays, genetic perturbations and functional in vitro and in vivo assays to dissect the histotype-dependent production of pro-angiogenic factors in TAFs. We observed greater angiogenesis and reduced necrosis/hypoxia in LUAD compared to LUSC across multiple patient cohorts. The LUAD-TAF secretome was primed for angiogenesis through SMAD3-dependent overproduction of key regulators, particularly TIMP-1 and VEGF-A. We also uncovered a novel function for TIMP-1 in promoting endothelial cell hyperbranching over basal VEGF signaling. Conversely, LUSC-TAFs displayed diminished angiogenic effects despite upregulating HIF-1α and a hypoxia-associated transcriptional signature, owing to their lower SMAD3 and compensatory increase in SMAD2. Our study unveils the critical influence of TAFs in shaping the distinct angiogenic landscapes in LUAD and LUSC through the opposing SMAD2/3 regulation of TIMP-1, VEGF-A and hypoxia signaling. These results also highlight the therapeutic potential of targeting stromal SMAD3/TIMP-1 in LUAD or microenvironmental stressors such as hypoxia and acidosis in LUSC. In addition, these findings provide a biological framework for understanding the histotype-dependent patterns of dissemination, immune evasion, and response to anti-angiogenic therapies in NSCLC.

DOI: https://doi.org/10.1038/s41419-026-08677-2
FASEB J. 2026 Apr 15. 40(7): e71591

Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.

Kentaro Takahashi, Julia Drolet, Jinghua Liu, Jasmine R Jackson, Madison Babcock, Muthusamy Thiruppathi, Milie Fang, Tyler Paul, Gayathri Ganesh, Yuri Fukasawa, Yoshikiyo Akasaka, Giamila Fantuzzi, Elizaveta V Benevolenskaya, Timothy J Koh, Norifumi Urao.

  Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.

Keywords:  bone marrow‐derived macrophages; epigenetics; high‐fat diet; histone modification; hypoxia; metabolism; obesity

DOI:  https://doi.org/10.1096/fj.202502626R
FASEB J. 2026 Apr 15. 40(7): e71726

Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.

Fan Wang, Ping Hu, Shengbo Han, Ya Zhang, Yang Li, Wenfeng Zhuo, Yong Zhao, Yan Huang, Guozheng Lv, Hongda Wang, Gang Zhao.

  Lactate has been considered as a tumor-promoting metabolite, however, its functional roles in pancreatic cancer (PC) have not yet been fully elucidated. Here, we explored the roles of lactate on the proliferation and invasion of PC cells under glucose deprivation. We found that lactate enhanced PC cells' proliferation and invasion under glucose deprivation, but not in normal conditions. The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset showed that monocarboxylic acid transporter 1 (MCT1), a lactate transporter, was overexpressed and correlated with poor prognosis in PC patients. Additionally, knockdown or inhibition of MCT1 distinctively attenuated lactate-induced proliferation and invasion of PC cells under glucose deprivation by suppressing their tricarboxylic acid (TCA) cycle. Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC.

Keywords:  MCT1; TCA; lactate; metastasis; proliferation

DOI:  https://doi.org/10.1096/fj.202503162RR
Cell Death Dis. 2026 Apr 03.

Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.

Hsin-An Lin, Hsin-Chung Lin, Ming-Hang Tsai, Yu-Jen Chen, Bo-Ying Bao, Kuen-Jou Tsai, Chieh-Tien Shih, Jau-Song Yu, Kun-Yi Chien, Kuo-Yang Huang, David M Ojcius, Lih-Chyang Chen.

Glycolysis is critical for NLRP3 inflammasome activation, yet the link between lactic acid metabolism and inflammasome signaling remains unclear. Here, we show that stimulation of macrophages with the NLRP3 activators nigericin or ATP induces lactic acid production and efflux via a lactate dehydrogenase-dependent pathway. Accumulation of intracellular lactic acid leads to cytoplasmic acidification, which promotes NLRP3 inflammasome activation. Concurrently, elevated extracellular lactic acid impairs lactate efflux, exacerbating intracellular acidification and amplifying ASC speck formation, caspase-1 activation, and IL-1β secretion. Alkalinization of the extracellular milieu prevents intracellular acidification and abolishes inflammasome activation. Mechanistically, intracellular lactic acidification promoted mitochondrial dysfunction and reactive oxygen species production, and concurrently induced phosphorylation of the stress kinase PKR, which facilitated PKR-NLRP3 interaction and inflammasome assembly through parallel pathways. Independently of inflammasome signaling, lactic acid also directly cleaves pro-IL-1β and pro-IL-18 into mature forms through a mechanism requiring its carboxyl group and mimicking caspase-1 substrate specificity. Mass spectrometry analysis revealed lactic acid-mediated cleavage of pro-IL-1β at Asp116, the canonical caspase-1 site. In a murine model of polymicrobial sepsis induced by cecal ligation and puncture, systemic lactate administration exacerbated inflammation, increased IL-1β levels and neutrophil infiltration, induced hypothermia, and worsened survival. Together, these findings identify intracellular lactic acidification as a metabolic signal that promotes inflammation predominantly through NLRP3 inflammasome activation, while also revealing a potential inflammasome-independent cytokine processing mechanism under conditions of severe metabolic stress.

