Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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Molecular simulations meet personalized medicine: The mechanism of action of CLC-5 antiporter and the origin of Dent's disease
(2025-11-01) MACALUSO, Veronica; Pérez, Carles; Soliva, Robert; Westermaier, Yvonne; Díaz, Lucía; WIECZOR, Milosz; Orozco Lopez, Modesto
ClC-5 is a Cl-/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dent's disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523 Delta Val deletion linked to Dent's disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can shed light on the origin of rare diseases and explore targets for personalized medicine.
Phylogeny-aware Simulations Suggest a Low Impact of Unsampled Lineages in the Inference of Gene Flow During Eukaryogenesis
(2025-11-01) Bernabeu, Moises; Manzano Morales, Saioa ; Gabaldón Esteban, Toni
The topologies of gene trees are broadly used to infer horizontal gene transfer events and characterize the potential donor and acceptor partners. Additionally, ratios between branch lengths in the gene tree can inform about the timing of transfers relative to each other. Using this approach, recent studies have proposed a relative chronology of gene acquisitions in the lineage leading to the last eukaryotic common ancestor. However, a recognized caveat of the branch-length ratio method are potential biases due to incomplete taxon sampling resulting in so-called "ghost" lineages. Here, we assessed the effect of ghost lineages on the inference of the relative ordering of gene acquisition events during eukaryogenesis. For this, we used a novel simulation framework that populates a dated Tree of Life with plausible "ghost" lineages and simulates their gene transfers to the lineage leading to last eukaryotic common ancestor. Our simulations suggest that a substantial majority of gene acquisitions from distinct ghost donors are inferred with the correct relative order. However, we identify phylogenetic placements where ghost lineages would be more likely to produce misleading results. Overall, our approach offers valuable guidance for the interpretation of future work on eukaryogenesis, and can be readily adapted to other evolutionary scenarios.
Effects of removable clear dental aligners on the composition of the oral microbiome
(2025-12-31) Peregrina Cabredo, Sara; Peiró Aubalat, Andrea; Manohar, Avié; Benavente, Alicia; Torres Carvajal, Martha; Gabaldón Esteban, Toni
Proper tooth alignment is important for oral and periodontal health, allowing better hygiene and reducing plaque build-up. While traditional braces are effective, clear aligners offer an aesthetic advantage and are also thought to promote better oral hygiene. However, their specific impact on the oral microbiome is not yet fully understood. This longitudinal study used 16S amplicon sequencing to study the oral microbiome (from saliva, subgingival, and supragingival samples) of 11 patients undergoing clear aligner treatment. Samples were collected at three time points: before treatment and at 3 and 6 months during therapy. Our results revealed large differences between the microbiomes of different oral sites but no significant overall changes in the oral microbiome composition due to orthodontic treatment. While some species-specific changes were observed, their effect sizes were very small. Although these results should be confirmed in a larger and more diverse cohort, they suggest that the treatment had a small or negligible impact. Given the observed stability of the oral microbiome in all three studied niches throughout the treatment and the known benefits to oral hygiene, clear aligners may present a favorable therapeutic alternative compared to fixed appliances.
Cytoplasmic Regulation of the Poly(A) Tail Length as a Potential Therapeutic Target
(2025-01-13) Fernandez, Mercedes; Méndez De La Iglesia, Raúl
Mendez, Raul
Sex and smoking bias in the selection of somatic mutations in human bladder
(Springer Nature, 2025-10-08) Calvet, Ferriol; Blanco Martínez Illescas, Raquel; Muiños Ballester, Ferran; Tretiakova, Maria; Latorre Esteves, Elena S.; Fredrickson, Jeanne; Andrianova, Maria; Pellegrini, Stefano; Rosendahl Huber, Axel; Ramis Zaldívar, Joan Enric; An, Shuyi Charlotte; Thieme, Elana; Kohrn, Brendan F.; Grau, Miguel L.; González Pérez, Abel; López Bigas, Núria; Risques, Rosa Ana
Men are at higher risk of several cancer types than women1. For bladder cancer the risk is four times higher for reasons that are not clear2. Smoking is also a principal risk factor for several tumour types, including bladder cancer3. As tumourigenesis is driven by somatic mutations, we wondered whether the landscape of clones in the normal bladder differs by sex and smoking history. Using ultradeep duplex DNA sequencing (approximately 5,000x), we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. Men had significantly more truncating driver mutations in RBM10, CDKN1A and ARID1A than women, despite similar levels of non-protein-affecting mutations. This result indicates stronger positive selection on driver truncating mutations in these genes in the male urothelium. We also found activating TERT promoter mutations driving clonal expansions in the normal bladder that were associated strongly with age and smoking. These findings indicate that bladder cancer risk factors, such as sex and smoking, shape the clonal landscape of the normal urothelium. The high number of mutations identified by this approach offers a new strategy to study the functional effect of thousands of mutations in vivo-natural saturation mutagenesis-that can be extended to other human tissues.
