bims-cesirm 2025-10-19 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–10–19
fifteen papers selected by
Tigist Tamir, University of North Carolina

Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.
Humanized monoacylglycerol acyltransferase 2 mice on a high-fat diet exhibit impaired liver detoxification during metabolic dysfunction-associated steatotic liver disease.
Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats.
Multi-omics profiling reveals downregulated tumor lysine metabolism reshaping the immune microenvironment and therapeutic responses in hepatocellular carcinoma.
Glycoprotein-Notebook: A pan-cancer glycoproteomic database and toolkit for analysis of protein glycosylation changes associated with cancer phenotypes.
Metabolic dysregulation in the heart in obesity-associated HFpEF.
Amino acid and cholesterol metabolism in innate immunity.
Computational Approaches for Pathway-Centric Analysis of Protein Post-Translational Modifications.
Biliverdin reductase B as a new target in breast cancer.
FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination.
Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.
The insulin-like peptides Dilp2 and Dilp6 exhibit divergent responses to dietary sugar and protein in Drosophila larvae.
OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells.
AIPred: comprehensive prediction and analysis of non-histone acetylation via protein language model and interpretable machine learning.
Tuning insulin receptor signaling using de novo-designed agonists.

Cancer Res. 2025 Oct 15.

Metabolic Dependency on De Novo Pyrimidine Synthesis is a Targetable Vulnerability in Platinum Resistant Ovarian Cancer.

Horacio Cardenas, Yinu Wang, Guangyuan Zhao, Delan Xingyue Hao, Ana Maria Isac, Vanessa Hernandez, Ujin Kim, Wenan Qiang, Hao F Zhang, Daniela Matei.

Ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. Here, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin sensitive and resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase (DHODH), decreased cell viability, delayed G2/M cell cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin resistant cells had a lower oxygen consumption rate (OCR) and spare respiratory capacity (SRC) than sensitive cells. BRQ suppressed OCR in both sensitive and resistant but only inhibited SRC in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0043
PLoS One. 2025 ;20(10): e0334213

Humanized monoacylglycerol acyltransferase 2 mice on a high-fat diet exhibit impaired liver detoxification during metabolic dysfunction-associated steatotic liver disease.

J Jose Corbalan, Pranavi Jagadeesan, Joseph T Nickels.

Obesity significantly increases the risk of hyperlipidemia, type 2 diabetes, and liver disease. This study examined humanized monoacylglycerol acyltransferase 2 mice (HuMgat2) and their response to a high fat diet (HFD) while investigating hepatocyte dysfunction during obesity development. HuMgat2 mice fed a HFD exhibited hyperlipidemia, hyperglycemia, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated levels of cholesterol and triglycerides were associated with increased expression of lipogenic genes and accumulation of nuclear Srebp1/Srebp2. Mice fed a HFD demonstrated impaired insulin signaling and increased glucose production through the expression of gluconeogenesis genes. Liver fibrosis was characterized by collagen deposition and activation of Jak2-Stat3 signaling, resulting in hepatocyte apoptosis. RNA sequencing identified extracellular matrix degradation and apolipoprotein metabolism as being altered. Levels of cytochrome P450 enzymes were downregulated, as indicated by decreased Cyp2b10 and Cyb3a11 levels, alongside reduced expression of the di- and tri-carboxylic acid transporter Slc13a2, correlating with elevated Krebs cycle intermediates. Notably, HuMgat2 mice exhibited responses to a high-fat diet that were comparable to those observed in mMgat2 mice. These findings suggest that HFD consumption and concomitant obesity disrupts metabolite homeostasis, contributing to liver damage and cell death. They also further validate HuMgat2 mice as an excellent preclinical model for testing human MOGAT2 inhibitors as therapeutics for treating obesity.

DOI: https://doi.org/10.1371/journal.pone.0334213
J Gerontol A Biol Sci Med Sci. 2025 Oct 17. pii: glaf231. [Epub ahead of print]

Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats.

Haiyan Wang, Søren Madsen, Elise J Needham, Sean J Humphrey, Amy Zheng, Edward B Arias, Jacqueline Stöckli, Harry B Cutler, David E James, Gregory D Cartee.

  Calorie restriction (CR; calorie intake reduced by ∼20-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-months-old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity.

