bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–04–26
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Separating food intake-dependent and -independent effects in cancer cachexia.
  2. An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.
  3. Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.
  4. Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.
  5. The Critical Role of GALNTs-Regulated O-GalNAc Glycosylation in Cancer Malignancy.
  6. Oleic Acid Fuels Cisplatin-Resistant Ovarian Cancer Through FABP4-Driven Lipid Uptake.
  7. Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
  8. Lipid metabolic reprogramming regulates macrophage senescence in the tumor microenvironment.
  1. iScience. 2026 May 15. 29(5): 115525
    Separating food intake-dependent and -independent effects in cancer cachexia.
    Yanshan Liang, Young-Yon Kwon, Sheng Hui.
      Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle, with diminished food intake commonly cited as a cause. However, the extent to which reduced food intake drives these symptoms, and other phenotypes such as physical weakness, remains unclear. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and tissue wasting, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing weakness. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.
    Keywords:  Cancer; Nutrition; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2026.115525
  2. J Biol Chem. 2026 Apr 22. pii: S0021-9258(26)00354-6. [Epub ahead of print] 111482
    An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.
    Jagannath Misra, Dan F Spandau, Jonah Z Vilseck, Tracy G Anthony, Kirk A Staschke, Ronald C Wek.
      The integrated stress response (ISR) is a major mechanism protecting cells against environmental and physiological stresses. Central to the ISR is a collection of stress-sensing kinases, such as GCN2 (EIF2AK4). When nutrients are limiting or translating ribosomes stall or collide, activated GCN2 phosphorylates eIF2, lowering global protein synthesis, which conserves resources and confers targeted expression of stress-adaptive genes, such as the transcription factor ATF4. While beneficial during acute stress, chronic GCN2 activation can promote cancer progression and neurological disease, spurring the development of GCN2 inhibitors. However, achieving therapeutic specificity and understanding the pathological context of ISR modulation remains challenging and requires careful evaluation. One of the earliest and most widely used GCN2 inhibitors is GCN2iB. In this study, we report that GCN2iB is a direct inhibitor of the ZAK protein kinase, a critical upstream regulator of stress-activated MAPK signaling that functions in the ribotoxic stress response (RSR). Using biochemical measurements, cell-based assays, and structural modeling, we demonstrate that inhibition of ZAK by GCN2iB dampens stress-induced JNK and p38 activation, thereby masking the cytotoxic consequences normally associated with GCN2 inhibition. While suppression of GCN2 activity may be beneficial in specific disease models, concurrent inhibition of ZAK can negate these effects, obscure its therapeutic benefits, and lead to unanticipated phenotypes. These findings highlight the importance of assessing kinase selectivity in pharmacological studies of ISR modulation and emphasize that dual inhibition of GCN2 and ZAK can yield complex and context-dependent cellular responses.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111482
  3. J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70295
    Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.
    Leng Han, Lingjie Jing, Xinting Zhu, Ciqin Li, Lu Bai, Yang Fang, Yuxuan Zhou, Dingyuan Bai, Jin Lu, Yonglong Han, Cheng Guo, Shumin Zhou, Quanjun Yang.
       BACKGROUND: Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer-associated cachexia remains inadequately defined. This study investigated the mechanistic role of Ido1 in cancer cachexia and evaluated the therapeutic potential of its inhibition.
    METHODS: We established Lewis lung carcinoma (LLC) models in C57BL/6 mice using wild-type, Ido1-overexpressing (Ido1-OE) and Ido1-knockout (Ido1-KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in vivo. Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In vitro, we examined the effects of tumour-conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy. In vivo experiments verified the efficacy of the Ido1 inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.
