bims-stacyt 2026-06-21 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–06–21
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia.
ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential.
A Drosophila tumor model identifies a conserved Upd-JAK/STAT-Akh signaling axis associated with metabolic changes in cancer cachexia.
Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.
Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.
FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

Cell Death Dis. 2026 Jun 17.

Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia.

Keren Peng, Jianshan Mo, Zhenjiao Yang, Wen Ding, Jiayu Yan, Shumin Ouyang, Minyuan Lu, Kai Zhu, Hongru Yao, Huiqin Chen, Xiongjun Xu, Peibin Yue, Jinjian Lu, Yuanxiang Wang, Shanyi Zhang, Yandong Wang, Xiaolei Zhang.

Chemotherapy resistance and intolerance present significant challenges in the effective treatment of acute myeloid leukemia (AML). However, the role of metabolic reprogramming, particularly lipid metabolic rewiring, in promoting chemotherapy resistance in leukemia has not been fully elucidated. Here, we found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, accompanied by upregulation of JAK-STAT3 signaling and key lipid metabolic regulators, notably SREBP1 and CPT2. Additionally, we discovered W1307, a potent and highly selective STAT3 inhibitor, which demonstrated significant anti-tumor activity both in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 simultaneously suppresses lipid synthesis and catabolism, leading to lipids metabolic disorder accompanied with lipids accumulation, ROS increase, lipid peroxidation and mitochondrial membrane potential decrease. Mechanistically, STAT3 binds to DNA response elements in the promoters of the lipid metabolism associated gene SREBF1 and CPT2, and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Our findings highlight the critical role of STAT3-driven lipid metabolism reprogramming in chemoresistance. Furthermore, W1307 emerges as a promising therapeutic candidate to overcome chemoresistance in leukemia treatment.

DOI: https://doi.org/10.1038/s41419-026-08988-4
Nat Commun. 2026 Jun 20.

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.

Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes.

Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.

DOI: https://doi.org/10.1038/s41467-026-74324-1
Arch Pharm Res. 2026 Jun 19.

Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential.

Muhammad Arif Aslam, Jongmin Lee, T Scott Bowen, Joo Young Huh.

  Skeletal muscle, once regarded solely as a contractile tissue, is now recognized as a dynamic endocrine organ that secretes exercise-induced myokines-bioactive peptides with autocrine, paracrine, and endocrine functions. These myokines coordinate systemic energy homeostasis by regulating glucose and lipid metabolism, mitochondrial function, inflammation, and interorgan communication. Building on our previous review published in 2018, this review synthesizes major advances in exercise-induced myokines within an evidence-based framework considering mechanistic support and translational relevance. We highlight both well-established and emerging myokines, including interleukin-6 (IL-6), irisin, myostatin, growth differentiation factor 11 (GDF11), IL-15, brain-derived neurotrophic factor (BDNF), meteorin-like (METRNL), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21 (FGF21), β-aminoisobutyric acid (BAIBA), leukemia inhibitory factor (LIF), apelin, and musclin, and discuss their roles across major target tissues including skeletal muscle, liver, adipose tissue, and bone. We also summarize natural and synthetic compounds reported to modulate myokine expression, secretion, or activity, and discuss the opportunities and current limitations of targeting myokine pathways. Although several myokine axes show therapeutic promise, the current literature indicates substantial heterogeneity in causal evidence, receptor or target certainty, and translational readiness. These insights support a more selective view of myokines as biologically heterogeneous mediators of muscle-organ crosstalk and provide a framework for mechanism-based therapeutic development in metabolic disease.

Keywords:  Exercise; Metabolism; Muscle–organ crosstalk; Myokines; Skeletal muscle

DOI:  https://doi.org/10.1007/s12272-026-01624-x
Dis Model Mech. 2026 Jul 01. pii: dmm052659. [Epub ahead of print]19(7):

A Drosophila tumor model identifies a conserved Upd-JAK/STAT-Akh signaling axis associated with metabolic changes in cancer cachexia.

Kewei Yu, Gurpreet S Moroak, Esther M Verheyen.

  Cancer-associated cachexia is a systemic wasting syndrome with no effective therapies, and it results in millions of deaths annually. Here, we established a Drosophila model of cancer cachexia using overexpression of Hipk and constitutively active Sik3 in larval epithelial tissue. Tumor-bearing larvae had significant muscle and fat body wasting, together with elevated carbohydrates and lipolysis. Mechanistically, tumors secrete Unpaired (Upd) ligands that activate JAK/STAT signaling in corpora cardiaca cells, inducing the expression of glucagon-like hormone Adipokinetic hormone (Akh). Elevated Akh, together with the lipase Brummer (Bmm), drives this systemic metabolic reprogramming and tissue catabolism. In conclusion, this study identifies a conserved tumor-host Upd-JAK/STAT-Akh signaling axis that contributes to organ wasting.

Keywords:   Drosophila ; Akh; Brummer; Cancer cachexia; Glucagon; Hipk; JAK/STAT; Organ wasting; Sik3; Tumor; Unpaired

DOI:  https://doi.org/10.1242/dmm.052659
Nat Cell Biol. 2026 Jun 15.

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.

DOI: https://doi.org/10.1038/s41556-026-01991-z
iScience. 2026 Jun 19. 29(6): 116253

The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.

