tbuckley/cabot-search huggingface dataset:
386P: Comparison between CSF circulating tumor DNA, cytology and imaging for diagnosis of leptomeningeal metastases in non-small cell lung cancer: A retrospective study
Authors: J.M-S. Leung, O.H. Chen, C. Chow, A.H. Cheung, W. Wong, K. Mok, B. Lam, A. Chen, K.C. Lam, S.T.F. Mok, W.C.K. Lee, H.H.F. Loong, D. Johnson, M.P. Lee, T.S.K. Mok, S.C.M. Li
Journal: Journal of Thoracic Oncology (2025)
On the adjuvanticity of hyaluronan: The case of a SARS-CoV-2 vaccine
Authors: Anna Dalla Pietà, Beatrice Genova, Alessandro Penna, Alessandro Sinigaglia, Stefania Vogiatzis, Luisa Barzon, Matteo Pagliari, Francesco Bonfante, Filippo Torrigiani, Tomasoni Sofia, Ranieri Verin, Anna Tosi, Debora Carpanese, Roberta Sommaggio, Vito Barbieri, Silvia Dalla Santa, Gaia Zuccolotto, Antonella Grigoletto, Gianfranco Pasut, Antonio Rosato
Journal: Journal of Controlled Release (2025)
395P: H3K27Me3-nucleosome is a strong prognostic biomarker in non-small cell lung cancer (NSCLC): Interim results from the analysis of up to 1050 samples at baseline
Authors: M. Piecyk, E. Grolleau, G. Lescuyer, S. Couraud, P. Merle, P. Mas, S. Larive, M. Duruisseaux, O. Pelton, G. Schnoering, A. Kotronoulas, J. Candiracci, M. Herzog, L.F-G. Payen
Journal: Journal of Thoracic Oncology (2025)
Editorial expression of concern: Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase
Authors: Susmita Mondal, Chandan Mandal, Rajender Sangwan, Sarmila Chandra, Chitra Mandal
Journal: Molecular Cancer (2025)
394P: Advancing lung cancer chemotherapy via single-lung perfusion and blood flow occlusion
Authors: E. Claes, S. Verleden, T. Lapperre, D. Peeters, J. De Raedemaecker, A. Neyrinck, A. Alves, J. van Daele, P. Annaert, J. Hendriks
Journal: Journal of Thoracic Oncology (2025)
Correction: A common longitudinal intensive care unit data format (CLIF) for critical illness research
Authors: Juan C. Rojas, Patrick G. Lyons, Kaveri Chhikara, Vaishvik Chaudhari, Sivasubramanium V. Bhavani, Muna Nour, Kevin G. Buell, Kevin D. Smith, Catherine A. Gao, Saki Amagai, Chengsheng Mao, Yuan Luo, Anna K. Barker, Mark Nuppnau, Michael Hermsen, Jay L. Koyner, Haley Beck, Rachel Baccile, Zewei Liao, Kyle A. Carey, Brenna Park-Egan, Xuan Han, Alexander C. Ortiz, Benjamin E. Schmid, Gary E. Weissman, Chad H. Hochberg, Nicholas E. Ingraham, William F. Parker
Journal: Intensive Care Medicine (2025)
400TiP: PYNNACLE phase II assessing rezatapopt in patients with advanced solid tumors, including lung cancer, harboring a TP53 Y220C mutation
Authors: M.J. De Miguel, E.E. Dumbrava, A. Body, L. Eberst, J-S. Frenel, A. Italiano, M.L. Johnson, J. Kaczmar, S. Kummar, P.M. Lorusso, M. Millward, I.L. Ray-Coquard, G. Scambia, A. Spira, D.S. Tan, J.A. Thompson, Y. Qin, M. Fellous, A. Schram
Journal: Journal of Thoracic Oncology (2025)
A neural geometry approach comprehensively explains apparently conflicting models of visual perceptual learning
Authors: Yu-Ang Cheng, Mehdi Sanayei, Xing Chen, Ke Jia, Sheng Li, Fang Fang, Takeo Watanabe, Alexander Thiele, Ru-Yuan Zhang
Journal: Nature Human Behaviour (2025)

Abstract Visual perceptual learning (VPL), defined as long-term improvement in a visual task, is considered a crucial tool for elucidating underlying visual and brain plasticity. Previous studies have proposed several neural models of VPL, including changes in neural tuning or in noise correlations. Here, to adjudicate different models, we propose that all neural changes at single units can be conceptualized as geometric transformations of population response manifolds in a high-dimensional neural space. Following this neural geometry approach, we identified neural manifold shrinkage due to reduced trial-by-trial population response variability, rather than tuning or correlation changes, as the primary mechanism of VPL. Furthermore, manifold shrinkage successfully explains VPL effects across artificial neural responses in deep neural networks, multivariate blood-oxygenation-level-dependent signals in humans and multiunit activities in monkeys. These converging results suggest that our neural geometry approach comprehensively explains a wide range of empirical results and reconciles previously conflicting models of VPL.
