bims-stacyt 2025-11-30 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–11–30
fifteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

New Horizons with Growth Differentiation Factor 15 in Oncology: From Cancer Cachexia and Tumour Immunity to Novel Therapeutic Strategies.
Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway.
WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.
Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
LC3-positive extracellular vesicles released from tumor cells promote lung metastasis of breast cancer by inducing vascular permeability.
Hypoxia-driven perturbations of proteostasis and therapeutic vulnerabilities in cancer.
Tumor-derived lactate fuels the STAT3-LCN2 pathway to promote bladder cancer malignancy and chemoresistance.
Integrin-specific signaling drives ER stress-dependent atherogenic endothelial activation.
ATF5-Dependent GDF15 Expression Mediates Anesthesia-Induced Neuroprotection Against Stroke.
Targeting of HIF2-driven cachexia in kidney cancer.
Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages.
SKA3-mediated hypoxia tolerance and metabolic reprogramming promote liver metastasis in lung adenocarcinoma.
The Adaptation of Cancer Cells to Serum Deprivation Is Mediated by mTOR-Dependent Cholesterol Synthesis.
Targeting the polyol pathway in NSCLC: Trans-(±)-kusunokinin demonstrates anti-migratory and survival benefits in in vitro and in vivo models.
Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity.

Curr Oncol. 2025 Oct 29. pii: 604. [Epub ahead of print]32(11):

New Horizons with Growth Differentiation Factor 15 in Oncology: From Cancer Cachexia and Tumour Immunity to Novel Therapeutic Strategies.

Keiji Sugiyama, Naureen Starling, Ian Chau.

  Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine produced by tumour cells and peripheral cells. It is implicated in the development of cancer cachexia, a debilitating condition for which no effective pharmacological therapy currently exists. GDF-15 regulates appetite and metabolic processes through complex neural and hormonal networks. Furthermore, it has been implicated in chemotherapy-induced nausea and vomiting, representing a potential therapeutic target. GDF-15 negatively affects tumour immunity, suggesting that anti-GDF-15 therapy could potentially enhance immune responses and help overcome resistance to immunotherapy. Recently, early clinical trials have reported preliminary results of GDF-15-targeted therapies in alleviating cancer cachexia and potentially enhancing the efficacy of immunotherapy. This review aims to provide an overview of the role of GDF-15 in cancer cachexia, including the underlying neural mechanisms and their involvement in tumour immunity. This review also summarises recent clinical trial findings and discusses future perspectives on GDF-15-targeted therapy in oncology, offering important insights for future research.

Keywords:  autonomic nervous system; cancer cachexia; growth differentiation factor 15; immune checkpoint inhibitors

DOI:  https://doi.org/10.3390/curroncol32110604
J Extracell Vesicles. 2025 Dec;14(12): e70182

Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway.

Xu Li, Sheng Hu, Ziqi Yuan, Xiaoyu Fu, Xiaohui Zhang, Liu Liu, Chaoqun Wang, Wei Yan, Juanjuan Li.

  Metastasis is the leading cause of death related to breast cancer. Premetastatic niches (PMNs), which are remodelled by the primary tumours in distant organs, are essential for the colonisation of disseminated cancer cells. The vascular niche is among the most pivotal PMNs in breast cancer lung metastasis, and the underlying mechanism remains unclear. Here, we report that breast cancer cells secrete dipeptidyl peptidase 3 (DPP3) via small extracellular vesicles (sEVs) to promote lung metastasis. Mechanistically, circulating DPP3 upregulates RAPGEF4 to activate the Rap1 signalling pathway in the lung endothelial cells through the DPP3-PFKP-YBX1 axis and promotes angiogenesis to remodel the vascular niche, thereby increasing lung metastasis. In addition, ARF4 recognises ISGylated DPP3, which facilitates its packaging into sEVs in breast cancer cells. Finally, treatment with losartan pharmacologically inhibits the ISGylation of DPP3, preventing its secretion via sEVs. In summary, our findings demonstrate that DPP3, which is encapsulated in sEVs and secreted by breast cancer cells, regulates angiogenesis in the lung and remodels vascular niches to promote breast cancer lung metastasis, making it a potential target for the diagnosis and treatment of breast cancer metastasis.