Keywords:  Ehpb1l1; Lmod1; glucose transport; insulin resistance; mTOR

DOI:  https://doi.org/10.1093/gerona/glaf231
J Transl Med. 2025 Oct 17. 23(1): 1117

Multi-omics profiling reveals downregulated tumor lysine metabolism reshaping the immune microenvironment and therapeutic responses in hepatocellular carcinoma.

Xinlan Lu, Min Qiang, Rufeng Li, Chen Guo, Kang Li, Yufei Yao, Jiayi Wang, Changcheng Wang, Kangsheng Tu, Yule Chen, Yungang Xu.

   BACKGROUND: Hepatocellular carcinoma (HCC) is a major global health challenge with high aggressiveness and recurrence rates. Metabolic reprogramming is a cancer hallmark, enabling tumor cells to sustain rapid growth and evade immune surveillance. Several amino acids have been found to undergo metabolic reprogramming in tumors, and thus are potential anti-tumor targets. However, the characterization and implication of lysine metabolic reprogramming in HCC remain largely unexplored.
METHODS: We performed multi-omics profiling, including transcriptomics, proteomics, single-cell omics, immunohistochemistry, and multiplex immunofluorescence on tumor and adjacent normal tissues obtained from 30 HCC patients. Integrative analyses and quantitative evaluations were carried out to characterize the lysine metabolism and investigate its implications for tumor progression, immune microenvironment, and immunotherapy responses.
RESULTS: Our analysis observed a significant downregulation of lysine metabolism in HCC, with inter-patient heterogeneity. Patients with low lysine metabolism in tumors exhibited worse prognoses and a predominance of immunosuppressive tumor immune microenvironment (TIME), characterized by increased infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and exhausted CD8+ T cells (TIM3+CD8+ and LAG3+CD8+). These immunosuppressive cells contribute to immunotherapeutic resistance and promote tumor progression. Notably, our conclusions were consistently supported by observations at both the bulk and single-cell resolutions, as well as T cell receptor (TCR) immune repertoire profiling, reinforcing the robustness of our findings.
CONCLUSIONS: This study provides comprehensive evidence that lysine metabolism plays a critical role in shaping the immunosuppressive TIME in HCC and is associated with clinical outcomes and resistance to immunotherapy, offering new insights into clinical molecular subtyping and potential therapeutic strategies.

Keywords:  Hepatocellular carcinoma; Immunotherapy; Lysine metabolism; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07056-3
Mol Cell Proteomics. 2025 Oct 13. pii: S1535-9476(25)00188-4. [Epub ahead of print] 101089

Glycoprotein-Notebook: A pan-cancer glycoproteomic database and toolkit for analysis of protein glycosylation changes associated with cancer phenotypes.

Hui Zhang, Trung Hoang, Yingwei Hu.

  Protein glycosylation plays a pivotal role in various biological processes, and the analysis of intact glycopeptides (IGPs) has emerged as a powerful approach for characterizing alterations in protein glycosylation associated with diseases. Despite the critical insights gained from IGP analysis, dedicated databases, and specialized tools for comprehensive glycoproteomics remain scarce. In response to this deficiency, we developed "Glycoprotein-Notebook", an online resource that consolidates the mass-spectrometry evidence for intact glycopeptides identified from 10 cancer types studied in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) projects and provides analytical tools for in-depth glycopeptide characterization. Using Pancreatic Ductal Adenocarcinoma (PDAC) as a case study, we validated and showcased the toolkit's analytical capabilities. Our results underscore the promise of IGPs as cancer-specific diagnostic and therapeutic targets. Accordingly, Glycoprotein-Notebook emerges as a valuable resource for cancer researchers exploring the intricate relationship between protein glycosylation and cancer phenotypes.

Keywords:  Cancer; Database; Glycopeptides; Glycoproteomics; Mass spectrometry; Pancreatic Ductal Adenocarcinoma (PDAC)

DOI:  https://doi.org/10.1016/j.mcpro.2025.101089
Front Cardiovasc Med. 2025 ;12 1678992

Metabolic dysregulation in the heart in obesity-associated HFpEF.

Maria Valero-Muñoz, Hannah L Cooper, Shanpeng Li, Eng Leng Saw, Richard M Wilson, Christine M Kusminski, Philipp E Scherer, Flora Sam.

