bims-cesirm 2025-07-27 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–07–27
24 papers selected by
Tigist Tamir, University of North Carolina

Nitrogen limitation causes a seismic shift in redox state and phosphorylation of proteins implicated in carbon flux and lipidome remodeling in Rhodotorula toruloides.
Metabolic reprogramming and functional crosstalk within the tumor microenvironment (TME) and A Multi-omics anticancer approach.
Hypoxia-Induced Suppression of FAM99A and FAM99B Contributes to the Development and Glucose Metabolic Reprogramming of Hepatocellular Carcinoma.
The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
Metabolic adaptations of brain metastasis.
Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.
UBD-mediated glycolytic reprogramming promotes M2 macrophage polarization in ovarian cancer immune evasion.
Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.
The ferroptotic effect of NRF2-GCLM signaling axis derived by radiotherapy of esophageal squamous cell cancer: the vivo study.
Polycyclic Aromatic Hydrocarbon Aggravates High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease through Disturbing Hepatocyte Sphingolipid Metabolism.
OCIAD2 Promotes Cancer Progression via Metabolic Reprogramming in Lung Adenocarcinoma.
BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.
Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.
Phosphoglycerate dehydrogenase stabilizes protein kinase C delta type mRNA to promote hepatocellular carcinoma progression.
A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis.
Proteomic analysis reveals inhibition of mevalonate and Glycolysis pathways in hepatocytes by 27-hydroxycholesterol.
APEX2-based quantitative proteomics of LAT and CD3σ interactomes in living human Jurkat T cells unveils new interactors.
PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate.
Nrf2-driven redox coupling of tumour and associated adipose tissue during early tumour growth in an orthotopic breast cancer model.
Genomic insertion of ancestral uricase into human liver cells to determine metabolic consequences of pseudogenization.
Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.
The Reciprocal Relationship Between Cell Adhesion Molecules and Reactive Oxygen Species.
DGAT2 reduction and lipid dysregulation drive psoriasis development in keratinocyte-specific SPRY1-deficient mice.

Biotechnol Biofuels Bioprod. 2025 Jul 21. 18(1): 80

Nitrogen limitation causes a seismic shift in redox state and phosphorylation of proteins implicated in carbon flux and lipidome remodeling in Rhodotorula toruloides.

Austin Gluth, Jeffrey J Czajka, Xiaolu Li, Kent J Bloodsworth, Josie G Eder, Jennifer E Kyle, Rosalie K Chu, Bin Yang, Wei-Jun Qian, Pavlo Bohutskyi, Tong Zhang.

BACKGROUND: Oleaginous yeast are prodigious producers of oleochemicals, offering alternative and secure sources for applications in foodstuff, skincare, biofuels, and bioplastics. Nitrogen starvation is the primary strategy used to induce oil accumulation in oleaginous yeast as part of a global stress response. While research has demonstrated that post-translational modifications (PTMs), including phosphorylation and protein cysteine thiol oxidation (redox PTMs), are involved in signaling pathways that regulate stress responses in metazoa and algae, their role in oleaginous yeast remain understudied and unexplored.
RESULTS: Towards linking the yeast oleaginous phenotype to protein function, we integrated lipidomics, redox proteomics, and phosphoproteomics to investigate Rhodotorula toruloides under nitrogen-rich and starved conditions over time. Our lipidomics results unearthed interactions involving sphingolipids and cardiolipins with ER stress and mitophagy. Our redox and phosphoproteomics data highlighted the roles of the AMPK, TOR, and calcium signaling pathways in regulation of lipogenesis, autophagy, and oxidative stress response. As a first, we also demonstrated that lipogenic enzymes including fatty acid synthase are modified as a consequence of shifts in cellular redox states due to nutrient availability.
CONCLUSIONS: We conclude that lipid accumulation is largely a consequence of carbon rerouting and autophagy governed by changes to PTMs, and not increases in the abundance of enzymes involved in central carbon metabolism and fatty acid biosynthesis. Our systems-level approach sets the stage for acquiring multidimensional data sets for protein structural modeling and predicting the functional relevance of PTMs using Artificial Intelligence/Machine Learning (AI/ML). Coupled to those bioinformatics approaches, the putative PTM switches that we delineate will enable advanced metabolic engineering strategies to decouple lipid accumulation from nitrogen limitation.

DOI: https://doi.org/10.1186/s13068-025-02657-y
Med Oncol. 2025 Jul 24. 42(9): 373

Metabolic reprogramming and functional crosstalk within the tumor microenvironment (TME) and A Multi-omics anticancer approach.

Rashid Mir, Jamsheed Javid, Mohammad Fahad Ullah, Salma Alrdahe, Ibrahim Abdullah Altedlawi, Syed Khalid Mustafa, Mohammed M Jalal, Malik A Altayar, Aziz Dhaher Albalawi, Muhammed Kamal Abunab, Hanadi Saud Alanazi, Jameel Barnawi, Naseh A Algehainy, Faisal H Altemani, Faris J Tayeb.

