bims-cesirm 2025-09-28 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–09–28
thirteen papers selected by
Tigist Tamir, University of North Carolina

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
The role of succinylation-mediated metabolic reprogramming in tumor progression.
Intrabody targeting of insulin receptor pY1150: A novel approach to modulate signaling pathways in colorectal cancer cells.
RAPDOR: Using Jensen-Shannon Distance for the computational analysis of complex proteomics datasets.
Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD⁺ production to alleviate HFpEF.
Proteomic Characterization Reveals CYP2S1 as a Mediator of Drug Resistance in PDAC.
The Role of Insulin Resistance in Cancer.
Global Profiling of Protein β-hydroxybutyrylome in Porcine Liver.
Accumulation of succinate in the blood is a potential early indicator of metabolic dysfunction-associated steatotic liver disease (MASLD).
UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.
Understanding O-GlcNAc Transferase (OGT): Every Amino Acid Matters.
Profiling of C-terminal prenylated proteins using tandem mass tagging.
Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling.

bioRxiv. 2025 Sep 20. pii: 2025.09.19.675739. [Epub ahead of print]

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.

Alica K Beutel, Sabrina Calderon, Ethan Nghiem, Kevin Gulay, Leonor P S Santana, Eleni Zimmer, Rima Singh, Cecily Anaraki, Natalie Yousefian, Chantal Allgöwer, Gregory Tong, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the HMGCR is gradually acquired during gemcitabine resistance, we observed that HMGCR expression predicts patient response to gemcitabine. Collectively, these data demonstrate that the mevalonate biosynthesis pathway represents a promising therapeutic target in gemcitabine resistance and may serve as a biomarker to stratify treatment selection in PDAC patients.

DOI: https://doi.org/10.1101/2025.09.19.675739
Mol Biol Rep. 2025 Sep 26. 52(1): 954

The role of succinylation-mediated metabolic reprogramming in tumor progression.

Siyi He, Chunduo Wang, Ranran Li, Kexin Xu, Wuzhiyi Zhang, Binbin Feng, Shengtao Cheng, Jihua Ren, Juan Chen.

  Metabolic reprogramming is a hallmark of tumors, whereby cancer cells remodel their own metabolism to meet the biosynthetic, energetic, and signaling demands required for rapid proliferation and malignant transformation. Posttranslational modifications (PTMs) serve as dynamic molecular switches that fine-tune cellular metabolic networks by precisely modulating the activity, stability, and subcellular localization of metabolic enzymes. This regulatory plasticity drives context-dependent metabolic reprogramming in tumor cells, enabling them to adapt to fluctuating physiological demands or pathological stressors while establishing tumor-specific metabolic signatures critical for survival and progression. Among PTMs, lysine succinylation-a recently identified modification catalyzed by succinyl-CoA-has emerged as a critical regulator of cancer metabolism. This unique modification involves the transfer of a negatively charged four-carbon succinyl group to lysine residues, inducing conformational and functional changes in target proteins. Notably, succinylation is evolutionarily conserved across eukaryotes and prokaryotes and has a broad influence on central metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid metabolism, and lipid homeostasis. Mounting evidence highlights its dual roles in both sustaining tumorigenic metabolism and directly activating oncogenic signaling cascades. This review summarizes current insights into how succinylation rewires tumor metabolism and delineates its mechanistic contributions to cancer progression.

Keywords:  Cancer; Lysine succinylation; Metabolic reprogramming; Posttranslational modification; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11033-025-11061-6
Cell Signal. 2025 Sep 19. pii: S0898-6568(25)00558-3. [Epub ahead of print]136 112143

Intrabody targeting of insulin receptor pY1150: A novel approach to modulate signaling pathways in colorectal cancer cells.

Ha Gyeong Shin, Na-Oh Yunn, Ji Woong Kim, Yea Bin Cho, Sung Ho Ryu, Hyunbo Shim, Sukmook Lee.