Chenyang Xianyu, Yuxiao Song, Ci Zhao, Qian Min, Zhixu Wang, Mingbo Zhang, Bicheng Zhang.

  Amino acids are important nutrients in the process of tumor proliferation. Dysregulated amino acid metabolism profoundly influences tumor growth and immune cell function. Within the tumor microenvironment (TME), metabolic reprogramming of amino acids modulates the polarization of tumor-associated macrophages (TAMs) and the differentiation of T cells, processes intimately linked to tumor immune evasion. Meanwhile, metabolic reprogramming leads to amino acid competition between tumor cells and immune cells, particularly TAMs and T cells. To meet their own amino acid needs, tumors carry out a series of optimized metabolic strategies by expressing specific enzymes, cytokines, and amino acid transporters, and so forth promoting the formation of an immunosuppressive microenvironment and hindering anti-tumor immunity. Notably, this metabolic competition may exhibit spatial heterogeneity and temporal dynamics. Given the central role of amino acid metabolism in tumor progression and immune evasion, targeting key metabolic pathways represents a promising therapeutic strategy for cancer treatment.

Keywords:  Cancer; Cancer systems biology; Human metabolism; Immune response

DOI:  https://doi.org/10.1016/j.isci.2026.116253
Neoplasia. 2026 Jun 16. pii: S1476-5586(26)00059-X. [Epub ahead of print]79 101329

Inhibition of PERK signaling suppresses tumor progression and blocks GP73-GRP78-dependent stromal activation in hepatocellular carcinoma.

Jaafar Khaled, Maria Kopsida, Tania Payo Serafín, Sofi Sennefelt Nyman, Fredrik Rorsman, Charlotte Ebeling Barbier, Hans Lennernäs, Markus Sjöblom, Femke Heindryckx.

  Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) progression and promotes the development of a pro-tumorigenic microenvironment. Here, we demonstrate that selective inhibition of the ER-stress sensor PERK using AMG-PERK substantially restrains tumor development when administered during early carcinogenesis in a chemically induced HCC model. PERK inhibition reduced tumor burden, proliferation, and cell viability in vivo, and impaired the growth of HCC cells and patient-derived organoids in vitro. In parallel, AMG-PERK markedly reduced stromal activation, fibrosis, and inflammatory signaling within the tumor microenvironment. Mechanistic analyses indicated that ER-stress enhances tumor-stromal communication in part through increased secretion of the glycoprotein GP73, which can activate hepatic stellate cells via GRP78-dependent signaling. Blocking PERK or using GRP78-targeting antibodies reduced stellate cell activation and fibrogenic responses. Single-cell RNA sequencing and patient biopsies showed that PERK/EIF2AK3 and GP73/GOLM1 are upregulated in malignant hepatocytes and associated with poor clinical outcomes. Transcriptomic profiling further revealed that ER-stress drives oncogenic programs, including MYC signaling, epithelial-to-mesenchymal transition, and inflammatory pathway activation, all of which were affected by pharmacological PERK inhibition. Together, these findings identify PERK signaling as a potential driver of malignant progression and microenvironmental remodeling in HCC and establish PERK inhibition as a promising therapeutic strategy to target both tumor cells and their stromal interactions during the initial stages of hepatocarcinogenesis.

Keywords:  Endoplasmic reticulum stress; GP73; Hepatocellular carcinoma; PERK pathway; Tumor-stromal interactions

DOI:  https://doi.org/10.1016/j.neo.2026.101329
Cell Metab. 2026 Jun 16. pii: S1550-4131(26)00221-4. [Epub ahead of print]

FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

Gerald Grandl, Ann-Christine König, Fabian Metzger, Arkadiusz Liskiewicz, Tanja Hefele, Shelly Nason, Aaron Novikoff, Nada Al-Refaie, Md Abdur Rahman, Ahmed Khalil, Qian Zhang, Gustav Collden, Brian Finan, Jonathan Douros, Kirk Habegger, Alberto Cebrian-Serrano, Stefanie M Hauck, Matthias H Tschöp, Timo D Müller.

  Fibroblast growth factor 21 (FGF21) is an endocrine hormone with broad metabolic actions at supraphysiological concentrations but unclear physiological function, related to endoplasmic reticulum (ER) stress. ER stress activates the unfolded protein response (UPR), a cellular repair mechanism that maintains cellular homeostasis during protein folding stress. Using proximity labeling, we assessed the intracellular action of FGF21 at its receptor β-klotho (KLB) and discovered associations with protein folding in the ER, ER stress, and H2S production. We found that FGF21 increases enzymatic sulfide production and enhances, but does not initiate, the UPR. This FGF21 action is blunted by genetic or pharmacological inhibition of sulfide signaling and is phenocopied by an H2S donor in vivo. FGF21 modulating the UPR requires KLB, and even physiological levels of FGF21 modulate the UPR via increased hepatic H2S production. Collectively, we reveal a novel physiological role of FGF21 as an endocrine stress hormone that enhances the UPR via increased sulfide signaling.

Keywords:  ER stress; FGF21; H(2)S; ISR, β-klotho, KLB; UPR; integrated stress response; sulfide signaling; unfolded protein response

DOI:  https://doi.org/10.1016/j.cmet.2026.05.011