  Tumors are characterized by a complex interplay of various cell types, each contributing to the unique metabolic landscape of the tumor microenvironment (TME). The key metabolic interactions explored within the TME include nutrient competition, symbiotic nutrient exchange, and the role of metabolites as signaling messengers. Metabolic flexibility allows cancer cells to survive and proliferate even under harsh conditions, such as hypoxia and nutrient deprivation. Recent advances highlight that tumors possess inherent metabolic heterogeneity, underpinning the intricate web of intra- and extra- tumoral metabolic connections. Harnessing the power of multi-omics approaches offers unprecedented insights into this metabolic diversity, paving the way for innovative therapeutic strategies targeting the metabolic crosstalk within the tumor microenvironment. Multi-omics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics data, provide a comprehensive view of tumor metabolism. This holistic approach allows for the identification of key metabolic pathways and regulatory networks that drive tumor progression, as well as potential vulnerabilities that can be exploited for therapeutic intervention. In this review, we discuss the metabolic symphony within the TME, the intricacies of tumor metabolism through multi-omics methodologies, and the prospects of devising innovative and effective cancer therapeutic strategies.

Keywords:  Cancer; Cancer therapeutic strategies; Metabolic reprogramming; Multi-omics; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-025-02945-5
FASEB J. 2025 Jul 31. 39(14): e70869

Hypoxia-Induced Suppression of FAM99A and FAM99B Contributes to the Development and Glucose Metabolic Reprogramming of Hepatocellular Carcinoma.

Cang-Sang Song, Guo-Hui Wang, Pan-Pan Mao, Han-Shu Zhang, Lu Liu, Xue-Jiao Ma, Xing-de Li, Yang Zhang.

  Hepatocellular carcinoma (HCC) is a highly aggressive and highly malignant cancer. Glucose metabolic reprogramming provides sufficient ATP to support HCC's rapid proliferation and invasion. Consequently, this study intends to investigate the effects of FAM99A and FAM99B on glucose metabolic reprogramming, and provide new insights for HCC treatment. Changes in malignant phenotypes and glycolysis-related indices of HCC cells (HCCLM3 and HEPG2) were assessed after exogenous regulation of FAM99A and FAM99B under hypoxic conditions. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glycolytic proton efflux rate (glycoPER) were measured using the Seahorse XF Glycolysis Rate Assay Kit (103344-100, Agilent). HCCLM3 cells were subjected to transcriptome and smallRNA sequencing to identify differentially expressed genes (DEGs) and miRNAs (DE-miRNAs) associated with FAM99A and FAM99B. Under hypoxic conditions, the expression of FAM99A and FAM99B was significantly downregulated in HCC cells. Overexpression of FAM99A or FAM99B significantly inhibited HCC cell proliferation, wound healing, and invasion. Moreover, they effectively decreased intracellular glucose, extracellular lactate, ATP, glycolysis-related enzymes, ECAR, and glycoPER, and increased pH, extracellular glucose, and mitoOCR/glycoPER. A total of 31 DEGs and 15 DE-miRNAs were present in HCCLM3 cells overexpressing FAM99A, and 375 DEGs and 68 DE-miRNAs were identified in HCCLM3 cells overexpressing FAM99B. These DEGs and DE-miRNA targets were involved in cell cycle, apoptosis, metastasis, extracellular matrix remodeling, and metabolic reprogramming. The FAM99B-associated ceRNA network contained one DE-miRNA and 10 DEGs, and their expression differences were consistent with the sequencing results. Hypoxia-induced suppression of FAM99A and FAM99B facilitates proliferation, metastasis, and glucose metabolic reprogramming of HCC.

Keywords:  LncRNA; bioinformatics; competing endogenous RNA; glucose metabolic reprogramming; hepatocellular carcinoma; hypoxia

DOI:  https://doi.org/10.1096/fj.202501058R
Cells. 2025 Jul 17. pii: 1096. [Epub ahead of print]14(14):

The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.

Eun Jung Choi, Yoon Young Jang, Eun Joo Choi, Chang Joo Oh.

  Lactate, once regarded as a metabolic byproduct, is now recognized as a critical immunometabolic regulator that shapes immune responses in both physiological and pathological contexts. This review examines how lactate accumulation occurs across diverse disease settings, including cancer, sepsis, and diabetes, through mechanisms such as hypoxia, mitochondrial dysfunction, and pharmacologic intervention. We then explore how lactate modulates immunity via four integrated mechanisms: transporter-mediated flux, receptor signaling (e.g., GPR81), context-dependent metabolic rewiring, and histone/protein lactylation. Particular emphasis is placed on the dichotomous effects of endogenous versus exogenous lactate, with the former supporting glycolytic effector functions and the latter reprogramming immune cells toward regulatory phenotypes via redox shifts and epigenetic remodeling. The review also highlights how the directionality of lactate transport, and the metabolic readiness of the cell determine, whether lactate sustains inflammation or promotes resolution. After analyzing emerging data across immune cell subsets and disease contexts, we propose that lactate serves as a dynamic rheostat that integrates environmental cues with intracellular metabolic and epigenetic programming. Understanding these context-dependent mechanisms is essential for the rational design of lactate-targeted immunotherapies that aim to modulate immune responses without disrupting systemic homeostasis.