  The activation of the insulin receptor (IR) is central to the regulation of physiological metabolism, growth, and proliferation, and is associated with various cancers, including colorectal cancer (CRC). Among the tyrosine residues in the intracellular kinase domain of IR, Tyr1150 plays a pivotal role in receptor activation by regulating substrate binding to the kinase active site. In this study, we introduce a novel approach for selectively modulating insulin signaling in CRC through the development of an intrabody targeting phosphorylated Tyr1150 (IR pY1150). Using phage display technology, we isolated a phosphorylation site-specific single-chain variable fragment (scFv), K109.1, from a human scFv antibody library, which specifically binds to IR pY1150. K109.1 was subsequently engineered as an intrabody designed to function within cells. Ectopic expression of K109.1 in CRC cells selectively inhibited insulin-mediated phosphorylation of key downstream effectors, including insulin receptor substrates and Akt, thereby leading to a significant reduction in insulin-dependent glucose uptake. Notably, K109.1 did not affect extracellular signal-regulated kinase phosphorylation or alter cell proliferation, migration, or invasion. We further evaluated K109.1 in BT-474 and HEK293 cells to assess its effects in additional cellular models. In BT-474 breast cancer cells, K109.1 selectively inhibited Akt phosphorylation, while in HEK293 cells it suppressed both Akt and ERK phosphorylation, indicating context-specific signaling responses. Taken together, these findings indicate that intrabody-mediated targeting of IR pY1150 is crucial for regulating glucose metabolism, suggesting that the developed antibody, K109.1, could serve as a tool for modulating insulin-mediated signaling pathways.

Keywords:  Colorectal cancer; Glucose metabolism; Insulin receptor; Intrabody; Tyrosine phosphorylation

DOI:  https://doi.org/10.1016/j.cellsig.2025.112143
Nat Commun. 2025 Sep 26. 16(1): 8527

RAPDOR: Using Jensen-Shannon Distance for the computational analysis of complex proteomics datasets.

Luisa Hemm, Dominik Rabsch, Halie Rae Ropp, Viktoria Reimann, Philip Gerth, Jürgen Bartel, Manuel Brenes-Álvarez, Sandra Maaß, Dörte Becher, Wolfgang R Hess, Rolf Backofen.

The computational analysis of large proteomics datasets from gradient profiling or spatially resolved proteomics is often as crucial as experimental design. We present RAPDOR, a tool for intuitive analyzing and visualizing such datasets, based on the Jensen-Shannon distance and analysis of similarities between replicates, applied to the identification of RNA-binding proteins (RBPs) and spatial proteomics. First, we examine the in-gradient distribution profiles of protein complexes with or without RNase treatment (GradR) to identify RBPs in the cyanobacterium Synechocystis 6803. RBPs play pivotal regulatory and structural roles. Although numerous RBPs are well characterized, the complete set of RBPs remains unknown for any species. RAPDOR identifies 165 potential RBPs, including ribosomal proteins, RNA-modifying enzymes, and proteins not previously associated with RNA binding. High-ranking putative RBPs, such as ribosome hibernation factor LrtA/RaiA, phosphoglucomutase Sll0726, antitoxin Ssl2245, and preQ(1) synthase QueF predicted by RAPDOR but not the TriPepSVM algorithm, are experimentally validated, indicating the existence of uncharacterized RBP domains. These data are available online, providing a resource for RNase-sensitive protein complexes in cyanobacteria. We then show by reanalyzing existing datasets that RAPDOR effectively examines the intracellular redistribution of proteins upon growth factor stimulation. RAPDOR is a generic, non-parametric tool for analyzing highly complex datasets.

DOI: https://doi.org/10.1038/s41467-025-64086-7
Res Sq. 2025 Sep 17. pii: rs.3.rs-7556256. [Epub ahead of print]

Succinate-GPR91 signaling promotes cardiomyocyte metabolic reprogramming and NAD⁺ production to alleviate HFpEF.

YuMeng Jia, WenHui Niu, Lu Liu, Qun Zhang, DingWei Li, TangYu Dai, Jurgen Wess, Lei Wang, Jie Du.