402P: Tumor suppressor genes (TSG) in NSCLC with gene fusions
Authors: L. Landi, M. Giammaruco, F. Bartoccini, A. Torchia, E. Melucci, G. Ciappina, M. Falconi, V. Gagliano, A. Di Benedetto, G. Minuti, A. Laudisi, E. Fidone, F. Rossi, G. Americi, S. Carpano, F.L. Cecere, P. Visca, G. Ciliberto, F. Cappuzzo, S. Buglioni
Journal: Journal of Thoracic Oncology (2025)
The complexity of tobacco smoke-induced mutagenesis in head and neck cancer
Authors: Laura Torrens, Sarah Moody, Ana Carolina de Carvalho, Mariya Kazachkova, Behnoush Abedi-Ardekani, Saamin Cheema, Sergey Senkin, Thomas Cattiaux, Ricardo Cortez Cardoso Penha, Joshua R. Atkins, Valérie Gaborieau, Priscilia Chopard, Christine Carreira, Ammal Abbasi, Erik N. Bergstrom, Raviteja Vangara, Jingwei Wang, Stephen Fitzgerald, Calli Latimer, Marcos Diaz-Gay, David Jones, Jon Teague, Felipe Ribeiro Pinto, Luiz Paulo Kowalski, Jerry Polesel, Fabiola Giudici, José Carlos de Oliveira, Pagona Lagiou, Areti Lagiou, Marta Vilensky, Dana Mates, Ioan N. Mates, Lidia M. Arantes, Rui Reis, Jose Roberto V. Podesta, Sandra V. von Zeidler, Ivana Holcatova, Maria Paula Curado, Cristina Canova, Elenora Fabianova, Paula A. Rodríguez-Urrego, Laura Humphreys, Ludmil B. Alexandrov, Paul Brennan, Michael R. Stratton, Sandra Perdomo
Journal: Nature Genetics (2025)

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). We explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC samples from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and alcohol-related signatures, indicating a combined effect of these exposures. Tobacco smoking was associated with differences in the mutational spectra, repertoire of driver mutations in cancer genes and patterns of copy number change. Our results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones. Whole-genome sequencing and mutational signature analysis of 265 head and neck cancer samples collected from eight different countries provide insight into the vital contribution of tobacco smoke in disease etiology.