DOI: https://doi.org/10.1038/s41419-026-08708-y
Biometals. 2026 Apr 02.

Aromatic amino acid metabolism shapes autophagy-mediated adaptation to iron deprivation in glioblastoma cells.

Kai Zhao, Lena Ludwig-Radtke, Yukai Wang, Tillmann Rusch, Christopher Nimsky, R Verena Taudte, Jörg W Bartsch.

  Glioblastoma (GBM) displays profound iron dependence and metabolic plasticity, yet how iron deprivation interfaces with stress-response pathways and amino acid metabolism in GBM remains incompletely understood. Deferoxamine (DFO), an iron chelator and hypoxia mimetic, is widely used experimentally, but the integration of autophagy, apoptosis, and ferroptosis under DFO-induced stress is unclear. This study aims to clarify how iron chelation reshapes stress signaling and metabolism in GBM cells and to define the role of aromatic amino acid metabolism in autophagy-mediated adaptation to iron deprivation. U87 and U251 human GBM cell lines were treated with DFO in the presence or absence of pan-caspase inhibitor Q-VD-OPh, the autophagy inhibitor CQ, or L-phenylalanine and L-tyrosine. AlamarBlue assessed cell viability. Hypoxia, autophagy, apoptosis, and ferroptosis-related genes and proteins were analyzed by qPCR, western blotting, and immunofluorescence. Global metabolic alterations were profiled by untargeted UHPLC-HRMS-based metabolomics followed by multivariate and pathway enrichment analyses. DFO stabilized HIF-1α, robustly induced hypoxia-related gene expression, and reduced GBM cell viability, with U251 cells being more sensitive than U87. DFO induced an autophagy response associated with ULK1 upregulation and reduced mTOR transcript levels, accompanied by increased LC3-II and changes in p62 levels. A lysosomal inhibition-based assay further supported increased autophagic flux, and meanwhile engaged apoptosis, particularly in U251, where Q-VD-OPh significantly rescued viability. In contrast, DFO induces an iron-starvation signature and maintains ferroptosis-associated antioxidant markers (GPX4/SLC7A11). CQ co-treatment potentiated DFO cytotoxicity in both lines, indicating a cytoprotective role of autophagy. Metabolomics revealed extensive DFO-induced reprogramming of amino acid and central carbon metabolism, with aromatic amino acid metabolism emerging as key pathway. DFO decreased intracellular L-phenylalanine and L-tyrosine in U87 but not U251 cells. Combined L-P + L-T supplementation attenuated DFO-induced autophagic responses and further enhanced DFO-mediated cytotoxicity. Iron chelation by DFO establishes a multifaceted stress state in glioblastoma cells, characterized by hypoxia-like transcription, cytoprotective autophagy, apoptosis, and ferroptosis resistance, coupled to profound amino acid-centric metabolic remodeling. Aromatic amino acid metabolism modulates autophagic responses and a determinant of GBM susceptibility to iron deprivation. Therefore, targeting aromatic amino acid metabolism to disable protective autophagy may enhance the therapeutic efficacy of iron-based strategies in GBM.

Keywords:  Apoptosis; Aromatic amino acid; Autophagy; Deferoxamine; Ferroptosis; Glioblastoma; Hypoxia; Metabolomics

DOI:  https://doi.org/10.1007/s10534-026-00809-7
Cell Death Dis. 2026 Mar 28.

REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.

Rocío Mora-Molina, Younes El Yousfi, Cathrin Hagenlocher, Francisco Javier Fernández-Farrán, Markus Rehm, Carmen Palacios, Maria A Christophorou, Abelardo López-Rivas.