Background: Disrupted cardiomyocyte energy metabolism is a hallmark of heart failure with preserved ejection fraction (HFpEF). Succinate, a key intermediate of the tricarboxylic acid cycle, is markedly decreased in HFpEF myocardium. Beyond its metabolic role, succinate functions as a signaling molecule that activates GPR91 to regulate metabolic and immune pathways. However, the precise contributions and mechanisms of cardiomyocyte succinate-GPR91 signaling in HFpEF pathogenesis remain largely unknown. Methods: HFpEF models were established in wild-type, global GPR91 knockout, and cardiomyocyte-specific GPR91 knockout mice with or without succinate supplementation. Cardiac structure, function, and metabolic phenotypes were assessed using echocardiography, histology, and molecular assays. Transcriptome sequencing of myocardial tissues was performed to identify succinate-GPR91-dependent signaling pathways. Mechanistic studies in isolated cardiomyocytes were conducted to validate pathway regulation and clarify downstream molecular mechanisms. Rescue experiments were further carried out to confirm the functional relevance of succinate-GPR91 signaling in cardiomyocyte metabolism and HFpEF progression. Results: Cardiac succinate levels and GPR91 expression were markedly decreased in HFpEF mice. Succinate supplementation restored systemic metabolism, improved diastolic function, and attenuated myocardial hypertrophy and fibrosis in wild-type (WT) HFpEF mice, but these protective effects were lost in both global Gpr91⁻/⁻ and cardiomyocyte-specific Gpr91 ΔCM knockouts. Transcriptomic analysis demonstrated that succinate activated AMPK signaling and enriched pathways related to glucose-lipid metabolism and NAD⁺ biosynthesis in Gpr91 fl/fl but not in Gpr91 ΔCM hearts. Mechanistically, succinate enhanced AMPK phosphorylation and NAD⁺ production via Gq-mediated signaling, thereby promoting metabolic reprogramming. Conclusion: These findings identify the succinate-GPR91 axis as a critical regulator of cardiometabolic homeostasis and a potential therapeutic target in HFpEF.

DOI: https://doi.org/10.21203/rs.3.rs-7556256/v1
Pancreas. 2025 Aug 29.

Proteomic Characterization Reveals CYP2S1 as a Mediator of Drug Resistance in PDAC.

Vera Thiel, Wiebke M Nadler, Alexander Kerner, Laura Kuhlmann, Manuel Reitberger, Tim Vorberg, Paul Schwerd-Kleine, Elisa Noll, Nathalia A Giese, Hsi-Yu Yen, Katja Steiger, Vanessa Vogel, Corinna Klein, Thilo Hackert, Ronald Koschny, Christiane A Opitz, Andreas Trumpp, Martin R Sprick, Christoph Rösli.

   OBJECTIVES: To investigate the proteomic profile of different molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and understand their impact on patient outcomes, particularly focusing on pathways involved in xenobiotic metabolism and drug resistance.
METHODS: The study utilized the serum-free PACO cell culture model and a quantitative prefractionation-based MALDI/MS approach to establish the proteomic profiles of various PDAC subtypes. Differential protein regulation was analyzed to identify systematic alterations in metabolic and drug resistance pathways. Mechanistic studies involved the knockdown and overexpression of key proteins to assess their role in drug resistance.
RESULTS: Proteomic analysis revealed subtype-specific alterations, particularly in pathways associated with xenobiotic metabolism and drug resistance. Notably, CYP2S1, a member of the CYP450 family, was upregulated in the HNF1A+ PDAC subtype. CYP2S1 levels were further inducible by polyaromatic hydrocarbons (PAHs) and SN38, the active metabolite of irinotecan via AHR. Mechanistic studies demonstrated that knockdown of AHR or CYP2S1 sensitized PDAC cells to SN38, whereas overexpression of CYP2S1 increased resistance to SN38.
CONCLUSIONS: The findings highlight the significant role of CYP2S1 in mediating drug resistance in certain PDAC subtypes. Targeting CYP2S1 and its regulatory pathways could enhance the efficacy of chemotherapeutic agents like irinotecan in treating PDAC. These results provide new insights into the molecular mechanisms underlying PDAC subtype-specific drug resistance and suggest potential therapeutic targets.