Keywords:  anti-inflammation; immunometabolism; lactate

DOI:  https://doi.org/10.3390/cells14141096
Cell Death Dis. 2025 Jul 21. 16(1): 539

Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.

Antigoni Diokmetzidou, Aurora Maracani, Anna Pellattiero, Mauricio Cardenas-Rodriguez, Erwan A Rivière, Luca Scorrano.

In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07878-5
Nat Rev Cancer. 2025 Jul 24.

Metabolic adaptations of brain metastasis.

Pravat Kumar Parida, Srinivas Malladi.

Brain metastases remain a major clinical challenge, characterized by high mortality rates and often limited therapeutic options. The cellular and molecular processes that drive brain metastases are highly intricate, underscored by dynamic metabolic adaptations that enable tumour cells to thrive in the unique microenvironment of the brain. Emerging clinical and preclinical evidence reveals that these metabolic adaptations are not uniform but vary based on the tumour's tissue of origin, oncogenomic landscape and capacity to endure nutrient stress. Notably, proliferative and dormant metastatic cells within the brain exhibit distinct metabolic profiles, highlighting the complexity of targeting these cells. Key metabolic pathways, including glucose, fatty acid and amino acid metabolism, are co-opted not only to sustain cancer cell survival and growth but also to modulate interactions with resident brain cells, reshaping their function to support metastasis. Importantly, this metabolic heterogeneity underscores the inadequacy of a one-size-fits-all therapeutic approach. Here, we review the adaptive metabolic reprogramming that facilitates brain metastases and discuss emerging strategies to tailor interventions aimed at preventing and treating overt brain metastases.

DOI: https://doi.org/10.1038/s41568-025-00848-1
FASEB J. 2025 Jul 31. 39(14): e70834

Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.

Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Alena Sipka, Antonia W Shand, Natasha Nassar, Sally L Dunwoodie.

  Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in hundreds of cellular processes. Genetic disruption of NAD de novo synthesis causes congenital NAD deficiency disorder (CNDD), characterized by multiple congenital malformations or death in utero. Patient outcomes are highly variable, likely due to differences in the availability of maternal NAD precursors vitamin B3 and tryptophan to the embryo and its extraembryonic tissues. Here, maternal plasma and yolk sac NAD metabolomes, embryonic NAD levels, and pregnancy outcomes were quantified in a CNDD mouse model to determine how maternal circulatory NAD precursor provision affects pregnancy outcome and to identify metabolic markers of CNDD risk. Maternal levels of nicotinamide positively correlated with embryonic NAD levels, highlighting its central role for embryonic NAD metabolism. Levels of nicotinamide-derived excretion metabolites were the best predictors of adverse pregnancy outcome. NAD metabolomic analysis of pregnant women confirmed the relationship between dietary NAD precursor intake and circulatory nicotinamide and derived excretion product levels seen in mice, as women taking vitamin B3 supplements had elevated levels. Furthermore, mouse embryos with genetic disruption of NAD de novo synthesis (Haao-/-) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD de novo from tryptophan. Metabolites originating from Haao-/- embryos were detectable in maternal plasma, showing that embryonic NAD metabolism also affects maternal circulation. Together, our findings elucidate the complex interplay between NAD metabolism of mother and conceptus and identify metabolic markers in maternal circulation that predict risk of NAD deficiency-related adverse pregnancy outcomes.

Keywords:  NAD; congenital malformation; embryonic development; metabolism; pregnancy

DOI:  https://doi.org/10.1096/fj.202500708RR
J Cell Commun Signal. 2025 Sep;19(3): e70034

UBD-mediated glycolytic reprogramming promotes M2 macrophage polarization in ovarian cancer immune evasion.

Nana Zhang, Fengming Zhao, Hailong Chen, Juli Wang, Haiyan Li.

  Ovarian cancer (OC) is one of the most common malignant tumors in women, with immunotherapy resistance (ITR) being a major challenge. Glycolytic metabolic reprogramming has been shown to play a crucial role in the tumor immune microenvironment and immune evasion, yet the underlying mechanisms remain unclear. This study aims to investigate the role of Ubiquitin D (UBD) in OC immunotherapy, particularly its regulation of macrophage polarization through glycolytic metabolism. Using data from the Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases, combined with proteomics techniques, we analyzed the expression of UBD in OC tissues and its correlation with key glycolytic enzymes. Through lentiviral-mediated gene manipulation and in vivo mouse models, we evaluated the effects of UBD on macrophage polarization, glycolytic metabolism, and immunotherapy. The results indicate that UBD promotes M2 macrophage polarization through glycolytic reprogramming, enhancing immune evasion and ITR in OC. Inhibiting UBD or targeting glycolytic pathways may provide new strategies for improving OC immunotherapy.

Keywords:  glycolytic metabolism; immunotherapy resistance; macrophage polarization; ovarian cancer; tumor microenvironment; ubiquitin D

DOI:  https://doi.org/10.1002/ccs3.70034
FEBS J. 2025 Jul 24.

Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.

Suman Pakhira, Sib Sankar Roy.