Keywords:  Angiogenesis; Dipeptidyl peptidase 3; ISGylation; Lung metastasis; Rap1 signalling pathway; Small extracellular vesicles

DOI:  https://doi.org/10.1002/jev2.70182
Nat Commun. 2025 Nov 24.

WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.

Rinskje B Tjeerdsma, Timothy F Ng, Maurits Roorda, Daniëlle Bianchi, Sora Yang, Clara Bonnet, Michael VanInsberghe, Marieke Everts, Femke J Bakker, H Rudolf de Boer, Nathalie Moatti, Nicole Hustedt, Jay Z Yin, Lisa Hoeg, Matthew Leibovitch, Frank Sicheri, Alexander van Oudenaarden, Steven de Jong, Jeroen van den Berg, Marvin E Tanenbaum, Thijn R Brummelkamp, Daniel Durocher, Marcel A T M van Vugt.

The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity to WEE1 inhibitors (WEE1i) are largely unknown. A genome-wide insertional mutagenesis screen revealed that mutation of EIF2A, a translation regulator, sensitized to WEE1i. Additionally, a genome-wide CRISPR-Cas9 screen revealed that inactivation of integrated stress response (ISR) kinase GCN2 or its co-factor GCN1 rescued WEE1i-mediated cytotoxicity. Conversely, loss of the collided ribosome sensor ZNF598 increased sensitivity to WEE1i. Mechanistically, WEE1i induced paradoxical GCN2 activation, ATF4 upregulation, and altered ribosome dynamics. ISR activation was independent of WEE1 presence, pointing at off-target GCN2 engagement by multiple chemically distinct WEE1i. ISR activation was observed in cancer cells as well as non-transformed cells, and required GCN1 and ongoing translation. Consequently, WEE1i induce multiple independent cellular effects: DNA damage, premature mitotic entry and sensitization to DNA-damaging chemotherapeutics in an ISR-independent fashion, as well as ISR activation independently of CDK1/2 activation. Importantly, low-dose WEE1 inhibition did not induce ISR activation, while it still synergized with PKMYT1 inhibition. Taken together, WEE1i trigger toxic ISR activation and translational shutdown, which can be prevented by low-dose or combination treatments, while retaining the cell cycle checkpoint-perturbing effects.

DOI: https://doi.org/10.1038/s41467-025-66514-0
Cell Death Differ. 2025 Nov 25.

Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.

Ismael Sánchez-Vera, Ana M Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T Jae, Daniel Iglesias-Serret, Joan Gil.

Prohibitins (PHBs) are predominantly located at the inner mitochondrial membrane, displaying significant roles in tumor progression, invasion, and apoptotic resistance, often overexpressed in primary tumors. Importantly, we developed a synthetic molecule, fluorizoline, that induces apoptosis by selectively targeting PHBs in various cancer cell lines and primary samples from different hematological neoplasms. Fluorizoline induces apoptosis by activating the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, specifically via the ATF4-CHOP-NOXA axis. We identified compensatory mechanisms for four ISR-related kinases, with HRI emerging as the primary kinase responsible for the activation of the ISR and apoptosis induction, implicating mitochondrial stress in ISR activation. Here, we investigate the mitochondrial stress response signaling pathway responsible for activating HRI after targeting PHBs either by fluorizoline treatment or by PHBs downregulation in HeLa and HAP1 cancer cell lines. In this study, we describe how PHBs regulate the localization of the mitochondrial stress sensor DELE1, leading to ISR activation and apoptosis induction in HeLa and HAP1 cells. Our findings demonstrate that DELE1 promotes ISR activation upon fluorizoline treatment and PHBs downregulation. Although fluorizoline treatment activates the cleavage of long DELE1 (L-DELE1) to its cleaved form (S-DELE1), OMA1 was found to be dispensable for activating the ISR upon fluorizoline treatment. Furthermore, our findings indicate a potential impairment of the mitochondrial protein import machinery upon targeting PHBs, as the import of other mitochondrial proteins beyond DELE1 is also disrupted. These findings reveal a previously unknown physiological role of PHBs in preserving the mitochondrial protein import pre-sequence pathway, possibly due to the interaction between PHBs and DNAJC19. This novel insight underscores the potential of targeting PHBs, such as with fluorizoline, to overwhelm mitochondrial stress in cancer.