Keywords:  AHR; CYP2S1; GeLC-based MALDI/MS; MSQBAT; PDAC

DOI:  https://doi.org/10.1097/MPA.0000000000002553
Curr Oncol. 2025 Aug 25. pii: 477. [Epub ahead of print]32(9):

The Role of Insulin Resistance in Cancer.

Bal Krishna Subedi, Charishma Bhimineni, Shivani Modi, Atousa Jahanshahi, Katherine Quiza, Daniel Bitetto.

  Insulin resistance (IR) is a prevalent metabolic condition characterized by reduced cellular responsiveness to insulin and consequent hyperinsulinemia, and it is a key component of type 2 diabetes and metabolic syndrome. A growing body of evidence suggests IR is a critical accomplice in the pathogenesis of various cancers. This review synthesizes evidence on underlying molecular mechanisms, including the integrated roles of the insulin/IGF system, chronic inflammation, metabolic reprogramming, and mitochondrial dysfunction. This review proposes that metabolic dysregulation should be viewed as a modifiable oncogenic force. This perspective illuminates new pathways for understanding cancer development and offers promising avenues for prevention and therapeutic intervention.

Keywords:  breast cancer; colorectal cancer; endometrial cancer; insulin resistance; liver cancer; obesity; pancreatic cancer

DOI:  https://doi.org/10.3390/curroncol32090477
Biology (Basel). 2025 Sep 02. pii: 1183. [Epub ahead of print]14(9):

Global Profiling of Protein β-hydroxybutyrylome in Porcine Liver.

Shuhao Fan, Jinyu Guan, Fang Tian, Haibo Ye, Qianqian Wang, Lei Lv, Yuanyuan Liu, Xianrui Zheng, Zongjun Yin, Xiaodong Zhang.

  The liver orchestrates metabolic homeostasis through dynamic post-translational modifications. β-hydroxybutyrylation (Kbhb), a ketone body-driven modification, regulates epigenetics and metabolism in humans and mice but remains unexplored in livestock. Here, we characterize the porcine hepatic β-hydroxybutyrylome using high-resolution mass spectrometry, identifying 4982 Kbhb sites on 2122 proteins-the largest dataset to date. β-hydroxybutyrylation predominantly targets non-histone proteins (99.68%), with enrichment in fatty acid β-oxidation, TCA cycle, and oxidative phosphorylation pathways. Subcellular localization revealed cytoplasmic (38.1%), mitochondrial (18.1%), and nuclear (15.3%) dominance, reflecting BHB-CoA synthesis sites. Motif analysis identified conserved leucine, phenylalanine, and valine residues at modified lysines, suggesting enzyme-substrate specificity. β-hydroxybutyrate treatment elevated global Kbhb levels, increasing TCA intermediates (e.g., α-ketoglutarate, +9.56-fold) while reducing acetyl-CoA, indicating enhanced mitochondrial flux. Cross-species comparisons showed tissue-specific Kbhb distribution (nuclear in human cells vs. mitochondrial in mice), highlighting metabolic adaptations. This study establishes pigs as a model for Kbhb research, linking it to energy regulation and providing insights into metabolic reprogramming.

Keywords:  TCA cycle; ketone bodies; metabolic regulation; porcine liver; β-hydroxybutyrylation

DOI:  https://doi.org/10.3390/biology14091183
Free Radic Biol Med. 2025 Sep 20. pii: S0891-5849(25)00986-4. [Epub ahead of print]241 220-235

Accumulation of succinate in the blood is a potential early indicator of metabolic dysfunction-associated steatotic liver disease (MASLD).

Olivia Chalifoux, Chloe Dagostino, Meijing Li, Stephanie Trezza, Cathryn Grayson, Mariana De Sa Tavares Russo, Daina Zofija Avizonis, Marek Michalak, Luis B Agellon, Ryan J Mailloux.