  Metabolic alterations are increasingly recognized as fundamental features of cancer. Recent studies have highlighted the involvement of altered fatty acid oxidation (FAO) at different stages of tumor development. As the rate-limiting enzyme of FAO, CPT1 plays a crucial role in these metabolic adaptations in cancer cells. However, the regulation of CPT1 expression and activity in tumor cells still requires detailed investigation. Our studies reveal that CPT1A, a variant of CPT1, is significantly upregulated in ovarian cancer (OC) and correlates with poor prognosis. Inhibition of CPT1A, either by siRNA-mediated knockdown or by etomoxir, reduces the migratory and invasive properties of the OC cells. CPT1A exerts these effects by modulating the expression of epithelial-to-mesenchymal transition (EMT)-associated genes at transcriptional and protein levels. Growth factors such as transforming growth factor beta (TGFβ) are abundant in the tumor microenvironment and modulate the metabolic profile of tumors, thereby promoting EMT. Our findings demonstrate that TGFβ treatment increases the rate of FAO in ovarian cancer cells. Mechanistically, TGFβ mediates this effect by enhancing CPT1A expression and its enzymatic activity in OC cells through an AMPK-dependent pathway. Additionally, we identified NRF2 as a potential transcriptional regulator of CPT1A within the context of TGFβ-AMPK signaling. Finally, inhibiting CPT1A successfully attenuates TGFβ-induced EMT in ovarian cancer cells. Cumulatively, our study underscores the role of CPT1A-mediated FAO in facilitating ovarian cancer progression through TGFβ-induced EMT.

Keywords:  CPT1A; EMT; FAO; TGFβ; ovarian cancer

DOI:  https://doi.org/10.1111/febs.70193
Sci Rep. 2025 Jul 24. 15(1): 26917

The ferroptotic effect of NRF2-GCLM signaling axis derived by radiotherapy of esophageal squamous cell cancer: the vivo study.

Yiliyaer Nuerrula, Zhaoyuan Xue, Aidiye Tiliwalidi, Xueling Xiao, Zihao Dong, Jingkun Liu, Mayinur Eli.

  Nuclearfactor erythroidderived 2-like 2(NRF2) is a major regulator of the body's antioxidant defense system and a key protein in the process of ferroptosis, which is upregulated in a variety of malignancies. This study aimed to investigate the role of NRF2 in the pathogenesis and progression of Esophageal squamous cell carcinoma (ESCC) from the in vivo and clinical levels. The expression levels of NRF2, Glutamate-Cysteine Ligase Modifier Subunit (GCLM) and Glutathione Peroxidase 4 (GPX4) in ESCC and adjacent normal tissues were detected by immunohistochemistry in 61 tissue biopsies collected from patients diagnosed with ESCC. The xenograft model was used to detect the growth of nude mouse tumors and the changes of ferroptosis-related indexes in different experimental groups. Co-immunoprecipitation was used to demonstrate the downstream interacting proteins of NRF2. The results showed that the expression of NRF2, GCLM and GPX4 was increased in ESCC compared with adjacent non-tumor tissues, and the high expression of NRF2, GCLM and GPX4 was significantly associated with poor prognosis. NRF2 overexpression promotes changes in tumor growth and ferroptosis-related markers in xenograft models. In addition, NRF2 overexpression was associated with upregulation of GCLM and GPX4. CO-IP demonstrated that GCLM is a downstream protein of NRF2. Bio-informatics analysis showed that GCLM was differentially expressed in a variety of tumors, and was significantly correlated with the prognosis of patients, as well as the infiltration of a variety of immune cells. Finally, GCLM promotes tumor growth and radiotherapy resistance to ESCC in vivo, and can therefore be used as a molecular target for tumor therapy.

Keywords:  Cell line-derived xenograft; ESCC; GCLM; NRF2; Prognosis; Radiotherapy

DOI:  https://doi.org/10.1038/s41598-025-10414-2
Environ Pollut. 2025 Jul 16. pii: S0269-7491(25)01219-9. [Epub ahead of print] 126846

Polycyclic Aromatic Hydrocarbon Aggravates High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease through Disturbing Hepatocyte Sphingolipid Metabolism.

Hui-Ru Kuo, Yu-Fen Chung, Li-Ting Wang, Chih-Wen Wang, Shih-Hsien Hsu, Li-Chen Chen, Ming-Hong Lin, Shau-Ku Huang, Kwei-Yan Liu.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition, with polycyclic aromatic hydrocarbons (PAHs) as a potential risk factor; however, the regulatory mechanisms remain unclear. PAH exposure oxidizes sphingosine-1-phosphate (S1P) lyase (S1PL) at position 317, reducing lyase activity and increasing S1P levels which is linked to MASLD progression. This study investigates how PAH exposure influences MASLD development and explores the role of S1PL and S1P in this process. C57BL/6J wild-type (WT) and mutant Sgpl1-knock-in (KI) (C317A, rendering resistance to oxidation) were fed either control diet (CD) or high-fat diet (HFD) for 8 weeks. Mice were treated with 500 μg/kg indeno(1,2,3-cd)pyrene (IP) every three days by oral gavage. Hepatocytes were isolated using classic two-step collagenase perfusion method and treated with IP or S1P. Increased lipid accumulation and upregulated S1P levels were observed in the MPH upon IP treatment. Reduced weight gain, fatty liver, and serum S1P levels were observed in Sgpl1-KI mice compared to those of WT mice upon HFD and IP treatments. Inhibition of S1PL increased lipid accumulation and S1P levels in Sgpl1-KI MPHs, whereas pharmacological inhibition of sphingosine kinase 1 (SphK1), not SphK2, decreased IP-induced lipid accumulation and S1P levels in WT MPH. S1P receptor 2 (S1pr2)-null MPHs developed alleviated IP-induced lipid accumulation as compared with WT MPHs. PAH elevated S1P via SphK1- and S1PL-mediated pathways, thereby increasing lipid accumulation through the S1P/S1PR2 axis in hepatocytes, worsening HFD-induced MASLD.