DOI: https://doi.org/10.1038/s41418-025-01618-0
FEBS J. 2025 Nov 27.

LC3-positive extracellular vesicles released from tumor cells promote lung metastasis of breast cancer by inducing vascular permeability.

Yuqing Shen, Yi Shen, Xuru Wang, Fuhua Wang, Piaopiao Liu, Chen Sun, Ying Zhang, Feng-Qin Miao, Jianqiong Zhang, Lixin Wang.

  Tight junctions (TJs) between pulmonary vascular endothelial cells (ECs) constitute the physical barrier that impedes the metastasis of tumor cells. We previously reported that circulating microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive extracellular vesicles (LC3+ EVs) derived from primary breast tumors were essential for establishing the premetastatic niche. However, the roles of LC3+ EVs in inducing vascular permeability and promoting tumor metastasis are unclear. In this study, we revealed that the expression of occludin and tight junction protein 1 [also known as zona occludens protein 1 (ZO-1)], two major TJ proteins, could be reduced by circulating LC3+ EVs, which subsequently increased vascular permeability, facilitated the invasion of circulating tumor cells, and eventually resulted in increased lung metastasis. Heat shock protein 60 (HSP60) was identified as the key molecule on LC3+ EVs that induced the reduction of occludin and ZO-1 through the Toll-like receptor 2 (TLR2)-myeloid differentiation primary response protein MyD88 (MYD88)-Snail Family Transcriptional Repressor 1 (Snai1) signal cascade. Combined with our previous findings, these results demonstrate that removing circulating LC3+ EVs or targeting HSP60 on LC3+ EVs might be a promising way to prevent breast cancer lung metastasis.

Keywords:  LC3+ EVs; breast cancer; lung metastasis; tight junction protein; vascular endothelial cells; vascular permeability

DOI:  https://doi.org/10.1111/febs.70335
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00130-0. [Epub ahead of print]148 507-528

Hypoxia-driven perturbations of proteostasis and therapeutic vulnerabilities in cancer.

Manvi Sharma, Tushar Singh Barwal, Neha, Yashika, N K Ganguly, Shivani Arora Mittal.

  Solid tumors are characterized by chaotic architecture and abnormal vasculature, which trigger rapid cell proliferation leading to steep oxygen gradients, and render the tumor core highly hypoxic or anoxic. These hypoxic regions within a tumor profoundly drive cancer progression by stabilizing key transcription factors, Hypoxia-Inducible Factors, HIF-1 and HIF-2. In addition to the well-established HIF pathways, hypoxic areas in tumors are being increasingly examined for their capacity to disrupt proteostasis, specifically influencing oxygen-dependent protein folding in the endoplasmic reticulum. Hypoxia acts as a key stressor, leading to the accumulation of misfolded proteins, triggering Unfolded Protein Response as a compensatory mechanism, mediated by the three main ER sensors: PKR-like ER kinase, Inositol-Requiring enzyme 1, and Activating Transcription factor 6. In a healthy cell, UPR typically seeks to induce cell death, reestablishing cellular equilibrium. Cancer cells subvert this response by utilizing it to their advantage, enhancing metabolic flexibility, evading immune surveillance, and establishing resistance. There is growing evidence that these hypoxia-induced misfolded proteins contribute to the progression of tumors by causing genomic instability and dysregulating oncogenic signaling. This chapter details how hypoxia regulates protein misfolding, leading to cancer cell adaptation, and outlines relevant therapeutic targets.

Keywords:  Cancer; ER stress; HIF; Hypoxia; Protein misfolding; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.11.001
Sci Rep. 2025 Nov 24. 15(1): 41610

Tumor-derived lactate fuels the STAT3-LCN2 pathway to promote bladder cancer malignancy and chemoresistance.