   Background: Obesity and hypertension are among the most prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). In addition to its relationship with hypertension in HFpEF, obesity is also strongly associated with insulin resistance (IR) and type 2 diabetes (T2D). However, the exact cardiac effects underlying this relationship are unknown. We sought to differentiate the cardiac phenotype associated with increased adiposity in the presence or absence of IR in obese HFpEF. We utilized adipose tissue-specific MitoNEET transgenic mice, which develop chronic, metabolically healthy adipose tissue expansion (obese non-insulin resistant, OB-NIR), and compared them with their wild-type, insulin-resistant littermates (OB-IR).
Methods: OB-NIR MitoNEET and OB-IR wildtype mice were fed a high-fat diet for 16 weeks, at which time HFpEF was induced via uninephrectomy, d-aldosterone infusion, and 1.0% sodium chloride drinking water for 4 additional weeks while maintained on the same diet.
Results: OB-NIR HFpEF mice exhibited reduced cardiac fibrosis without changes in hypertrophy. This reduction was accompanied by increased cardiac expression of SIRT3. Upregulation of several downstream mitochondrial targets of SIRT3 was also observed. These included mitochondrial fission protein 1 (Fis1), a critical regulator of mitochondrial dynamics, and the antioxidant enzyme heme oxygenase-1 (Hmox1). In contrast, levels of hydroxy-3-methylglutaryl coenzyme A (CoA) synthase 2 (HMGCS2) were decreased, while both 3-hydroxybutyrate dehydrogenase 1 (Bdh1) and succinyl-CoA:3-ketoacid CoA transferase (Oxct1) were elevated. Furthermore, genes involved in the electron transport chain, such as ubiquinol-cytochrome C reductase hinge protein (Uqcrh, Complex III) and mitochondrially encoded cytochrome c oxidase I (Mt-Co1, Complex IV), were upregulated.
Discussion: Distinct alterations in cardiac mitochondrial function were observed depending on the presence or absence of IR in obese HFpEF mice. These findings suggest that SIRT3 may play a central role in mediating mitochondrial adaptations in the heart and could represent a promising therapeutic target in HFpEF.

Keywords:  HFPEF; SIRT3; insulin resistance; mitochondria metabolism; obesity

DOI:  https://doi.org/10.3389/fcvm.2025.1678992
Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00779-8. [Epub ahead of print]85(20): 3760-3778

Amino acid and cholesterol metabolism in innate immunity.

Weiyun Li, Miao Jin, Hongye Li, Ruiyue Zhong, Zhaoheng Lin, Miao Shen, Hongyan Wang.

Innate immune cells not only serve as the first line of defense against pathogen invasion but also play essential roles in the immune regulatory function of various diseases. Distinct innate immune cells and their subtypes exhibit unique metabolic profiles, and their activation, differentiation, and effector functions are tightly governed by a complex regulatory network involving both intracellular metabolism and metabolites derived from the surrounding microenvironment. Cholesterol and amino acids function not only as structural constituents of membranes and proteins but also as signaling mediators that fine-tune immune cell activity. Importantly, their metabolic pathways are tightly interconnected. This review focuses on amino acid and cholesterol metabolism, offering comprehensive insights into how these metabolic processes shape innate immune cell function during homeostasis or pathological conditions. We further discuss emerging metabolic targets and therapeutic strategies aimed at modulating innate immunity in the context of immune-related diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.09.019
Proteomics. 2025 Oct 18. e70055

Computational Approaches for Pathway-Centric Analysis of Protein Post-Translational Modifications.

Julian Müller, Bernhard Kuster, Matthew The.

  Protein function is dynamically modulated by post-translational modifications (PTMs). Many different types of PTMs can nowadays be identified and quantified at a large scale using mass spectrometry. It is well known that many PTMs have an effect on protein function and cellular processes, and they should be studied not in isolation, but in the holistic context of cellular pathways. This is increasingly facilitated by a wide variety of computational efforts. This review aims to give a systematic overview of tools for pathway-centric analysis of PTM data and critically evaluate the state of play in this research field. Starting from databases that make up the foundational prior knowledge, we follow typical steps that an analytical workflow might contain, including pathway enrichment analysis, algorithms for pathway reconstruction, and the integration and visualization of results. We then reflect on common limitations of all existing tools and give our opinion on future directions that we think are currently most desirable.