Regulated in development and DNA damage response-1 (REDD1/DDIT4) is induced in response to environmental stress to restrain the mechanistic target of rapamycin complex 1 (mTORC1) signaling as an adaptive strategy to restore cellular homeostasis. Interestingly, REDD1/DDIT4 expression is upregulated in several tumor types including colorectal cancer, suggesting it may have a role in tumourigenesis. Here, we report that activating transcription factor 4 (ATF4)-dependent REDD1/DDIT4 expression is required for survival of colon tumor cells undergoing endoplasmic reticulum (ER) stress through the modulation of TRAILR2/DR5 gene expression. Our findings further demonstrate that resistance to ER stress-induced apoptosis in multicellular tumor spheroids (MCTS) is associated with constitutive expression of REDD1/DDIT4 and diminished mTORC1 activity. CRISPR/Cas9-mediated deletion of REDD1/DDIT4 markedly increases TRAILR2/DR5 expression and enhances apoptosis in spheroids exposed to ER stress. Interestingly, RNA sequencing analysis reveals that the loss of the transcriptional regulator EVI-1/MECOM in cells deficient in REDD1/DDIT4 amplifies the ER stress-induced upregulation of TRAILR2/DR5, leading to enhanced apoptosis. In summary, our findings underscore the crucial role of REDD1/DDIT4 in regulating TRAILR2/DR5-induced caspase-8 activation and apoptosis under chronic ER stress, by inhibiting mTORC1 activity and promoting EVI-1/MECOM-mediated suppression of TRAILR2/DR5 gene expression.

DOI: https://doi.org/10.1038/s41419-026-08648-7
iScience. 2026 Apr 17. 29(4): 115173

ATF6 ameliorates renal warm ischemia-reperfusion injury through FHL2-mediated NF-κB signaling pathway.

Xuan Wu, Ji-Hua Shi, Yang Bai, Dong-Jing Yang, Meng-Yao Jia, Dan-Feng Guo, Jia-Kai Zhang, Xiao-Yi Shi, Hua-Peng Zhang, Wen-Zhi Guo, Shui-Jun Zhang.

  Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury and transplant dysfunction, involving endoplasmic reticulum stress. Although activating transcription factor 6 (ATF6) regulates ER stress resolution through the unfolded protein response, its specific role in renal I/R injury remains undefined. Here, we employed murine models of renal I/R and cellular hypoxia/reoxygenation (H/R) models to systematically investigate ATF6's function. Our results show that I/R injury significantly upregulates ATF6 expression, particularly in proximal tubular epithelial cells. Functionally, ATF6 activation improved renal function and attenuated inflammation, whereas its inhibition exacerbated tubular damage. Mechanistically, we demonstrated that ATF6 transcriptionally represses four and a half LIM domain protein 2 (FHL2) through direct promoter binding. FHL2, in turn, interacts with TRAF6 to activate the nuclear factor kappa-B (NF-κB) pathway. ATF6 overexpression effectively counteracted FHL2-mediated NF-κB hyperactivation, establishing a protective ATF6/FHL2/NF-κB axis. These findings identify ATF6 as a key renoprotective factor and reveal mechanistic avenues for potential therapies targeting renal I/R injury and transplant complications.

Keywords:  molecular biology; physiology

DOI:  https://doi.org/10.1016/j.isci.2026.115173
Nat Cell Biol. 2026 Apr 03.

Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis.

Junyu Xiang, Tao Wang, Shuoran Tian, Jinyang Li, Mengyun Luo, Yuzhu Wang, Aibei Du, Xu Chen, Fanxuan Tian, Lei Wang, Yongchao Zhang, Mengyi Han, Wenqing Hou, Xinyu Wang, Tao Hou, Qin Liu, Dongfeng Chen, Liangzhi Wen, Zhongyi Qin, Xianfeng Li, Cong Jiang, Qiaoqiao Zhang, Pengda Liu, Xiuwu Bian, Wenyi Wei, Bin Wang.

Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5-S127, thereby recruiting the Cullin3ZBTB5 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8+ T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5-pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5-pS127-mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.

DOI: https://doi.org/10.1038/s41556-026-01926-8
Aging (Albany NY). 2026 Mar 27. 18(1): 213-233

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Victoria C Sanfrancesco, David A Hood.

  In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response

DOI:  https://doi.org/10.18632/aging.206365