Shih-Yu Yu, Hao-Yi Li, Chi-Yun Wang, Wei-Jan Wang, Shih-Hao Hsu, Min-Chen Hsiang, Ke-Xin Yee, Kuen-Haur Lee, Yu-Cheng Lee.

  Bladder cancer progression is closely linked to metabolic changes within the tumor microenvironment (TME), particularly elevated lactate levels. Lipocalin 2 (LCN2), a protein involved in iron regulation, has been implicated in tumor progression in several cancers, but its regulatory mechanisms and role in bladder cancer remain unclear. Bladder cancer cell lines were treated with exogenous lactate or subjected to inhibition of endogenous lactate production to evaluate changes in LCN2 expression. The role of Signal Transducer and Activator of Transcription 3 (STAT3) was assessed using genetic knockdown and pharmacological inhibitors. Functional assays including migration, epithelial-to-mesenchymal transition (EMT), sphere formation, and stemness marker analysis were performed to determine the biological effects of LCN2. Chemoresistance to gemcitabine was examined with and without LCN2 silencing. Clinically, LCN2 expression was significantly associated with the pathological relevance of bladder tumors. Lactate significantly induced LCN2 expression in bladder cancer cells through activation of STAT3. Disruption of STAT3 signaling reduced LCN2 levels. High LCN2 expression correlated with advanced tumor grade, poor prognosis, and shorter overall survival. Functionally, LCN2 promoted EMT, enhanced cell migration, and increased stem cell-like properties, as evidenced by elevated stemness markers and sphere-forming ability. Moreover, lactate-induced LCN2 expression conferred resistance to gemcitabine treatment, while LCN2 knockdown restored chemosensitivity. This study identifies tumor-derived lactate as a key inducer of LCN2 expression via STAT3 activation in bladder cancer. LCN2 contributes to tumor aggressiveness, cancer stemness, and chemoresistance. Targeting the STAT3-LCN2 signaling axis may offer a promising therapeutic strategy to suppress bladder cancer progression and overcome treatment resistance within a lactate-rich TME.

Keywords:  Bladder cancer; Chemoresistance; Lipocalin-2 (LCN2); STAT3; Tumor microenvironment (TME); Tumor-derived lactate

DOI:  https://doi.org/10.1038/s41598-025-25534-y
Redox Biol. 2025 Oct 30. pii: S2213-2317(25)00424-0. [Epub ahead of print]88 103911

Integrin-specific signaling drives ER stress-dependent atherogenic endothelial activation.

Cyrine Ben Dhaou, Zaki Al-Yafeai, G Ali Cruz-Marquez, Matthew L Scott, Brenna Pearson-Gallion, Elizabeth Cockerham, Hanna Li, Jonette M Peretik, Yuning Hong, Nirav Dhanesha, Arif Yurdagul, Oren Rom, Md Shenuarin Bhuiyan, A Wayne Orr.

  Atherogenic endothelial activation is driven by both the local arterial microenvironment, marked by altered extracellular matrix (ECM) composition and disturbed blood flow, and soluble proinflammatory cues such as oxidized low-density lipoprotein (oxLDL). Fibronectin, a provisional extracellular matrix protein enriched at atheroprone sites, augments these proinflammatory stimuli. Although endoplasmic reticulum (ER) stress is a hallmark of atheroprone regions, its regulation by extracellular matrix and its precise role in endothelial inflammatory activation are not well defined. Here, we show that oxLDL and disturbed flow induce ER stress selectively in endothelial cells adhered to fibronectin, but not in those adhered to basement membrane proteins. This matrix-specific ER stress response requires activation of the integrin family of ECM receptors, as endothelial cells deficient for integrin activation (talin1 L325R mutation) fail to activate ER stress in response to disturbed flow and oxLDL, while direct stimulation of integrins using CHAMP peptides is sufficient to induce ER stress. Silencing fibronectin-binding integrins (α5, αv) using siRNA blocks ER stress induction in vitro, and endothelial-specific deletion of α5 or αv reduces ER stress at atheroprone regions in vivo. Mechanistically, integrin-dependent ER stress is not associated with increased protein synthesis, unfolded protein accumulation, or superoxide production. Scavenging superoxide with TEMPOL does not alleviate ER stress. However, pharmacological inhibition of ER stress using TUDCA suppresses proinflammatory and metabolic gene expression (bulk RNA-seq), without affecting NF-κB activation. Instead, TUDCA prevents activation of the JNK-c-Jun signaling axis, which we show to be essential for proinflammatory gene induction. Blocking this pathway using a JNK inhibitor (SP600125) or dominant-negative c-Jun (TAM67) abrogates inflammatory gene expression following oxLDL or disturbed flow. Together, these findings identify a novel mechanism by which fibronectin-integrin signaling promotes ER stress in response to mechanical and metabolic stressors, amplifying endothelial inflammation through JNK-c-Jun signaling.