Keywords:  Metabolic dysfunction-associated steatotic liver disease; Polycyclic aromatic hydrocarbon; Sphingosine-1-phosphate; Sphingosine-1-phosphate lyase; Sphingosine-1-phosphate receptor 2

DOI:  https://doi.org/10.1016/j.envpol.2025.126846
J Proteome Res. 2025 Jul 21.

OCIAD2 Promotes Cancer Progression via Metabolic Reprogramming in Lung Adenocarcinoma.

Yi-Hui Huang, Wen-Hsin Chang, Chi-Ya Shen, Kang-Yi Su, Gee-Chen Chang, Jin-Shing Chen, Wen-Yao Lee, Yu-Ju Chen, Sung-Liang Yu.

  Given the limited proteomic insights and high incidence of lung adenocarcinoma, further investigation of uncharacterized proteins in cancer progression remains crucial. In this study, a poorly characterized protein, OCIA domain-containing 2 (OCIAD2), encoded by chromosome 4 was identified as being upregulated in lung adenocarcinoma from our previous proteogenomics data using the Taiwan Cancer Moonshot cohort. OCIAD2 was highly expressed in tumor tissues in 95.5% of lung adenocarcinoma patients in our cohort, with elevated expression correlating with worse survival. Functional studies revealed that the silencing of the OCIAD2 decreased cell migration, invasion, and colony-forming abilities. Gene Set Enrichment Analysis (GSEA) indicated the involvement of OCIAD2 in oxidative phosphorylation (OXPHOS). Subsequently, mitochondrial metabolic assay demonstrated that OCIAD2 impairs OXPHOS function, accompanied by a metabolic shift toward glycolysis. These findings suggest that OCIAD2 promotes cancer progression through metabolic reprogramming, highlighting the role of OCIAD2 as a potential biomarker and therapeutic target for lung adenocarcinoma.

Keywords:  Chromosome-centric Human Proteome Project; Lung adenocarcinoma; Ovarian Cancer Immunoreactive Antigen Domain Containing 2; Uncharacterized protein existence level 1

DOI:  https://doi.org/10.1021/acs.jproteome.5c00273
J Pathol. 2025 Jul 21.

BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.

Qiang Zhang, Hongxu Sheng, Dongnan Ping, Jixiang Gao.

  In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8+ T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8+ T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8+ T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8+ T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of GOT2 in LUSC reinforced the exhaustion of cocultured CD8+ T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of GOT2 effectively curbed tumor growth and boosted the CD8+ T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366-372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of BIRC3 in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8+ T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8+ T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords:  BIRC3; CD8+ T cells; GOT2; immune response; lung squamous cell carcinoma; ubiquitination

DOI:  https://doi.org/10.1002/path.6448
Sci Signal. 2025 Jul 22. 18(896): eadp6006

Deletion of PTP1B in cardiomyocytes alters cardiac metabolic signaling to protect against cardiomyopathy induced by a high-fat diet.

Yan Sun, Abhishek Kumar Mishra, Vasanth Chanrasekhar, Michaela Door, Chase W Kessinger, Bing Xu, Peiyang Tang, Yunan Gao, Sarah Kamli-Salino, Katherine Nelson, Mirela Delibegovic, E Dale Abel, Jonanthan A Kirk, Maria I Kontaridis.

Cardiomyocytes (CMs) normally use fatty acid oxidation (FAO) as their primary energy source. In response to pathological stress, the substrate preference of CMs switches from FAO to glucose metabolism, leading to the development of heart failure. Obesity increases this pathological risk of cardiovascular disease. We focused on protein tyrosine phosphatase 1B (PTP1B), an inhibitor of insulin signaling, the abundance and activity of which are increased in brain, muscle, and adipose tissues in obese and/or diabetic animals and in obese human patients. We generated mice with CM-specific deficiency in PTP1B (PTP1Bfl/fl::ꭤMHCCre/+) to investigate the CM-specific role of PTP1B in response to cardiac dysfunction induced by high-fat diet (HFD) feeding. Although no physiological or functional cardiac differences were observed at baseline, PTP1Bfl/fl::ꭤMHCCre/+ mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and cardiac steatosis induced by HFD feeding. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased FAO and lipolysis but reduced glucose metabolism. Furthermore, phosphoproteomics analyses and mechanistic studies identified an axis involving the kinases PKM2 and AMPK downstream of PTP1B in the heart, which collectively acted to promote FAO and suppress lipogenesis. Together, these results suggest that CM-specific deletion of PTP1B prevents a substrate switch from FAO to glucose metabolism, protecting the heart against the development of HFD-induced cardiac hypertrophy and dysfunction.