    RESULTS: Compared to LLC mouse models, Ido1-OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (p < 0.01, p < 0.0001, p < 0.001). Gastrocnemius muscle fibre cross-sectional area significantly decreased in the Ido1-OE group (p < 0.0001). Transcriptomic analysis revealed that Ido1-OE activated pro-inflammatory and protein degradation pathways (upregulating MuRF1/Atrogin1, p < 0.05) while suppressing anabolic signalling pathways (oestrogen pathways, p < 0.01). Metabolomics analysis revealed unique metabolic signatures in Ido1-OE mice: Trp depletion and Kyn accumulation. In vitro experiments demonstrated that Ido1-OE enhanced LLC cell proliferation and migration capabilities (p < 0.0001, p < 0.0001). Tumour-conditioned medium (TCM) derived from Ido1-OE tumours significantly induced C2C12 myotube atrophy (p < 0.01). Similarly, direct treatment with Kyn led to dose-dependent muscle fibre shrinkage, with significant atrophy observed at 30 μM (p < 0.01) and 100 μM (p < 0.0001). Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (p < 0.0001). Compared with the Ido1-OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (p < 0.01; p < 0.05). Mechanistically, PAL inhibited the mRNA expression levels of MuRF1/Atrogin1 (p < 0.0001, p < 0.001), as well as their corresponding protein levels (p < 0.0001, p < 0.0001). Furthermore, PAL restored the phosphorylation level of mTOR (p < 0.001), as well as the mRNA expression of myosin heavy chain (p < 0.01).
    CONCLUSIONS: Our findings demonstrate that Ido1 accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp-Kyn pathway. Pharmacological inhibition of Ido1 with PAL effectively mitigates these effects, positioning Ido1 as a promising therapeutic target for treating cancer cachexia.
    Keywords:  cancer cachexia; indoleamine 2,3‐dioxygenase 1; kynurenine; metabolic reprogramming; muscle atrophy; tryptophan
    DOI:  https://doi.org/10.1002/jcsm.70295
  4. FEBS Open Bio. 2026 Apr 21.
    Pharmacological inhibition of the PERK pathway modulates hepatocellular carcinoma growth and immune signaling.
    Ada Lerma-Clavero, Maria Kopsida, Nathalie Arendt, Hans Lennernäs, Markus Sjöblom, Femke Heindryckx.
      The unfolded protein response (UPR) plays an important role in tumor progression and cellular stress adaptation. In hepatocellular carcinoma (HCC), pharmacological inhibition of the protein kinase R-like endoplasmic reticulum kinase (PERK) is a potential therapeutic strategy, yet its effects on tumor growth and the microenvironment remain unclear. We investigated the selective PERK inhibitor AMG PERK 44 in a diethylnitrosamine (DEN)-induced mouse model of advanced HCC. Tumor burden, proliferation, fibrosis, immune-related gene expression, and ER stress signaling were assessed alongside analyses of single-cell RNA-sequencing data from HCC mouse models and liver-specific PERK knockout mice. Our results show that AMG PERK 44 did not alter tumor number nor cause a decrease in tumor area and proliferation. Furthermore, fibrotic burden was unchanged, although fibrosis architecture and stromal gene expression (TGF-β, CTGF, F4/80) were modified. Despite PERK inhibition, the expression of ER stress associated genes (CHOP, EIF2AK3, ERdj4) increased. Single-cell analysis revealed context-dependent PERK activity, highest in dendritic cells and macrophages under inflammatory and tumor conditions, while PERK knockout livers showed impaired UPR responses after tunicamycin treatment. Finally, AMG PERK 44 did not enhance idarubicin efficacy and caused no major off-target effects. These findings highlight the context-dependent role of PERK in the HCC microenvironment and its implications for targeting UPR pathways in liver cancer. Impact statement This study provides an evaluation of PERK as a therapeutic target in hepatocellular carcinoma by demonstrating that its inhibition does not produce the anticipated anti-tumor effects in advanced disease, but instead exerts nuanced, context-dependent influences on the tumor microenvironment.
    Keywords:  AMG PERK44; ER stress; PERK; carcinogenesis; fibrosis; hepatocellular carcinoma; idarubicin; inflammation
    DOI:  https://doi.org/10.1002/2211-5463.70252
  5. FASEB J. 2026 Apr 30. 40(8): e71790
    The Critical Role of GALNTs-Regulated O-GalNAc Glycosylation in Cancer Malignancy.