Keywords:  Atherosclerosis; ER stress; Inflammation; Integrin; Oxidized LDL; Shear stress

DOI:  https://doi.org/10.1016/j.redox.2025.103911
Adv Sci (Weinh). 2025 Nov 26. e17086

ATF5-Dependent GDF15 Expression Mediates Anesthesia-Induced Neuroprotection Against Stroke.

Xianshu Ju, Tao Zhang, Jianchen Cui, Yulim Lee, Suho Lee, Ho Min Kim, Boohwi Hong, Jiho Park, Chul Hee Choi, Hyon-Seung Yi, Jun Young Heo, Woosuk Chung.

  Perioperative stroke is a rare but serious complication with a rising incidence in aging populations. Although preclinical studies consistently demonstrate that anesthetics such as sevoflurane can induce neuroprotective preconditioning against ischemic injury, clinical results have remained inconclusive. In this study, it is demonstrated that sevoflurane-induced neuroprotection is associated with the upregulation of genes involved in the mitochondrial unfolded protein response (UPRmt) and mitochondrial bioenergetic metabolism. The findings emphasize the critical role of ATF5 (activating transcription factor-5) in mediating these protective effects. Sevoflurane preconditioning markedly increases ATF5 expression and its downstream target GDF15, a key regulator of mitochondrial homeostasis, in the cerebral cortex. However, this protective mechanism is not activated in the aged brain, suggesting that aging impairs the ability to mount a mitochondrial stress response. The results imply a need for age-specific strategies to reduce perioperative stroke risk, including approaches that target mitochondrial function in elderly patients.

Keywords:  ATF5 / GDF15; anesthesia; preconditioning; stroke

DOI:  https://doi.org/10.1002/advs.202417086
Nat Med. 2025 Nov 28.

Targeting of HIF2-driven cachexia in kidney cancer.

Muhannad Abu-Remaileh, Laura A Stransky, Nikita Bhalerao, Nitin H Shirole, Qinqin Jiang, Eddy Saad, Marc Machaalani, Sean M Vigeant, Hilina Woldemichael, Charles Xu, Jing Lu, Hairong Wei, Zhihong Liu, William Sun, Kei Enomoto, Toni K Choueiri, Jason R Pitarresi, Steven A Carr, Namrata D Udeshi, William G Kaelin.

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.

DOI: https://doi.org/10.1038/s41591-025-04054-2
Cell Res. 2025 Nov 25.

Glucose starvation mimetic aldometanib removes immune barriers permitting mice with hepatocellular carcinoma to live to normal ages.

Hui-Hui Hu, Xuefeng Wang, Bin Lan, Haili Cheng, Hong Wen, Fangfang Chen, Jianfeng Wu, Mengqi Li, Jiazhou Chen, Jinhui Zhang, Dongxu Chen, Shiyu Lin, Jieyu Lin, Mingyang Yang, Zhenhua Wu, Zhong-Zheng Zheng, Fuqing Chen, Jianyin Zhou, Gang Chen, Yu Chen, Xianming Deng, Chen-Song Zhang, Jingfeng Liu, Sheng-Cai Lin.

Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.

DOI: https://doi.org/10.1038/s41422-025-01195-4
Cell Death Dis. 2025 Nov 26.

SKA3-mediated hypoxia tolerance and metabolic reprogramming promote liver metastasis in lung adenocarcinoma.

Zedong Sun, Minmin Zhou, Ningdan Song, Can Wang, Mingrui Liu, Simian He, Feifan Ji, Jiayu Chen, Lin Xu, Xiufen Zheng, Binhui Ren.

Late-stage lung adenocarcinoma (LUAD) frequently results in distant metastasis, with liver metastasis indicating the poorest prognosis. To successfully colonize the liver, metastatic LUAD cells must overcome its relatively hypoxic microenvironment. This study explores the metabolic adaptations that facilitate LUAD liver metastasis, identifying Spindle and Kinetochore Associated Protein 3 (SKA3) as a critical mediator. Under hypoxic conditions, SKA3 expression is significantly upregulated, driving glucose metabolic reprogramming in LUAD cells to enable survival within the liver's hypoxic niche. Mechanistically, SKA3 competitively binds to prolyl hydroxylase domain-containing protein 2 (PHD2), disrupting its interaction with hypoxia-inducible factor 1-alpha (HIF-1α). Consequently, stabilized HIF-1α further enhances glycolytic enzyme transcription, amplifying glycolysis and enabling adaptation to liver hypoxia. Furthermore, hypoxia upregulates the E3 ubiquitin ligase MDM2, promoting p53 ubiquitination and degradation, thereby relieving p53-mediated repression of SKA3 and further reinforcing the SKA3/HIF-1α axis. Interestingly, HIF-1α directly binds to the hypoxia response element (HRE) in the SKA3 promoter, creating a positive feedback loop to maintain high SKA3 expression. Thus, SKA3-mediated metabolic reprogramming significantly contributes to LUAD cells colonization and proliferation in the liver. Finally, our findings demonstrated that the SKA3/HIF-1α axis was critical for establishing hypoxia tolerance in LUAD cells, underscoring its potential as a therapeutic target for treating liver metastasis in LUAD.

DOI: https://doi.org/10.1038/s41419-025-08270-z
Int J Mol Sci. 2025 Nov 12. pii: 10932. [Epub ahead of print]26(22):

The Adaptation of Cancer Cells to Serum Deprivation Is Mediated by mTOR-Dependent Cholesterol Synthesis.

Bayansulu Ilyassova, Nargiz Rakhimgerey, Saule Rakhimova, Nazerke Satvaldina, Asset Daniyarov, Ainur Akilzhanova, Ulykbek Kairov, Dinara Begimbetova, Dos D Sarbassov.

  Cancer cells can sustain survival independently of exogenous growth factors. To investigate their adaptation to serum deprivation, we analyzed transcriptomic responses in two cancer cell lines. Transcriptome analysis revealed upregulation of mRNAs encoding cholesterol biosynthesis enzymes. This was a critical adaptive response, as a pharmacological inhibition of the pathway with statin triggered a robust apoptotic cell death accompanied by generation of a mitochondrial reactive oxygen species. The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, is known to be engaged in controlling lipid biosynthesis. We detected the high polysomal and preribosomal peaks not only in serum-containing medium but also under serum deprivation, indicating a high rate of protein synthesis and ribosomal biogenesis independent of serum. In addition, the inhibition of mTOR kinase activity substantially reduced polysome abundance, with a more pronounced effect in serum-deprived cancer cells. Notably, the mTOR kinase inhibition also prevented the upregulation of the cholesterol synthesis enzyme that established a direct link between mTOR activity, protein synthesis, and cholesterol biosynthesis. Together, our results show that cancer cells adapt to serum withdrawal by activating the cholesterol synthesis pathway through mTOR-dependent regulation of gene expression and protein synthesis, underscoring a critical mechanism of survival under serum withdrawal.

