{"doi":"10.1093/cvr/cvaf191","title":"Nucleoporin 35: a novel nuclear pore complex protein involved in pathological cardiac remodeling","abstract":"Initially identified in the 1950s by Callan and Tomlin, the nuclear pore complex (NPC) comprises multiple subcomplexes forming a physical channel between the nucleus and the cytoplasm, where it plays a crucial role in regulating macromolecule transport between these two cellular compartments.1 The NPC is built from approximately 30 different nucleoporins (Nups) arranged in a symmetrical structure, grouped into distinct subcomplexes such as the cytoplasmic filaments, nuclear basket, inner ring scaffold, and central channel.2 These components work together to ensure selective permeability, allowing passive diffusion of small molecules while tightly controlling the active transport of larger macromolecules via nuclear transport receptors. During embryogenesis, the heart is the first organ to form, and the process of cardiomyocyte differentiation is driven by a tightly regulated cascade of transcription factors in which Nups play a pivotal role. During the early embryonic phase, cardiomyocyte differentiation is marked by a high macromolecule transport between the nucleus and cytoplasm, reflecting increased activity, expression, and distribution of NPCs. As cardiomyocytes mature, they exit the cell cycle and enter a state of terminal differentiation. This maturation is accompanied by a reduction in the number of nuclear pores, suggesting a decrease in nucleo-cytoplasmic communication. Cardiovascular disease and Nups abnormality were first reported in a study linking a mutation in the NUP155 gene to atrial fibrillation in a family with sudden cardiac deaths in infants. This mutation disrupts the nuclear localization of the NUP155 gene, compromising nuclear membrane permeability.3 Since the report, the association between Nups and cardiovascular disease has emerged as a significant focus within biomedical research. In this issue of Cardiovascular Research, Zhuang et al.4 elucidate the role of Nup35 in the development of myocardial fibrosis and hypertrophy.4 Their findings demonstrate that Nup35 is the most significantly downregulated nucleoporin in murine models undergoing cardiac remodeling induced by either angiotensin II infusion or transverse aortic constriction. Consistently, reduced transcriptional levels of Nup35 are observed in patients with dilated and ischaemic cardiomyopathy. Cardiac-specific Nup35-deficient mice develop pronounced myocardial fibrosis, hypertrophy, and left ventricular (LV) diastolic dysfunction following angiotensin II administration. In contrast, Nup35 overexpression significantly mitigates these pathological changes. Mechanistically, the study provides compelling evidence that Nup35 facilitates the nuclear export of WNT inhibitory factor 1 (Wif1) mRNA, enabling its translation in the cytoplasm. Since ribosomes responsible for protein synthesis are cytoplasmic, the export of Wif1 mRNA from the nucleus is essential for the production of functional Wif1 protein. Wif1 is a secreted antagonist of Wnt proteins, binding to them and thereby attenuating the Wnt signaling pathway.5 The Wnt/β-catenin signaling cascade is a well-established contributor to myocardial fibrosis and hypertrophy. While largely quiescent in the healthy adult heart, this pathway can be reactivated under pathological conditions such as pressure overload, driving maladaptive cardiac remodeling.6 Importantly, the current study demonstrates that cardiac-specific delivery of Wif1 via adeno-associated virus serotype 9 (AAV9) effectively rescues the hypertrophy, fibrosis, and LV diastolic dysfunction observed in Nup35-deficient mice (Figure 1). By identifying the Nup35/Wif1 axis as a key regulator of Wnt/β-catenin signaling in pathological cardiac remodeling, this work underscores the therapeutic potential of targeting the NPC and Wnt signaling pathway as a strategy for treating heart failure, although substantial challenges remain before clinical translation can be achieved. Nonetheless, the results of Zhuang et al.4 should be viewed with some ","journal":"Cardiovascular Research","year":2025,"id":581717,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":747321,"name":"Jun Yoshioka","orcid":"0000-0002-7176-3414","position":1,"is_corresponding":false},{"id":1493284,"name":"Marie Louise Ndzie Noah","orcid":"0000-0003-3262-7556","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41258937","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}