    Jiahao Liu, Sihan Wu, Ge Zhang, Jiehan Li, Yuhan Yin, Aman Uiiah, Sanfei Peng, Yang Fu.
      Aberrant mucin-type O-glycosylation, mediated by the Polypeptide N-acetylgalactosaminyltransferase (GALNT) family of enzymes, is a defining feature of many cancers and has also been strongly linked to non-neoplastic conditions, including developmental disorders and metabolic abnormalities. Mucin-type O-GalNAc glycosylation, a prevalent and highly specific form of post-translational modification, is centrally involved in key processes underlying cancer progression, such as cell signaling, invasion, angiogenesis, and metastasis. It is intricately linked to a diverse array of human diseases, with a particular association with cancer. Ongoing research endeavors to elucidate the functional mechanisms by which GALNT enzymes regulate O-GalNAc glycosylation, thereby enhancing our understanding of their pivotal roles in cancer biology. Although significant advances have been made in understanding their contributions to cancer initiation and progression, a comprehensive characterization of both the GALNT family and O-GalNAc glycosylation in oncology remains lacking. This review aims to summarize the structure of the GALNT family and its regulatory roles in the initiation and elongation of O-GalNAc glycans, providing an in-depth exploration of the functions of GALNT-mediated O-GalNAc glycosylation in cancer. Ultimately, these insights will help uncover underlying oncogenic mechanisms and may offer new potential directions for the development of anticancer therapeutics and diagnostic biomarkers.
    Keywords:  GALNT family; O‐GalNAc glycosylation; cancer biomarkers; cancer progression
    DOI:  https://doi.org/10.1096/fj.202504815R
  6. Mol Metab. 2026 Apr 21. pii: S2212-8778(26)00058-X. [Epub ahead of print] 102374
    Oleic Acid Fuels Cisplatin-Resistant Ovarian Cancer Through FABP4-Driven Lipid Uptake.
    Ana Maria Isac, Andres Valdivia, Didi Zha, Yinu Wang, Vanessa Hernandez, Guangyuan Zhao, Chinmayee Vallabh Prabhu Dessai, Ujin Kim, Annapurna Sai Josyula, Wenan Qiang, Sandra Orsulic, Ji-Xin Cheng, Daniela Matei.
       BACKGROUND: Ovarian cancer (OC) depends on lipids as fuel for metastasis and growth. We previously showed that cisplatin resistant (Pt-R) OC cells uptake higher amounts of fatty acids (FAs) compared to sensitive (Pt-S) cells, a process which facilitates cancer cell survival under cisplatin-induced oxidative stress.
    METHODS: Isogenic pairs of Pt-S and Pt-R OC cell lines were cultured in low serum conditions supplemented with either 50 μM oleic acid (OA, unsaturated) or 50 μM palmitic acid (PA, saturated) and used for viability assays, RNA-Sequencing, and cell cycle analysis. The effects of an OA enriched diet were assessed in intraperitoneal ovarian xenografts. The FABP inhibitor BMS-309403 was used to block lipid import in vitro and in vivo.
    RESULTS: Pt-R cells were less viable than Pt-S cells under serum depletion and OA rescued starvation induced inhibition of cell proliferation, with more significant effects in Pt-R compared to Pt-S cells. RNA-sequencing showed that OA promoted upregulation of cell cycle-related pathways, including G2/M checkpoints, driven by the transcription factor E2F1. Supplementation with OA increased S- and G2/M phase cell populations in both Pt-S and Pt-R cells (p<0.05) and E2F1 inhibition reduced OA-induced cell proliferation. An OA enriched diet promoted the growth and peritoneal dissemination of Pt-R ovarian xenografts. When co-cultured with adipocytes, Pt-R cells expressed higher levels of FA transporter proteins FABP4 and CD36 compared to sensitive cells and FABP4 expression was upregulated in paired metastatic and recurrent vs. primary human ovarian tumors (p<0.05). An FABP inhibitor sensitized OC cells to cisplatin and suppressed the in vivo growth of Pt-R xenografts and patient derived xenografts.