Keywords:  apoptosis; cholesterol synthesis; mechanistic target of rapamycin complex 1 (mTORC1); polysomes; protein synthesis; reactive oxygen species; serum deprivation

DOI:  https://doi.org/10.3390/ijms262210932
Biomed Pharmacother. 2025 Nov 24. pii: S0753-3322(25)00989-8. [Epub ahead of print]193 118795

Targeting the polyol pathway in NSCLC: Trans-(±)-kusunokinin demonstrates anti-migratory and survival benefits in in vitro and in vivo models.

Tanotnon Tanawattanasuntorn, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Mohammad Aarif Siddiqui, Vignesh Ramesh, Tienthong Thongpanchang, Khotchawan Bangpanwimon, Adisak Noonai, Paolo Ceppi, Potchanapond Graidist.

  Trans-(±)-kusunokinin (KU), a potential anticancer agent, has been reported as an AKR1B1 inhibitor, a key enzyme in the polyol pathway that converts glucose to sorbitol and subsequently to fructose via sorbitol dehydrogenase (SORD). This pathway contributes to oxidative stress and metabolic dysregulation which promote cancer progression and metastasis. Overexpression of AKR1B1 is associated with a poor prognosis in non-small cell lung cancer (NSCLC). This study aimed to elucidate the anticancer mechanism of KU in NSCLC. KU inhibited proliferation in a dose-dependent manner in human A549 cells and in mouse lung cancer cell lines derived from AAV-CRISPR/Cas9-induced KRASG12DP53-/- (KP) and KRASG12DP53-/-LKB1-/- (KPL) models. KU also significantly reduced cell migration in a dose-dependent manner under both normal and high glucose conditions. Remarkably, KU suppressed AKR1B1 and SORD expression, reduced intracellular sorbitol and fructose levels, and induced alterations in EMT-related proteins, such as ZEB1, E-cadherin, and vimentin, at a lower concentration than epalrestat (EP), a known AKR1B1 inhibitor. In vivo, KU significantly prolonged the survival of mice carrying KPL lung tumors compared to the control group. Collectively, these findings suggest that KU inhibits the aggressive phenotype of lung cancer by targeting the polyol pathway and modulating EMT processes. These results support its potential as a therapeutic candidate, highlighting the need for clinical evaluation in NSCLC patients.

Keywords:  AKR1B1; EMT; Lung cancer; Migration; SORD; Trans-(±)-kusunokinin

DOI:  https://doi.org/10.1016/j.biopha.2025.118795
Metabol Open. 2025 Dec;28 100417

Hepatic activating transcription factor 3 protects against systemic inflammation by attenuating lipotoxicity.

Chencheng Hu, Qian Yang, Runzhi Yu, Shuwei Hu, Bing Meng, Yanyong Xu.

   Background: Activating transcription factor 3 (ATF3) is known to play a key role in regulating lipid and lipoprotein metabolism. However, the effects of hepatic ATF3 on systemic inflammation and the underlying mechanisms remain unclear.
Methods: An adeno-associated virus with hepatocyte-specific promoter was used to construct mouse models with hepatocyte-specific overexpression or knockdown of ATF3.
Results: Overexpression of human ATF3 in hepatocytes prevented high-fat (HF) diet-induced systemic inflammation in C57BL/6J mice and reversed systemic inflammation in db/db mice. Conversely, hepatocyte-specific loss of ATF3 aggravated diet-induced systemic inflammation. In co-culture studies, the anti-inflammatory effect of hepatocyte ATF3 on adipose tissue was found to be dependent on the presence of free fatty acids mixture. Mechanistically, ATF3 ameliorated HF diet-induced hepatic lipid accumulation and lipotoxicity likely mediated through AMPKα activation.
Conclusion: Our findings collectively indicate that hepatocyte ATF3 alleviates systemic inflammation by reducing hepatic lipotoxicity, a mechanism that may involve the activation of AMPKα. Targeting hepatic ATF3 represents a promising therapeutic strategy for systemic inflammation induced by hepatic lipotoxicity.

Keywords:  ATF3; Lipid accumulation; Lipotoxicity; Systemic inflammation

DOI:  https://doi.org/10.1016/j.metop.2025.100417