403P: Higher predilection of driver mutation positive squamous lung cancer in the Asia Pacific region
Authors: S. Limaye, A.K. Vaid, D. Koppaka, R.R.K.K. Choudhary, R. Vijayakumar, P.S. Kataria, N. Shah, D.K. Shah, S. Schuster, V. Datta, D. Akolkar, P. Kumar, A. Sarin, A. Mudgal, D. Sharma, N. Shrivastava, S. Apurwa, A. Saha, R. Datar, J. Wilson
Journal: Journal of Thoracic Oncology (2025)
401P: Access to molecular testing for lung cancer in France: A national cross-sectional survey of routine practices
Authors: A. Bayle, F. Erdogan, D. Chaltiel, D. Debieuvre, F. Morin, C. Chouaid, E. Rouleau, B. Besse, A. Vezian, J. Bonastre
Journal: Journal of Thoracic Oncology (2025)
Invigorating discovery and clinical translation of aging biomarkers
Authors: Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J. Hastings, Alexander Tyshkovskiy, Sara Hägg, John C. Earls, Christian E. Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S. Tsang, Riccardo E. Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S. Gootenberg, Omar O. Abudayyeh, M. Austin Argentieri, Raymond H. Mak, Lynne S. Cox, Andrew S. Brack, Gordan Lauc, David Furman, Jason D. Buenrostro, Björn Schumacher, Jamie N. Justice, Tina Woods, David Gobel, Viviana I. Perez, David A. Sinclair, Andrea B. Maier, Nir Barzilai, Michael P. Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R. Poganik, Mahdi Moqri, Vadim N. Gladyshev
Journal: Nature Aging (2025)
Transcriptional profiles of mouse oligodendrocyte precursor cells across the lifespan
Authors: Dongeun Heo, Anya A. Kim, Björn Neumann, Valerie N. Doze, Yu Kang T. Xu, Yevgeniya A. Mironova, Jared Slosberg, Loyal A. Goff, Robin J. M. Franklin, Dwight E. Bergles
Journal: Nature Aging (2025)
415P: Transformer-based AI approach to unravel long-term, time-dependent prognostic complexity in patients with advanced NSCLC and PD-L1 ≥50%: Insights from the pembrolizumab 5-year global registry
Authors: A. Cortellini, E. Garbo, L. Brunetti, M. Li, F. Passiglia, S. Yendamuri, E.M. Karapanagiotou, R. Giusti, E. Bria, M. Rost, G. Minuti, M. Tiseo, L. Cantini, G. Mountzios, T. Beninato, F. Aboubakar, A. Nassar, B. Ricciuti, C.M. Caruso, V. Guarrasi
Journal: Journal of Thoracic Oncology (2025)
411P: Tumor miRNAs in small-extracellular vesicles dampen the CD8+ T cell response against tumor and predict response to immunotherapy in NSCLC
Authors: M. Chang, V. Dehame, P. Hulo, J.Q-Y. Chen, E. Pons-Tostivint, D. Fradin
Journal: Journal of Thoracic Oncology (2025)
Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease
Authors: Kanta Horie, Gemma Salvadó, Rama K. Koppisetti, Shorena Janelidze, Nicolas R. Barthélemy, Yingxin He, Chihiro Sato, Brian A. Gordon, Hong Jiang, Tammie L. S. Benzinger, Erik Stomrud, David M. Holtzman, Niklas Mattsson-Carlgren, John C. Morris, Sebastian Palmqvist, Rik Ossenkoppele, Suzanne E. Schindler, Oskar Hansson, Randall J. Bateman
Journal: Nature Medicine (2025)

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R2 = 0.56) and cognitive performance (β = 0.60, R2 = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials. Plasma eMTBR-tau243 is a specific biomarker of tau tangles in Alzheimer's disease and enables the detecting and tracking of Alzheimer's clinical impairment.
409P: IMpower010: Digital pathology (DP) vs manual SP263 PD-L1 tumour cell (TC) scoring on whole imaging slides from patients (pts) with stage II-IIIA PD-L1 TC ≥50% NSCLC
Authors: M. Reck, E. Felip, N.K. Altorki, H. Wakelee, E. Vallieres, R. Liersch, S. Oizumi, H. Tanaka, S. Novello, D. Ruderman, B. Nabet, L. Brunner, S. Hennek, B.J. Gitlitz, M. Ballinger, E. Bennett, J. Giltnane, M. Srivastava, C. Zhou
Journal: Journal of Thoracic Oncology (2025)
405P: Targeting AURKA, nuclear factor erythroid-2-related factor 2 (Nrf2), and phosphoserine aminotransferase 1 (PSAT1) in KRASG12C-mutant lung adenocarcinoma
Authors: M. Zhou, J. Codony-Servat, D. Olmo González, Y. Wang, K. Valencia, J. González, F. Zhou, J.Z. Zhang, F. Yan, R. Rosell
Journal: Journal of Thoracic Oncology (2025)
412P: Re-GraDE NSCLC: First real-world data on the daily practice of pathologic response assessment following Immune oncologic combination therapies in NSCLC in Germany
Authors: F. Elsner, C. Kümpers, G. Ott, A. Fisseler-Eckhoff, M. von Laffert, M. Kögel, A. Arndt, V. Büchele, H. Bohnenberger, K. Steinestel
Journal: Journal of Thoracic Oncology (2025)