There is currently a need to identify new biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD). Here, using C57BL6N male mice fed a high-fat diet (HFD), we provide evidence that extracellular succinate buildup is a sex-dependent diagnostic marker for MASLD. Male mice fed the HFD for 2-weeks developed simple steatosis, which was associated with the plasma buildup of succinate to 50 μM. Feeding the mice this diet for up to 7 weeks advanced the condition to MASLD, resulted in cardiac fibrosis, and the further increased plasma succinate to 100 μM. Using Huh-7 hepatoma cells as a model, we found fructose overload increased the concentration of succinate in the culture media, and this was associated with mitochondrial dysfunction and the hyper production of mitochondrial hydrogen peroxide (mtH2O2). HepG2 hepatocellular blastoma cells subjected to fructose overload in culture also accumulated succinate in the media. Treatment of the Huh-7 and HepG2 cells exposed to fructose with ursodeoxycholic acid (UDCA) or its taurine-conjugated form, TUDCA, which are known to elicit protective hepatocellular effects by inducing antioxidant defenses, strongly inhibited succinate build up by preserving mitochondrial function and preventing H2O2 hyper-production. Finally, using our glutaredoxin-2 (Glrx2-/-) gene knockout mouse model on a C57BL6N background, we found deleting the Glrx2 gene in male mice completely abrogated the accumulation of succinate, cis-aconitate, and itaconate in plasma. Importantly, wild-type (Wt) or Glrx2-/-female littermates did not accumulate any of these metabolites in plasma when fed the HFD, which coincided with MASLD resistance. Collectively, our findings show succinate accumulates rapidly in the extracellular milieu in our mouse model for MASLD and cell culture models for hepatic lipotoxicity. These findings suggest the applicability of succinate as a biomarker of early MASLD particularly among males and especially in pediatric populations.

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.09.029
Br J Cancer. 2025 Sep 22.

UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.

Haksoo Lee, Dahye Kim, Byeongsoo Kim, DongJoo Joung, Jaewan Jeon, Tae-Oh Kim, HyeSook Youn, BuHyun Youn.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor characterized by a poor prognosis and resistance to radiotherapy. Although multiple mechanisms of radioresistance have been proposed, the contribution of membrane-driven metabolic adaptations to radioresistance remains poorly understood.
METHODS: The role of UDP-glucose ceramide glucosyltransferase (UGCG) was investigated using radioresistant GBM cell lines and in vivo xenograft models. After inhibiting UGCG function through genetic or pharmacological (miglustat) approaches, we assessed the effects on lipid raft integrity, localization of the ASCT2 transporter, glutamine uptake, oxidative stress, and radiosensitivity.
RESULTS: UGCG was upregulated in radioresistant GBM cells and promoted lipid raft stabilization. This facilitated the membrane recruitment of the glutamine transporter ASCT2 (SLC1A5), thereby sustaining redox homeostasis under radiation stress. Genetic or pharmacological inhibition of UGCG disrupted lipid raft integrity, impaired ASCT2 localization, reduced glutamine uptake, and increased oxidative stress, leading to enhanced radiosensitivity. In GBM xenograft models, UGCG inhibition combined with radiotherapy significantly suppressed tumor growth and extended survival.
CONCLUSIONS: These findings reveal a previously underexplored, membrane-centric mechanism of radioresistance in which UGCG orchestrates lipid raft remodeling to facilitate glutamine-dependent redox balance. This highlights UGCG as a potential therapeutic target to enhance the efficacy of radiotherapy in GBM.

DOI: https://doi.org/10.1038/s41416-025-03191-2
J Biol Chem. 2025 Sep 24. pii: S0021-9258(25)02612-2. [Epub ahead of print] 110760

Understanding O-GlcNAc Transferase (OGT): Every Amino Acid Matters.

Ningda Xu, Yucheng Zhao, Wei Chi, Yanqiu Yuan, Jing Li.