Keywords:  computational biology; enrichment analysis; pathways; post‐translational modifications

DOI:  https://doi.org/10.1002/pmic.70055
Breast Cancer Res. 2025 Oct 16. 27(1): 179

Biliverdin reductase B as a new target in breast cancer.

Natalia Marchenko, Natasha M Nesbitt, Evguenia Alexandrova, Julie A Reisz, Angelo D'Alessandro, Joonhyuk Suh, Stan Uryasev, Lisa Pennacchia, Wadie F Bahou.

   BACKGROUND: Enhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells is associated with intracellular redox imbalance that impacts cellular viability. To restore redox homeostasis cancer cells evolve to activate redox protective mechanisms. This differential activation of redox defense pathways compared to normal cells provides a therapeutic window for novel targeted therapies in cancer. Although heme metabolism emerges as a crucial regulator of redox homeostasis and iron metabolism in cancer cells with frequent alteration in breast cancer, it remains largely unexplored, and no targeted translational approaches have been developed. Heme-regulated redox homeostasis is coordinately maintained through biosynthetic and degradation pathways. As a byproduct of TCA cycle, cytotoxic heme is initially derivatized by heme oxygenases and progressively metabolized to the potent antioxidant bilirubin by two non-redundant biliverdin reductases, BLVRA and BLVRB. BLVRB overexpression has been observed in breast cancers, although its function in breast cancer pathogenesis remains unknown.
METHODS: CRISPR/Cas9 deletion of BLVRB in multiple breast cancer cell lines demonstrated its profound effect on intracellular redox state and cell proliferation in vitro and in xenograft models. Integrated proteomic, metabolomic, and lipidomic studies identified and validated BLVRB-mediated adaptive metabolic responses required for breast cancer cell cytoprotection.
RESULTS: We have established BLVRB as a requisite component of the pro-survival redox defense mechanism in breast cancer cells. Targeted deletion of BLVRB induces reductive stress, leading to alterations in endoplasmic reticulum proteostasis and lipid composition. These defects impact plasma membrane functionality and endosomal recycling of multiple oncogenic receptors, such as HER2 and transferrin receptors.
CONCLUSIONS: These data collectively identify BLVRB as a novel metabolic target in breast cancer, distinct from other redox-regulating pathways. This study, along with our recent progress in developing novel specific BLVRB inhibitors, offers a unique translational opportunity for targeted therapies in personalized breast cancer medicine.

Keywords:  HER2 positive breast cancer; Heme metabolism; Redox homeostasis; Transferrin receptor

DOI:  https://doi.org/10.1186/s13058-025-02147-x
J Exp Clin Cancer Res. 2025 Oct 14. 44(1): 289

FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination.

Zhiwen Qian, Ying Jiang, Yun Cai, Erli Gao, Cenzhu Wang, Jianfeng Dong, Fengxu Wang, Lu Liu, Danping Wu, Feng Zhang, Yida Wang, Xin Ning, Qi Li, Yilan You, Yanfang Gu, Jie Mei, Xinyuan Zhao, Yan Zhang.

  Increasing studies have reported that dysregulated lipid metabolism is an independent risk factor for breast cancer (BC); it would be, therefore, enlightening to investigate the relationship between metabolic reprogramming and the tumor microenvironment in the future. Ferroptosis, a novel form of programmed cell death, is characterized by glutathione (GSH) depletion and inactivation of glutathione peroxidase 4 (GPX4), the central regulator of the antioxidant system. While the close association between fatty acid metabolism and ferroptosis has been studied in various diseases, the interplay between the key fatty acid metabolic enzyme fatty acid synthase (FASN) and ferroptosis in BC remains unexplored. At the beginning of the current study, we demonstrated that FASN expression positively correlates with an immune-cold tumor microenvironment in BC. Subsequent findings revealed that FASN knockdown promotes GPX4 degradation-induced ferroptosis, thereby enhancing the efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy. Co-immunoprecipitation coupled with mass spectrometry (IP/MS) and co-IP experiments demonstrated that ubiquitin specific protease 5 (USP5) stabilizes GPX4 by binding to and deubiquitinating it. Furthermore, knockdown of FASN inhibited the palmitoylation of USP5, reducing its interaction with GPX4 and consequently increasing GPX4 ubiquitination and degradation. Our results demonstrate that FASN suppresses ferroptosis in BC by stabilizing GPX4 via USP5-mediated mechanisms, highlighting FASN inhibition as a potential therapeutic approach to enhance immunotherapy response.