DOI: https://doi.org/10.1126/scisignal.adp6006
Signal Transduct Target Ther. 2025 Jul 18. 10(1): 236

Phosphoglycerate dehydrogenase stabilizes protein kinase C delta type mRNA to promote hepatocellular carcinoma progression.

Bin Cheng, Pai Peng, Shi Chen, Rui Liu, Xiaosong Li, Ke Wang, Jing Ma, Kai Wang, Ni Tang, Ailong Huang.

Metabolic reprogramming not only reshapes cellular bioenergetics but also profoundly influences RNA metabolism through metabolite signaling and the RNA-binding activities of metabolic enzymes. Emerging evidence highlights that certain metabolic enzymes act as RNA-binding proteins (RBPs) to regulate gene expression and promote tumor progression. However, the non-catalytic post-transcriptional regulatory functions of metabolic enzymes in hepatocellular carcinoma (HCC) remain largely unexplored. In this study, we performed RNA-protein interactome profiling to identify potential non-canonical RBPs in HCC cells and established phosphoglycerate dehydrogenase (PHGDH) as a functional RBP. We further uncovered a previously unrecognized RNA-binding domain in PHGDH that directly binds cellular mRNAs and plays a key role in HCC cell proliferation. Mechanistically, PHGDH bound directly to the 3'untranslated region (3'UTR) of protein kinase C delta type (PRKCD) mRNA via its RNA-binding domain, thereby stabilizing the transcript and elevating PRKCD protein levels. PHGDH-dependent PRKCD upregulation promoted HCC progression by inducing mitophagy and inhibiting apoptosis. Additionally, decoy oligonucleotides that specifically block the RNA-binding activity of PHGDH markedly impaired its regulation of target genes and suppress HCC cell proliferation. Combination therapy using decoy oligonucleotides or the PRKCD inhibitor sotrastaurin with sorafenib synergistically inhibited HCC progression. Collectively, our findings reveal a non-canonical role of PHGDH in regulating mRNA metabolism and modulating mitophagy. Targeting the RNA-binding activity of PHGDH with decoy oligonucleotides represents a promising therapeutic strategy for HCC.

DOI: https://doi.org/10.1038/s41392-025-02304-w
Nat Cell Biol. 2025 Jul 18.

A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis.

Hemeng Zhang, Jialin Ma, Chunyan Hou, Xuehui Luo, Shiya Zhu, Yihan Peng, Changmin Peng, Ping Li, Heng Meng, Yuqi Xia, Zhinuo Jiang, Susree Modepalli, Anju Duttargi, Gary M Kupfer, Mengjiao Cai, Heng Zhang, Junfeng Ma, Juanjuan Li, Suxia Han, Huadong Pei.

Reactive oxygen species (ROS) play a crucial role in lipid peroxidation and the initiation of ferroptosis, markedly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, as a sensor for ROS during ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT O-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2's nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting ferroptosis. The elevated OGT-FOXK2-SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-O-GlcNAcylation cascade that integrates ROS signalling, O-GlcNAcylation, FOXK2-mediated SLC7A11 transcription and resistance to both ferroptosis and chemoradiotherapy.

DOI: https://doi.org/10.1038/s41556-025-01722-w
Biochem J. 2025 Jul 22. pii: BCJ20253035. [Epub ahead of print]

Proteomic analysis reveals inhibition of mevalonate and Glycolysis pathways in hepatocytes by 27-hydroxycholesterol.

Wan-Seog Shim, Seulah Lee, Bakhovuddin Azamov, Chanhee Lee, Yeowon Kang, Kwang Min Lee, Changwan Hong, Sang-Mo Kwon, Koanhoi Kim, Dongjun Lee, Jong Hyuk Yoon, Parkyong Song.

  27-Hydroxycholesterol (27OHC), an endogenous oxysterol, has been implicated in various physiological processes, including regulation of estrogen receptor activity and lipid metabolism. However, studies on how 27OHC affects the metabolic changes associated with lipogenesis inhibition in the liver remain limited. This study aimed to investigate the systemic effects of 27OHC on hepatocytes through a comparative proteomic analysis of the proteomes in the 27OHC-treated AML12 cells. Ingenuity Pathway Analysis revealed significant downregulation of certain metabolic pathways, such as cholesterol biosynthesis and glycolysis, which are highly associated with lipid metabolism, following 27OHC treatment. Furthermore, in vitro biochemical analysis revealed significant inhibition of the expression of genes associated with the mevalonate pathway and a decrease in the total cellular cholesterol levels in AML12 cells and primary hepatocytes following 27OHC treatment. In addition, it was observed that 27OHC significantly reduced the transcripts levels of critical glycolytic enzymes such as aldolase, phosphofructokinase, and pyruvate kinase. This inhibition resulted in decreased lactate production and extracellular acidification (ECAR), indicating suppression of glycolytic flux. Concurrently, we proved that downregulation of reactive oxygen species generation and HIF-1α expression following 27OHC treatment partially contributed to glycolysis inhibition. Overall, we demonstrated the inhibitory effects of 27OHC on the hepatic mevalonate pathway and glycolysis, revealing a novel mechanism by which 27OHC regulates lipid metabolism. As the accumulation of cholesterol and lipids promotes hepatic fatty liver disease and increased glycolysis contributes to triacylglycerol maturation, the suppressive effects of 27OHC on hepatic lipid and glucose metabolism may contribute to protect against fatty liver development.