410P: Cetuximab enhances cytotoxicity of fulzerasib and sotorasib in KRAS-mutant lung cancer
Authors: D. Olmo González, M. Zhou, J. Codony-Servat, Y. Wang, N. Oliveira, J.Z. Zhang, F. Zhou, F. Yan, J. González, K. Valencia, M.A. Molina-Vila, J. Bertran-Alamillo, A. Giménez-Capitán, R. Rosell
Journal: Journal of Thoracic Oncology (2025)
408P: Real-life experience of rare hepatoid adenocarcinomas of the lung: A large retrospective french cohort
Authors: T. Favé, J. Nguyen, R. Descourt, G. Quere, V. Basse, A. Uguen, E. Dhamelincourt, C. Ntshaykolo, A. Simaki Amah, C. Decroisette, F. Lucia, M. Geier
Journal: Journal of Thoracic Oncology (2025)
407P: Dissecting clinicopathologic features and treatment response in patients with LKB1-inactive NSCLC
Authors: G. Di Liberti, M. Occhipinti, M. Brambilla, C. Proto, A. Prelaj, L. Mazzeo, T. Beninato, D. Miliziano, G. Corrao, D. Signorelli, G. Galli, A. Busico, A. Fabbri, M. Broggini, E. Rulli, M.C. Garassino, F.G.M. De Braud, G. Lo Russo, M. Marabese, M. Ganzinelli
Journal: Journal of Thoracic Oncology (2025)
Anatomical Distribution and Quantification of <scp>IgE</scp> Secretion in Mouse Models of House Dust Mite Allergy
Authors: Paul Haase, Angga Perima, Venkat Raman Ramnarayan, Patrick England, Bruno Iannascoli, Andre Limnander, Seblewongel Asrat, Andrea Vecchione, Jamie M. Orengo, Matthew A. Sleeman, Pierre Bruhns
Journal: Allergy (2025)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43
Authors: Jens Rummens, Bilal Khalil, Günseli Yıldırım, Pedro Silva, Valentina Zorzini, Nicolas Peredo, Marta Wojno, Meine Ramakers, Ludo Van Den Bosch, Philip Van Damme, Kristofer Davie, Jelle Hendrix, Frederic Rousseau, Joost Schymkowitz, Sandrine Da Cruz
Journal: Neuron (2025)

Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks of several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain and demonstrate that sonicated fibrils trigger TDP-43 pathology in human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic TDP-43 inclusions acquire distinct biophysical properties, recapitulate pathological hallmarks such as phosphorylation, ubiquitin, and p62 accumulation, and recruit nuclear endogenous TDP-43, leading to its loss of function. A transcriptomic signature linked to both aggregation and nuclear loss of TDP-43, including disease-specific cryptic splicing, is identified. Cytoplasmic TDP-43 aggregates exhibit time-dependent heterogeneous morphologies as observed in patients-including compacted, filamentous, or fragmented-which involve upregulation/recruitment of protein clearance pathways. Ultimately, cell-specific progressive toxicity is provoked by seeded TDP-43 pathology in human neurons. These findings identify TDP-43-templated aggregation as a key mechanism driving both cytoplasmic gain of function and nuclear loss of function, offering a valuable approach to identify modifiers of sporadic TDP-43 proteinopathies.
Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures
Authors: Carlo Scialò, Weijia Zhong, Somanath Jagannath, Oscar Wilkins, Davide Caredio, Marian Hruska-Plochan, Flavio Lurati, Martina Peter, Elena De Cecco, Luigi Celauro, Adriano Aguzzi, Giuseppe Legname, Pietro Fratta, Magdalini Polymenidou
Journal: Neuron (2025)

Neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) results from both gain of toxicity and loss of normal function of the RNA-binding protein TDP-43, but their mechanistic connection remains unclear. Increasing evidence suggests that TDP-43 aggregates act as self-templating seeds, propagating pathology through the central nervous system via a prion-like cascade. We developed a robust TDP-43-seeding platform for quantitative assessment of TDP-43 aggregate uptake, cell-to-cell spreading, and loss of function within living cells, while they progress toward pathology. We show that both patient-derived and recombinant TDP-43 pathological aggregates were abundantly internalized by human neuron-like cells, efficiently recruited endogenous TDP-43, and formed cytoplasmic inclusions reminiscent of ALS/FTD pathology. Combining a fluorescent reporter of TDP-43 function with RNA sequencing and proteomics, we demonstrated aberrant cryptic splicing and a loss-of-function profile resulting from TDP-43-templated aggregation. Our data highlight known and novel pathological signatures in the context of seed-induced TDP-43 loss of function.