Clonal tracing with somatic epimutations reveals dynamics of blood ageing
(Springer Nature, 2025-05-21) Scherer, Michael; Singh, Indranil; Braun, Martina Maria; Szu Tu, Chelsea; Sánchez Sánchez, Pedro; Lindenhofer, Dominik; Jakobsen, Niels Asger; Körber,Verena; Kardorff, Michael; Nitsch, Lena; Kautz, Pauline; Rühle, Julia; Bianch, Agostina; Cozzuto, Luca; Frömel, Robert; Beneyto Calabuig, Sergi; Lareau, Caleb; Satpathy, Ansuman T.; Beekman, Renée; Steinmetz, Lars M.; Raffel, Simon; Ludwig, Leif S.; Vyas, Paresh; Rodríguez Fraticelli, Alejo E.; Velten, Lars
Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
Mutations that stick: Unexpected discovery of molecular glue mimicry
(Elsevier, 2025-04-17) Whelan, Rory; José Durán, Ferran; Mayor Ruiz, Cristina
Opportunities in proximity modulation: Bridging academia and industry
(Elsevier, 2025-08-21) Mayor-Ruiz, Cristina; Winter, Georg E.; Koch, Kerstin; Ciulli, Alessio; Thomä, Nicolas H.; Dikic, Ivan
In the past decade, exciting therapeutic strategies to harness the ubiquitin-proteasome system (UPS) for degradation of target proteins have emerged. Proximity-inducing modalities are at the center of these strategies and act by modulating protein-protein interactions. While we are still learning to harvest this approach, it holds tremendous promise for developing treatments for hitherto undruggable proteins. Here, we discuss how academic efforts and academic-industrial collaboration have advanced the development of therapeutic modalities based on the principle of roximity induction. We make a case for forming a global academia-industry alliance to enhance access to training and expertise while accelerating innovation and translation from ground-breaking ideas to proof of concept in the clinic.
Dysregulation of the FGF21-adiponectin axis in a large cohort of patients with severe obesity and liver disease
(MDPI, 2025-09-02) Castañé Vilafranca, Helena; Jiménez Franco, Andrea; Onoiu, Alina Iuliana; Cambra Cortés, Vicente; Hernández Aguilera, Anna; Parada Domíngues, David; Riu, Francisco; Zorzano Olarte, Antonio; Camps, Jordi; Joven, Jorge
We investigated the impact of liver damage on systemic inter-organ communication in an extensive observational case-control study of 923 patients with severe obesity and biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) undergoing bariatric surgery. Using a comprehensive panel of circulating organokines, including fibroblast growth factor (FGF) 19, FGF21, adiponectin, galectin-3, irisin, and leptin, along with choline metabolites, we characterized metabolic signaling patterns associated with liver disease severity. Compared to controls, patients with MASLD/MASH exhibited significantly lower levels of FGF19, choline, and trimethylamine, while FGF21, galectin-3, irisin, and leptin were elevated. Sex-specific alterations in leptin and adiponectin were observed in patients with severe obesity but not in controls. Network analysis revealed a complex and individualized interplay among organokines, shaped by age, sex, and anthropometric factors. Despite this complexity, a dysregulation of the FGF21-adiponectin axis was associated with more advanced liver involvement. The large cohort and comprehensive organokine profiling studied provide valuable insights into the role of the FGF21-adiponectin axis on systemic metabolic alterations in severe obesity and their potential clinical implications.
A bioinformatics screen identifies TCF19 as an aggressiveness-sustaining gene in prostate cancer
(FEBS Press, 2025-09-15) Ercilla Eguiarte, Amaia; Crespo, Jana R.; García Longarte, Saioa; Fidalgo, Marta; Palacio, Sara del; Martín Martín, Natalia; Carlevaris, Onintza; Astobiza, Ianire; Fernández Ruiz, Sonia; Guiu Comadevall, Marc; Bárcena, Laura; Mendizabal, Isabel; Aransay, Ana M.; Graupera i Garcia-Milà, Mariona; Gomis i Cabré, Roger; Carracedo, Arkaitz
Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental in improving the survival rate of prostate cancer patients. By means of gene expression meta-analysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and negatively associated with the activity of the androgen receptor. By combining computational and empirical approaches, our data revealed that TCF19 is required for full metastatic capacity, and its depletion influences core cancer-related processes, such as tumor growth and vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells.