    CONCLUSIONS: Pt-R OC cells harbor heightened dependence on unsaturated FAs compared to Pt-S cells and upregulate key transporters to increase FAs uptake. OA supports the proliferation of Pt-R cells in vitro and in vivo and a combination of carboplatin and FABP4 inhibitor reduces OC growth in vivo. These findings suggest that lipid composition may influence therapeutic response and raise important considerations for dietary guidance in patients with cancer.
    DOI:  https://doi.org/10.1016/j.molmet.2026.102374
  7. Cell Metab. 2026 Apr 22. pii: S1550-4131(26)00111-7. [Epub ahead of print]
    Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
    Anthony H Tsang, Nicholas Heeley, Constanza Alcaino, Eunsang Hwang, Brian Y Lam, Taufiq Rahman, Tamana Darwish, Danae Nuzzaci, Richard G Kay, Amar Sarkar, Ruiyan Wang, Nihal Basha, Austin Punnoose, Peter Kirwan, Marcella Ma, Giles S Yeo, Florian T Merkle, Fiona M Gribble, Frank Reinmann, Kevin W Williams, Clémence Blouet.
      Dietary protein promotes satiety and weight loss, yet how appetite-regulating neurons sense dietary protein remains poorly understood. Here, we show that Cacna1g, which encodes the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates neuronal leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of pro-opiomelanocortin (POMC) neurons in cultured neurons and brain slices, thereby suppressing the anorectic response to hypothalamic leucine in vivo. Genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, leucine binds a hydrophobic pocket of Cav3.1 and lowers its threshold for voltage-dependent activation. Finally, pharmacological activation of mediobasal hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates responses to anorectic agents, including liraglutide. Together, these findings establish hypothalamic Cav3.1 as a neuronal leucine sensor and nominate it as a tractable target for anti-obesity therapy.
    Keywords:  POMC neurons; appetite; arcuate nucleus; dietary proteins; hypothalamus; leucine; metabolic diseases; nutrient sensing; obesity; voltage-gated calcium channel
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.017
  8. Cytokine Growth Factor Rev. 2026 Apr 19. pii: S1359-6101(26)00031-6. [Epub ahead of print]89 41-57
    Lipid metabolic reprogramming regulates macrophage senescence in the tumor microenvironment.
    Yixi Liu, Chenchi Li, Jiao Wang, Miaomiao Gao, Shulong Jiang.
      Immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of many malignant tumors; however, their efficacy remains limited by the complex immune-suppressive characteristics of the tumor microenvironment (TME), with only a subset of patients experiencing durable remission. Identifying new targets for immune modulation has therefore become a major focus of current cancer research. In this context, tumor-associated macrophages (TAMs) have emerged as key regulators of tumor initiation, progression and immune modulation owing to their striking functional plasticity. TAMs exhibit considerable phenotypic plasticity, with metabolic reprogramming shaping their polarization towards anti-tumor M1-like or pro-tumor M2-like states. The alterations in lipid metabolism not only affect the phenotypic transformation of TAMs, but more importantly, they also drive macrophage senescence, leading to impaired immune surveillance, weakened anti-tumor immunity and ultimately immune escape. This process is marked by lipid accumulation, mitochondrial dysfunction, and activation of the senescence-associated secretory phenotype (SASP), collectively contributing to the establishment of an immunosuppressive TME. In this review, we summarize the key mechanisms by which lipid metabolic reprogramming in TAMs regulates macrophage senescence, with particular emphasis on the role of SASP in shaping the immunosuppressive microenvironment. We also discuss therapeutic strategies targeting TAM senescence and lipid metabolism, highlighting their potential synergy with ICIs and metabolic modulators. Collectively, targeting these TAM-related pathways may provide a promising strategy to overcome immune evasion and ICIs resistance.
    Keywords:  Immune checkpoint inhibitors; Lipid metabolism reprogramming; Senescence-associated secretory phenotype; Tumor immune microenvironment; Tumor-associated macrophages senescence
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.04.002
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