Keywords:  27-hydroxycholesterol; Nrf2/HO-1 signaling; Proteomics; glycolysis; mevalonate pathway

DOI:  https://doi.org/10.1042/BCJ20253035
J Cell Sci. 2025 Jul 22. pii: jcs.263981. [Epub ahead of print]

APEX2-based quantitative proteomics of LAT and CD3σ interactomes in living human Jurkat T cells unveils new interactors.

Juan-José Saez, Michaël Richard, Vivien Caillens, Stéphanie Dogniaux, Federico Marconi, Florent Dingli, Damarys Loew, Hermine Ferran, Loredana Saveanu, Claire Hivroz, Laurence Bataille.

  TCR stimulation induces a signaling cascade starting by the phosphorylation of immunoreceptor tyrosine-based activation motif (ITAMs) present in the TCR-CD3 complex. This is followed by the phosphorylation of proteins including LAT, which once phosphorylated interacts with multiple proteins allowing signal diversification and amplification. We take advantage of APEX2-based peroxidase- catalyzed proximity labeling combined with quantitative mass spectrometry to track the formation of CD3σ and LAT interactome dynamics in TCR activated Jurkat cells. We find more than 1 000 high confidence proteins for each bait and provide a quantitative molecular map of proteins enriched or reduced from the vicinity of CD3σ and LAT, after stimulation. We detail and compare the recruitment kinetics of signaling proteins to CD3σ and LAT and identify uncharacterized mediators of T cell activation. We show that the kinase MARK2, which is in the proximity of LAT and CD3σ at resting state and lost upon activation, is a negative regulator of cytokine production by T cells. This study provides a resource for uncovering the complex signaling networks that regulate TCR activation and highlights new players of this signaling cascade.

Keywords:  CD3σ; LAT; Proximity labeling assay; Quantitative proteomic; TCR signaling

DOI:  https://doi.org/10.1242/jcs.263981
Nat Commun. 2025 Jul 22. 16(1): 6736

PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate.

Pianpian Lin, Yijun Qi, Huiying Chu, Hongyu Wu, Yajuan Zhang, Xiaolan Huang, Chen Li, Xiaoyan Xu, Hong Gao, Rong Zeng, Guohui Li, Weiwei Yang.

Emerging evidence indicates that metabolic signals-including nutrient availability, biosynthetic intermediates, and energy balance-are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation.

DOI: https://doi.org/10.1038/s41467-025-62111-3
Free Radic Biol Med. 2025 Jul 18. pii: S0891-5849(25)00842-1. [Epub ahead of print]239 63-79

Nrf2-driven redox coupling of tumour and associated adipose tissue during early tumour growth in an orthotopic breast cancer model.

Tamara Zakic, Jelena Jevtic, Maja Vukobratovic, Strahinja Djuric, Igor Golic, Aleksandra Korac, Vanja Pekovic-Vaughan, Aleksandra Jankovic, Bato Korac.

  The redox-based two-way communication between breast cancer cells and their tumour microenvironment (TME) contributes significantly to the establishment of the malignant phenotype. Due to its well-established role in redox-metabolic reprogramming, Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) has emerged as a potentially key player in the bilateral interaction between breast cancer cells and cancer-associated adipose tissue (CAAT), the main cellular component of the TME. In this study, we used an orthotopic model of Nrf2+/+ luminal type B breast cancer in wild-type (WT) mice and mice lacking functional Nrf2 (Nrf2KO) to investigate the role of Nrf2-driven redox coupling between breast cancer and CAAT. To this end, we examined the expression profiles, localisation, and activity of the main antioxidant defence (AD) enzymes in breast tumour tissue in the Nrf2+/+ or Nrf2-/- host environment at different phases of early tumour growth. In addition, we analysed key enzymes involved in nicotinamide adenine dinucleotide phosphate (NADPH) metabolism. We demonstrate the establishment of a distinct redox profile of breast cancer cells in the Nrf2-/- TME when compared to WT TME. Furthermore, the activity and protein levels of AD enzymes in CAAT showed both Nrf2-dependent and/or tumour-dependent changes. Taken together, these results highlight the importance of Nrf2-driven modulations in the host TME for establishing the redox profile of breast cancer. Moreover, the initial phase of early tumour growth appears most susceptible to the absence of functional Nrf2 in the host TME, thus providing a new potential therapeutic target point for breast cancer therapy.

Keywords:  Antioxidant defence; Breast cancer; Cancer-associated adipose tissue; Nrf2; Redox reprogramming; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.027
Sci Rep. 2025 Jul 18. 15(1): 26093

Genomic insertion of ancestral uricase into human liver cells to determine metabolic consequences of pseudogenization.