Regulatory Mechanisms of SPARC Overexpression in Melanoma Progression
(MDPI, 2025-09-08) Vinyals, Antònia; Ferreres Riera, Jose Ramon; Campos Martín, Rafael; Jorge Torres, Olga C.; Mainez Villoro, Jessica; Puig Butillé, Joan Anton; Marcoval Caus, Joaquim; Puig i Sardà, Susana; Fabregat Romero, Isabel; Fabra Fres, Àngels
The expression of the Secreted Protein, Acidic and Rich in Cysteine (SPARC) gene in human melanoma increases during progression and is associated with epithelial-to-mesenchymal transition (EMT), which is a major determinant of metastasis in melanoma patients. However, the underlying molecular mechanisms that control SPARC expression in this context remain elusive. Herein, we identified Paired-related homeobox 1 (PRRX1), an EMT transcription factor, as a transcriptional activator of SPARC by direct binding to the promoter, thereby increasing its activity. Moreover, we found a strong positive correlation between SPARC and PRRX1 expression levels in clinical samples and cell lines. Furthermore, the switch from the proliferative/melanocytic phenotype toward the invasive/mesenchymal-like phenotype favors the expression of TCF7L2, a beta-catenin cofactor, which, together with Sp1, binds to the proximal SPARC promoter, thereby bolstering protein expression. We also show that SPARC is a target of the miR-29 family, whose members are expressed in clinical melanoma samples and cell lines. Indeed, we found that miR-29b1 similar to a expression is inversely correlated with SPARC levels, and it is significantly reduced in samples with a mesenchymal-like phenotype. Taken together, SPARC expression in melanoma cells relies on transcriptional activation by PRRX1/TCF7L2-Sp1 and is modulated through miR-29b1 similar to a, which provides fine-tuning regulation over the switch between phenotypic states.
Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue
(Nature Publishing Group, 2025-09-04) Sánchez Feutrie, Manuela; Romero De Pablos, Montserrat; Veiga, Sonia Rosa Pereira da; Borràs Ferré, Núria; Berrow, Nick; Ràfols, Martina; Giménez, Noemí; Rodgers Furones, Andrea; Sabaté Pérez, Alba; Rodríguez Pérez, Ángela; Cataldo, Luis Rodrigo; Burghardt, Hans; Sebastián, David; Plana, Natàlia; Hernández, Vanessa; Alcaide, Laura Isabel; Reina, Óscar; Monte, M. Jesús; García Marin, José Juan; Palacín Prieto, Manuel; Burcelin, Remy; Antonson, Per; Gustafsson, Jan-Ake; Zorzano Olarte, Antonio
Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
A site-specific MiniAp4-Trastuzumab conjugate prevents brain metastasis
(American Chemical Society, 2025-03-03) Masmudi-Martín, Mariam; Oller Salvia, Benjamí; Perea, María; Teixidó Turà, Meritxell; Valiente, Manuel; Giralt Lledó, Ernest; Sánchez-Navarro, Macarena
Monoclonal antibodies (mAbs) are changing cancer treatments. However, the presence of the blood–brain barrier (BBB) and the blood–tumor barrier (BTB) limits the use of mAbs to treat brain cancer or brain metastasis. Molecules that hijack endogenous transport mechanisms on the brain endothelium (brain shuttles) have been shown to increase the transport of large molecules and nanoparticles across the BBB. Among these shuttles, protease-resistant peptides such as MiniAp-4 are particularly efficient. Here, we report the synthesis, characterization, and evaluation of site-specific mAb–brainshuttle antibody conjugates (ASC) based on the anti-HER2 mAb trastuzumab (Tz) and four molecules of MiniAp-4. The ASCs preserve the binding and cell cycle arrest capacity of Tz. MiniAp-4 ASC displays enhanced transport across an in vitro BBB cellular model with respect to Tz and Tz conjugated to Angiopep-2, the brain shuttle that has advanced the most in clinical trials. More importantly, evaluation of Tz-MiniAp4 in a murine brain metastasis model demonstrated that the protease-resistant peptide showed preferential transport across the BBB/BTB, displaying a marked therapeutic effect and protecting against metastasis development. The technology described herein could be applied to any antibody of interest to treat central nervous system-related diseases. MiniAp-4 enhances the brain transport of the monoclonal antibody trastuzumab, preventing brain metastasis.