  O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) mediate all the "writing" and "erasing" of intracellular O-GlcNAc modification events on the Ser or Thr residues of proteins. Decades of investigations have revealed many O-GlcNAc substrates, spanning almost all areas of biological research. The question remains, however: why is there only one OGT? Here we provide a tentative answer to the "one OGT" question. We propose that OGT is a sensor of various biological stimuli and responds accordingly by incurring post-translational modifications (PTMs) or through its short linear motifs (SLiMs). Both PTMs and SLiMs reside in its intrinsic disordered regions, tetratricopeptide repeats or catalytic domains, and contribute to altering its enzymatic activity, protein-protein interaction, subcellular localization and protein stability. OGA follows the same pattern, although to a lesser extent. We propose that OGT, or OGA, can sense biological cues and, via its PTMs or SLiMs, adjust the downstream OGT interactome and O-GlcNAcome correspondingly.

Keywords:  O-GlcNAc Transferase (OGT); O-GlcNAcase (OGA); post-translational modification (PTM); protein-protein interaction; short linear motifs (SLiMs)

DOI:  https://doi.org/10.1016/j.jbc.2025.110760
Methods Enzymol. 2025 ;pii: S0076-6879(25)00216-2. [Epub ahead of print]719 317-345

Profiling of C-terminal prenylated proteins using tandem mass tagging.

Harinarayanan Kottala, Yuanzhe Chen, Mark D Distefano.

  Protein prenylation is a crucial post translational modification that involves the attachment of one or two isoprenoid groups at the C-terminus of a protein, facilitating membrane localization and regulating protein function. Consequently, prenylation is linked to numerous diseases. Identification of prenylated proteins and their quantification is crucial to defining the role of prenylation in these diseases and therapy development. Here, a method for profiling and quantifying prenylated proteins using a bio-orthogonal probe is described. The workflow consists of metabolic incorporation of the probe and click chemistry-mediated biotinylation followed by streptavidin purification and LC-MS3 based proteomic analysis of the enriched proteins. In this chapter, we provide a comprehensive protocol to accomplish this using tandem mass tag (TMT) labels in mammalian cell culture. This includes sample preparation from adherent and suspension cell lines, in-gel fluorescence analysis to verify probe incorporation, click reaction with a biotin handle, streptavidin enrichment of prenylated proteins, multiplexing using TMT labels, LCMS3 data acquisition and data analysis.

Keywords:  Farnesylation; Geranylgeranylation; Post-translational modification; Prenylation; Tandem mass tagging

DOI:  https://doi.org/10.1016/bs.mie.2025.06.008
Sci Rep. 2025 Sep 26. 15(1): 32986

Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling.

Lihong Su, Chunlin Qiao, Jin Luo, Bianling Zhu, Yunxiao Liu.

  The identification of novel therapeutic targets in triple negative breast cancer (TNBC) continues to be of paramount importance. In this context, ADH1A (Alcohol Dehydrogenase 1 A), a protein involved in tyrosine metabolism, was comprehensively examined to assess its expression and functional roles in TNBC. A combination of bioinformatics approaches and local tissue analyses was utilized to determine the expression levels of ADH1A in TNBC samples. Genetic manipulation techniques were employed to alter ADH1A expression, and the subsequent effects on TNBC cell behavior were systematically analyzed. This study is the first to report on the alterations of 14 genes related to tyrosine metabolism within the TCGA-TNBC cohorts. Notably, reduced expression of these enzymes is associated with poorer survival outcomes in patients with TNBC. An analysis of the TCGA database revealed reduced levels of ADH1A in human TNBC tissues. Furthermore, ADH1A protein expression was diminished in TNBC tissues of patients who received local treatment, in contrast to the elevated expression observed in adjacent normal tissues. In the MDA-MB-231 and SUM159PT cell lines, ADH1A knockdown significantly promoted cell proliferation, migration, and invasion. On the contrary, ADH1A overexpression inhibited cell proliferation, migration, and invasion, while inducing cell apoptosis. Mechanistically, the overexpression of ADH1A may attenuate the malignant characteristics of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway. In conclusion, ADH1A may be a useful biomarker for TNBC prognosis. This study is the first to reveal that ADH1A inhibits the malignant progression of TNBC via the Wnt/β-catenin signaling pathway.

Keywords:  Breast cancer; Migration; Prognosis; Proliferation; Tyrosine metabolism

DOI:  https://doi.org/10.1038/s41598-025-17643-5