Lais de Lima Balico, Eric A Gaucher.

The biological role of urate (uric acid) during primate evolution has been unclear ever since it was discovered over 100 years ago that humans have unusually high levels of the small molecule compared to most other mammals. Humans (including all apes) are uncharacteristically susceptible to the build-up of urate because we no longer have a functional uricase enzyme capable of oxidizing this highly insoluble molecule. We have now utilized CRISPR technology to insert functional ancestral uricase into the genome of human liver cells to address recent metabolic hypotheses that our ancestral primates inactivated uricase as a mechanism to increase triglyceride production in response to fructose and/or starvation. Uricase expression is confirmed in both hepatocyte monolayer and spheroid tissue cultures, and its expression reduces intracellular urate levels. The presence of uricase is also shown to prevent an increase in triglyceride production upon cellular uptake of fructose in both culture conditions. Our results make progress that further describes a potential advantageous biological role of urate during primate evolution.

DOI: https://doi.org/10.1038/s41598-025-10551-8
Oncogene. 2025 Jul 22.

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.

Míriam Tarrado-Castellarnau, Carles Foguet, Josep Tarragó-Celada, Marc Palobart, Claudia Hernández-Carro, Jordi Perarnau, Erika Zodda, Ibrahim H Polat, Silvia Marin, Alejandro Suarez-Bonnet, Juan José Lozano, Mariia Yuneva, Timothy M Thomson, Marta Cascante.

Several mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such resistance mechanisms represent optimal targets has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenastat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenastat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenastat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenastat. In conclusion, combination with Telaglenastat optimally forestalls acquired resistance to Palbociclib in cancer cells.

DOI: https://doi.org/10.1038/s41388-025-03495-w
Cells. 2025 Jul 17. pii: 1098. [Epub ahead of print]14(14):

The Reciprocal Relationship Between Cell Adhesion Molecules and Reactive Oxygen Species.

Muayad Al-Hadi, Alexander G Nikonenko, Vladimir Sytnyk.

  Cell adhesion molecules (CAMs) are cell-surface-localized proteins mediating interactions of cells with other cells and the extracellular matrix. CAMs influence cell behavior and survival by inducing various intracellular signaling cascades that regulate diverse cellular processes including cytoskeleton remodeling and gene expression. Here, we review the evidence demonstrating that the levels, subcellular distribution, and binding affinities of CAMs of several major families including integrins, cadherins, immunoglobulin superfamily, and selectins are regulated by intracellularly generated or extracellular reactive oxygen species (ROS). Remarkably, CAMs themselves induce ROS production in response to binding to their ligands by activating lipoxygenases or NADPH oxidases or influencing ROS generation in mitochondria. CAM-dependent ROS production is essential for CAM-mediated cell adhesion and CAM-dependent intracellular signaling. Importantly, CAMs also protect cells from the ROS-induced cell death by stimulating the synthesis of antioxidants and suppressing the cell death signaling. A better understanding of the role ROS play in controlling CAM functions and mechanisms of this control may pave the way to modulating the functions of CAMs in various disorders associated with abnormal cell adhesion.

Keywords:  cadherin; cell adhesion molecule; cell death; immunoglobulin superfamily; integrin; reactive oxygen species; selectin

DOI:  https://doi.org/10.3390/cells14141098
JCI Insight. 2025 Jul 22. pii: e192507. [Epub ahead of print]

DGAT2 reduction and lipid dysregulation drive psoriasis development in keratinocyte-specific SPRY1-deficient mice.

Ying-Ying Li, Li-Ran Ye, Ying-Zhe Cui, Fan Xu, Xi-Bei Chen, Feng-Fei Zhang, Yi Lu, Yu-Xin Zheng, Xiao-Yong Man.

  Psoriasis is a chronic autoimmune skin disease characterized by abnormal keratinocyte proliferation and immune dysregulation. Altered lipid metabolism has been implicated in its pathogenesis, but the underlying mechanisms remain unclear. In this study, we generated an keratinocyte-specific Sprouty RTK signaling antagonist 1 (SPRY1) knockout (Spry1ΔEpi) mouse model, which exhibits psoriasis-like symptoms. Using both psoriasis patient samples and Spry1ΔEpi mice, we investigated the role of diacylglycerol acyltransferase 2 (DGAT2) in psoriasis. Our results show that DGAT2 expression is reduced, and glycerides metabolism is disrupted in psoriatic lesions in both psoriasis patients and Spry1ΔEpi mice. Lipidomic analysis reveals significant alterations in glycerides, glycerophospholipids, sphingolipids, and fatty acids in Spry1ΔEpi mice. At the cellular level, DGAT2 downregulation and lipid dysregulation enhance Toll-like receptor 3 (TLR3)-mediated inflammatory signaling in keratinocytes. Furthermore, increased DGAT2 secretion from keratinocytes promotes CD8⁺ T cell activation, proliferation and survival, amplifying psoriatic inflammation. These findings highlight the role of DGAT2 and lipid metabolism in the pathogenesis of psoriasis and reveal their interaction with immune responses in psoriasis.

Keywords:  Cellular immune response; Dermatology; Inflammation; Lipidomics; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.192507