430P: Privacy-preserving LLMs for automated clinical feature extraction: A real-world study in NSCLC EGFR-mutated patients
Authors: L. Mazzeo, F. Corso, V. Peppoloni, G. Leone, C. Bisotti, F. Wolf, V. Miskovic, I. Wiest, C. Silvestri, M. Occhipinti, M. Brambilla, T. Beninato, M. Meazza Prina, C. Proto, P. Baili, M. Ganzinelli, A. Pedrocchi, G. Lo Russo, J.N.N. Kather, A. Prelaj
Journal: Journal of Thoracic Oncology (2025)
435P: Inequities in anticancer drug access in neighboring countries in East Central and South-East Europe for the treatment of non-small cell lung cancer (NSCLC) patients
Authors: U. Janzic, M. Jakopovic, A. Pasic, T. Ceric, M.T. Stolic, A.M. Delic Vukicevic, B. Zaric
Journal: Journal of Thoracic Oncology (2025)
439P: Standardization of endpoints in early NSCLC randomized clinical trials (RCTs): The DATECAN initiative
Authors: P. Cascetta, C. Bellera, N. Cozic, M.C. Garassino, T. Mitsudomi, A-M.C. Dingemans, F.A. Shepherd, K.M. Kerr, S. Peters, D. Planchard, S. Michiels
Journal: Journal of Thoracic Oncology (2025)
434P: Clinicopathological characteristics and aggressive behavior of SMARCA4-deficient undifferentiated thoracic tumors mimicking NSCLC: Data from a tertiary cancer center in India
Authors: N. Patnaik, R. Duggal, A. Dua, J. Singh, P.S. Mane, S. Saxena, V. Goel
Journal: Journal of Thoracic Oncology (2025)
436P: Demographics, clinical characteristics and treatment of lung cancer in a developing country: A pilot study in Malaysia
Authors: W.X. Lee, W.F. Lim, C.J. Vellan, C.M.Y. Foo, C. Jyeyi, X.N. Cheah, K.S. Kow, C.N.B. Lai, T.P. Lau, C.L. Wong
Journal: Journal of Thoracic Oncology (2025)
433P: Clinical characterization of tracheal and pulmonary adenoid cystic carcinoma: A French institutional experience
Authors: E. Sais, D. Diaz-Jimenez, D. Miliziano, L. Zullo, M.R. Ghigna, A. Lopez-Gutierrez, V. Thomas De Montpreville, O. Mercier, P. Lavaud, D. Planchard, F. Barlesi, C. Le Pechoux, A. Levy, A. Botticella, B. Besse, J. Remon Masip
Journal: Journal of Thoracic Oncology (2025)
438P: Clinical trials in thoracic oncology: Where do we come from, and where are we now?