Rare but specific: 5-bp composite motifs define SMAD binding in BMP signaling
(BioMed Central, 2025-03-13) Jatzlau, Jerome; Do, Sophie-Nhi; Mees, Rebeca Angelique; Mendez, Paul Lennard; Khan, Rameez Jabeer; Maas, Lukas; Ruiz Sainz, Lidia; Martín Malpartida, Pau; Macías Hernández, María J.; Knaus, Petra
BackgroundReceptor-activated SMADs trimerize with SMAD4 to regulate context-dependent target gene expression. However, the presence of a single SMAD1/5/8 binding motif in cis-regulatory elements alone does not trigger transcription in native contexts. We hypothesize that binding to composite motifs in which at least two SMAD binding sites are in close proximity would be enough to induce transcription as this scenario allows the simultaneous interaction of at least two SMAD proteins, thereby increasing specificity and affinity.ResultsUsing more than 65 distinct firefly luciferase constructs, we delineated the minimal requirements for BMP-induced gene activation. We propose a model in which two SMAD-MH1 domains bind a SMAD-composite motif in a back-to-back fashion with a 5-bp distance between the SMAD-motifs on opposing DNA strands. However screening of SMAD1-bound regions across a variety of cell types highlights that these composite motifs are extremely uncommon, explaining below 1% of SMAD1 binding events.ConclusionsDeviations from these minimal requirements prevent transcription and underline the need for co-transcription factors to achieve gene activation.
Flexibility in PAM recognition expands DNA targeting in xCas9
(eLife Sciences, 2025-02-10) Hossain, Kazi A.; Nierzwicki, Lukasz; Orozco López, Modesto; Czub, Jacek; Palermo, Giulia
xCas9 is an evolved variant of the CRISPR-Cas9 genome editing system, engineered to improve specificity and reduce undesired off-target effects. How xCas9 expands the DNA targeting capability of Cas9 by recognising a series of alternative protospacer adjacent motif (PAM) sequences while ignoring others is unknown. Here, we elucidate the molecular mechanism underlying xCas9’s expanded PAM recognition and provide critical insights for expanding DNA targeting. We demonstrate that while wild-type Cas9 enforces stringent guanine selection through the rigidity of its interacting arginine dyad, xCas9 introduces flexibility in R1335, enabling selective recognition of specific PAM sequences. This increased flexibility confers a pronounced entropic preference, which also improves recognition of the canonical TGG PAM. Furthermore, xCas9 enhances DNA binding to alternative PAM sequences during the early evolution cycles, while favouring binding to the canonical PAM in the final evolution cycle. This dual functionality highlights how xCas9 broadens PAM recognition and underscores the importance of fine-tuning the flexibility of the PAM-interacting cleft as a key strategy for expanding the DNA targeting potential of CRISPR-Cas systems. These findings deepen our understanding of DNA recognition in xCas9 and may apply to other CRISPR-Cas systems with similar PAM recognition requirements.
Systematic study of hybrid triplex topology and stability suggests a general triplex-mediated regulatory mechanism
(Oxford University Press, 2025-03-24) Genna, Vito; Portella, Guillem; Sala, Alba; Terrazas Martínez, Montserrat; Serrano Chacón, Israel; Gonzalez-Díaz, Joaquín; Villegas, Núria; Mateo, Lidia; Castellazzi, Chiara; Labrador, Mireia; Aviño, Anna; Hospital, Adam; Gandioso, Albert; Aloy, Patrick; Brun-Heath, Isabelle; Gonzalez, Camille; Eritja i Casadellà, Ramon; Orozco López, Modesto
By combining in silico, biophysical, and in vitro experiments, we decipher the topology, physical, and potential biological properties of hybrid-parallel nucleic acids triplexes, an elusive structure at the basis of life. We found that hybrid triplex topology follows a stability order: r(Py)-d(Pu)·r(Py) > r(Py)-d(Pu)·d(Py) > d(Py)-d(Pu)·d(Py) > d(Py)-d(Pu)·r(Py). The r(Py)-d(Pu)·d(Py) triplex is expected to be preferred in the cell as it avoids the need to open the duplex reducing the torsional stress required for triplex formation in the r(Py)-d(Pu)·r(Py) topology. Upon a massive collection of melting data, we have created the first predictor for hybrid triplex stability. Leveraging this predictor, we conducted a comprehensive scan to assess the likelihood of the human genome and transcriptome to engage in triplex formation. Our findings unveil a remarkable inclination—of both the human genome and transcriptome—to generate hybrid triplex formation, particularly within untranslated (UTRs) and regulatory regions, thereby corroborating the existence of a triplex-mediated regulatory mechanism. Furthermore, we found a correlation between nucleosome linkers and Triplex-forming sequence (TFS) which agree with a putative role of triplexes in arranging chromatin structure.
Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms
(EMBO Press, 2025-08-29) Luo, Lin; Lechuga Vieco, Ana Victoria; Sattentau, Clara; Borsa, Mariana; Simon, Anna Katharina
Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
Gromologist: A GROMACS-oriented utility library for structure and topology manipulation
(Elsevier B.V., 2025-03-12) Wieczór, Miłosz; Czub, Jacek; Orozco López, Modesto
Despite the increasing automation of workflows for the preparation of systems for molecular dynamics simulations, the custom editing of molecular topologies to accommodate non-standard modifications remains a daunting task even for experienced users. To alleviate this issue, we created Gromologist, a utility library that provides the simulation community with a toolbox of primitive operations, as well as useful repetitive procedures identified during years of research. The library has been developed in response to users' feedback, and will continue to grow to include more use cases, thorough automatic testing and support for a broader spectrum of rare features. The program is available at gitlab.com/KomBioMol/gromologist and via Python's pip.
The pseudotorsional space of RNA
(Cold Spring Harbor Laboratory Press, 2023-12-01) Grille, Leandro; Gallego Perez, Diego; Darré, Leonardo; da Rosa, Gabriela; Battistini, Federica; Orozco López, Modesto; Dans, Pablo D.
The characterization of the conformational landscape of the RNA backbone is rather complex due to the ability of RNA to assume a large variety of conformations. These backbone conformations can be depicted by pseudotorsional angles linking RNA backbone atoms, from which Ramachandran-like plots can be built. We explore here different definitions of these pseudotorsional angles, finding that the most accurate ones are the traditional η (eta) and θ (theta) angles, which represent the relative position of RNA backbone atoms P and C4′. We explore the distribution of η − θ in known experimental structures, comparing the pseudotorsional space generated with structures determined exclusively by one experimental technique. We found that the complete picture only appears when combining data from different sources. The maps provide a quite comprehensive representation of the RNA accessible space, which can be used in RNA-structural predictions. Finally, our results highlight that protein interactions lead to significant changes in the population of the η − θ space, pointing toward the role of induced-fit mechanisms in protein–RNA recognition.
CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis
(Elsevier, 2025-03-03) Delgado, M. Eugenia; Naranjo Suárez, Salvador; Ramirez Pedraza, Marta; Cárdenas, Beatriz I.; Gallardo Martínez, Carmen; Balvey Gil, Alexandra; Belloc Rocasalbas, Eulàlia; Martín Ortega, Judit; Boyle, Mark; Méndez de la Iglesia, Raúl; Fernández Lobato, Mercedes
Background & Aims Liver cancer is a significant global health issue, with its incidence rising in parallel with the obesity epidemic. The limited therapeutic options available emphasize the need for a better understanding of the molecular pathways involved in its pathogenesis. While much of the previous research has focused on transcriptional changes, this study examines translational alterations, specifically the role of cytoplasmic polyadenylation element binding protein 4 (CPEB4), a key regulator of translation. Methods We analyzed publicly available patient databases and conducted studies using human and mouse liver cancer cells, xenograft and allograft models, mouse models of high-fat diet-related liver cancer, and CPEB4 knockout and knockdown mice and cell lines. Results Patient data analysis (n = 87) showed a strong correlation between low CPEB4 levels and reduced survival rates (p <0.001). In mouse models of diet-induced liver cancer (n = 10–15 per group), both systemic and hepatocyte-specific CPEB4 knockout mice exhibited significantly increased tumor burden compared with wild-type controls (p <0.05). In vitro studies using human and murine liver cancer cells (n = 3 biological replicates) demonstrated reduced sensitivity to ferroptosis upon CPEB4 depletion when induced by erastin or RSL3 (p <0.01). Mechanistically, CPEB4 deficiency suppressed hepcidin expression, leading to elevated ferroportin levels, decreased intracellular iron accumulation, and reduced lipid peroxidation (p <0.05). Conclusions This study uncovers a novel CPEB4-dependent mechanism linking translational control to liver cancer progression and ferroptosis regulation. Therapeutic strategies targeting CPEB4-mediated pathways hold promise for advancing treatment options in liver cancer.

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