Keywords:  Breast cancer; FASN; Ferroptosis; Palmitoylation; USP5

DOI:  https://doi.org/10.1186/s13046-025-03548-8
Mol Cancer. 2025 Oct 14. 24(1): 255

Purine metabolism: a pan-cancer metabolic dysregulation across circulation and tissues.

Mengjie Yu, Cheng Liu, Minmin Cao, Dou Yang, Tongshan Wang, Jing Xu, Danxia Zhu, Guangji Wang, Jiye Aa, Wei Zhu.

  Tumors function as organ-like entities within complex ecosystems, interacting with diverse components of their microenvironment, including blood and lymphatic vessels, neurons, immune cells, metabolites, and cytokines, to drive tumorigenesis and progression. Our pan-cancer study investigated the universal tumor hallmarks, integrating metabolite characteristics with molecular mechanisms. Metabolomic profiling on plasma from 2,561 patients across 20 cancer types and 604 healthy controls in two clinical centers, identified three biomarkers in pan cancers: elevated levels of hypoxanthine and reduced levels of cysteine and pyruvic acid. Given the profound significance of hypoxanthine, we further discovered 33 core purine metabolism-related genes in The Cancer Genome Atlas (TCGA) pan-cancer tissues, and their influences on immunomodulation and overall survival. Lastly, candidate therapeutic compounds, intervening purine metabolism, were proposed based on pharmaco-transcriptomics and pharmaco-proteomics analysis. Through interdisciplinary multi-omics investigations, such approaches may enhance insight into antitumor immunotherapy by targeting cancer metabolic reprogramming.

Keywords:  Circulation; Hypoxanthine; Metabolomics; Pan-cancer; Purine metabolism

DOI:  https://doi.org/10.1186/s12943-025-02482-9
Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2426930122

The insulin-like peptides Dilp2 and Dilp6 exhibit divergent responses to dietary sugar and protein in Drosophila larvae.

Miyuki Suzawa, W Kyle McPherson, Kelly E Dunham, Elizabeth E Van Gorder, Shivani Reddy, Leila A Jamali, Michelle L Bland.

  Nutrient intake drives secretion of insulin and insulin-like peptides that stimulate anabolic metabolism and tissue growth. Eight Drosophila insulin-like peptides (Dilps) are encoded in the Drosophila genome; whether these Dilps respond uniformly to changes in dietary nutrients is unknown. Here, we investigate the endocrine responses of Dilp2, secreted by brain insulin-producing cells, and Dilp6, produced by the fat body, to dietary sugar and protein in mid-third instar Drosophila larvae. Starvation leads to a profound reduction in circulating Dilp2 without affecting circulating Dilp6 levels. Diets containing sugar alone drive nutrient storage and increase hemolymph Dilp6, but do not promote Dilp2 release. In contrast, dietary protein drives growth and restores hemolymph Dilp2 but strongly reduces circulating Dilp6. Furthermore, circulating levels of Dilp2 and Dilp6 are modulated by the ratio of sugar to protein in the diet. We find that depleting circulating Dilp6 via fat body specific knockdown or increasing insulin receptor (InR) levels in fat body leads to increased levels of triglyceride storage but decreased peripheral growth. Our results suggest that Dilp6, a hormone produced in response to dietary sugar, may direct the use of sugar for growth instead of fat storage at the end stage of larval development. Our findings reveal different modes of regulation for Dilp2 and Dilp6 and raise the question of how the single known Drosophila InR integrates divergent signals from distinct Dilps to control growth and metabolism.

Keywords:  Drosophila; dietary nutrients; growth; insulin signaling; metabolism

DOI:  https://doi.org/10.1073/pnas.2426930122
FASEB J. 2025 Oct 31. 39(20): e71128

OTUB1 Modulates Ferroptosis by Regulating SLC7A11 Ubiquitination in Pancreatic β-Cells.

Soyeon Yoo, Dongkyu Kim, Miyeon Kim, Ju Young Bae, Sang Ah Lee, Eui Tae Kim, Gwanpyo Koh.

  Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, plays a significant role in pancreatic β-cell failure associated with diabetes. In this study, we investigated how 2-deoxy-d-ribose (dRib) induces ferroptosis in β-cells and identified the OTUB1-SLC7A11 axis as a critical regulatory mechanism. Using rat insulinoma-derived RIN5mF cells and isolated rat islets, we found that dRib exposure markedly impaired cystine uptake via system χc-, resulting in intracellular glutathione (GSH) depletion, accumulation of lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal, and increased lipid reactive oxygen species (ROS). Although SLC7A11 mRNA levels were upregulated, its protein levels were reduced due to increased ubiquitination and proteasomal degradation. Further analysis revealed that dRib suppressed the expression of OTUB1, a deubiquitinating enzyme that directly interacts with SLC7A11 and inhibits its ubiquitination. Overexpression of either OTUB1 or SLC7A11 restored cystine transport, replenished GSH levels, reduced lipid ROS and cell death, supporting their protective roles against ferroptosis. Transmission electron microscopy confirmed that dRib induced mitochondrial morphological changes consistent with ferroptosis, such as shrinkage and cristae loss. These findings demonstrate that the loss of OTUB1 promotes ferroptosis in pancreatic β-cells through destabilization of SLC7A11. Targeting the OTUB1-SLC7A11 pathway may offer a novel therapeutic approach for preserving β-cell survival and preventing the progression of diabetes.

Keywords:  2‐deoxy‐d‐ribose; OTUB1; SLC7A11; ferroptosis; β‐cell

DOI:  https://doi.org/10.1096/fj.202502289R
BMC Biol. 2025 Oct 17. 23(1): 311

AIPred: comprehensive prediction and analysis of non-histone acetylation via protein language model and interpretable machine learning.

Yuqing Geng, Hao Luo, Feng Gao.

   BACKGROUND: Non-histone lysine acetylation is a widespread protein post-translational modification that regulates almost all key cellular processes, and its dysregulation is closely associated with various human diseases. Precise identification of non-histone acetylation sites is crucial for understanding their biological functions, but existing computational methods face challenges in prediction accuracy, model interpretability, and usability.
RESULTS: Here, we presented AIPred (Acetylation Interpretable Prediction), an integrated framework that combines ESM Cambrian protein language model embeddings with diverse bioinformatics features through interpretable machine learning for prediction and analysis. Systematic evaluation demonstrated AIPred's superior performance, achieving improvements of 16.7%, 19.8%, and 20.8% over the state-of-the-art model in F1-score, Matthews correlation coefficient (MCC), and area under the precision-recall curve (AUPRC), respectively. Through Shapley additive explanations and gradient attribution analysis, we revealed key features and sequence patterns driving model decisions. Moreover, we developed a user-friendly online prediction server and a comprehensive prediction database. AIPred analysis of TDP-43 protein revealed functionally important acetylation sites, including novel predictions consistent with recent experimental findings.
CONCLUSIONS: AIPred provides an accurate, interpretable, and accessible computational framework for predicting non-histone acetylation sites, which is expected to accelerate targeted research on non-histone acetylation-related mechanisms in cellular regulation and disease pathways.

Keywords:  Database; Interpretable analysis; Machine learning; Non-histone acetylation; Protein language model; Web server

DOI:  https://doi.org/10.1186/s12915-025-02418-1
Mol Cell. 2025 Oct 13. pii: S1097-2765(25)00780-4. [Epub ahead of print]

Tuning insulin receptor signaling using de novo-designed agonists.

Xinru Wang, Sarah Cardoso, Kai Cai, Preetham Venkatesh, Albert Hung, Michelle Ng, Catherine Hall, Brian Coventry, David S Lee, Rishabh Chowhan, Stacey Gerben, Jie Li, Weidong An, Mara Hon, Michael Gao, Ya-Cheng Liao, Domenico Accili, Eunhee Choi, Xiao-Chen Bai, David Baker.

  Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.

Keywords:  cancer; computational protein design; diabetes; insulin; insulin receptor; metabolism; receptor tyrosine kinase; severe insulin-resistance syndromes; signaling; trafficking

DOI:  https://doi.org/10.1016/j.molcel.2025.09.020