Authors: B. Allignet, F. Izarn, I. Martel-Lafay, C. Decroisette, O. Bylicki, F. Guisier, R. Corre, R. Schott, J.B. Auliac, L. Greillier, C. Chouaid
Journal: Journal of Thoracic Oncology (2025)
429P: Real-world versus pathology panel-reviewed treatment outcomes in patients with stage IV LCNEC: A nationwide registry study
Authors: F.W.J. Heijboer, J. Derks, F. van Nederveen, L. Hillen, M. Den Bakker, T. Radonic, E-J. Speel, J. von der Thüsen, A-M.C. Dingemans
Journal: Journal of Thoracic Oncology (2025)
432P: Real-world biomarker testing and treatment patterns in Belgian lung cancer patients: Insights from the AIBED study
Authors: L. Decoster, P. Germonpre, D. Verleyen, I. Masuy, B. Verheyden, C.L. Oeste, E. Callewaert, S. Derijcke, E. Wauters, A. Janssens, K.M. Muylle, A.T.L. Verbiest
Journal: Journal of Thoracic Oncology (2025)
425P: Real-world data of everolimus in patients with thymic epithelial tumors (TETs)
Authors: Á. López Gutiérrez, J.D. Florez Arango, J.C. Benitez Montanez, D. Miliziano, E. Dansin, G. Giaccone, C. Basse, J. Mazieres, T. Pierret, E. Pons-Tostivint, J. Arrondeau, M. Aldea, D. Diaz Jiménez, L. Zullo, F. Aboubakar, P. Missy, J. Remon Masip, T. Molina, N. Girard, B. Besse
Journal: Journal of Thoracic Oncology (2025)
424P: Real-world data of lenvatinib in patients with thymic epithelial tumors (TETs)
Authors: Á. López Gutiérrez, J.C. Benitez Montanez, J.D. Florez Arango, D. Miliziano, E. Dansin, G. Giaccone, C. Basse, J. Mazieres, T. Pierret, E. Pons-Tostivint, J. Arrondeau, M. Aldea, D. Diaz Jiménez, L. Zullo, F. Aboubakar, P. missy, J. Remon Masip, T. Molina, N. Girard, B. Besse
Journal: Journal of Thoracic Oncology (2025)
Srsf3-Dependent APA Drives Macrophage Maturation and Limits Atherosclerosis
Authors: Xian Yang, Xin Zhang, Yaru Tian, Jiaxuan Yang, Yunhui Jia, Yuhuai Xie, Lianping Cheng, Shenglai Chen, Linfeng Wu, Yihong Qin, Zhen Zhao, Dejian Zhao, Yuanyuan Wei
Journal: Circulation Research (2025)

BACKGROUND: Circulating monocytes largely contribute to macrophage buildup in atheromata, which is crucial for clearing subendothelial LDLs (low-density lipoproteins) and dead cells; however, the transitional trajectory from monocytes to macrophages in atherosclerotic plaques and the underlying regulatory mechanism remain unclear. Moreover, the role of alternative polyadenylation, a posttranscriptional regulator of cell fate, in monocyte/macrophage fate decisions during atherogenesis is not entirely understood. METHODS: To identify monocyte/macrophage subtypes in atherosclerotic lesions and the effect of alternative polyadenylation on these subtypes and atherogenesis, single-cell RNA sequencing, 3′-end sequencing, flow cytometric, and histopathologic analyses were performed on plaques obtained from Apoe −/− mouse arteries with or without myeloid deletion of Srsf3 (serine/arginine-rich splicing factor 3). Cell fractionation, polysome profiling, L-azidohomoalanine metabolic labeling assay, and metabolomic profiling were conducted to disclose the underlying mechanisms. Reprogramming of widespread alternative polyadenylation patterns was estimated in human plaques via bulk RNA sequencing. RESULTS: We identified a subset of lesional cells in a monocyte-to-macrophage transitional state, which exhibited high expression of chemokines in mice. Srsf3 deletion caused a maturation delay of these transitional cells and phagocytic impairment of lesional macrophages, aggravating atherosclerosis. Mechanistically, Srsf3 deficiency shortened 3′ untranslated regions of mitochondria-associated Aars2 (alanyl-tRNA synthetase 2), disrupting its translation. The resultant impairment of protein synthesis in mitochondria led to mitochondrial dysfunction with declined NAD + levels, activation of the integrated stress response, and metabolic reprogramming in macrophages. Administering an NAD + precursor nicotinamide mononucleotide or the integrated stress response inhibitor partially restored Srsf3 -deficient macrophage maturation, and nicotinamide mononucleotide treatment mitigated the proatherosclerotic effects of Srsf3 deficiency. Consistently, Srsf3 downregulation, global 3′ untranslated region shortening, and accumulation of these transitional macrophages were associated with atherosclerosis progression in humans. CONCLUSIONS: Our study reveals that Srsf3-dependent generation of long 3′ untranslated region is required for efficient mitochondrial translation, which promotes mature phagocytic macrophage formation, thereby playing a protective role in atherosclerosis.