eLife最新文献

{"title":"Evolutionary unique <i>N</i>-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in <i>Cryptococcus neoformans</i>.","authors":"Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang","doi":"10.7554/eLife.103729","DOIUrl":"10.7554/eLife.103729","url":null,"abstract":"<p><p>A conserved <i>N</i>-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system has evolved in eukaryotes to ensure accuracy during glycoprotein folding. The human pathogen <i>Cryptococcus neoformans</i> possesses a unique <i>N</i>-glycosylation pathway that affects microbial physiology and interactions with the infected host. To investigate the molecular features and functions of the ERQC system in <i>C. neoformans,</i> we characterized a set of mutants with deletion of genes coding for the ERQC sensor UDP-glucose:glycoprotein glucosyltransferase (<i>UGG1</i>) and putative α1,2-mannose-trimming enzymes (<i>MNS1</i>, <i>MNS101</i>, <i>MNL1</i>, and <i>MNL2</i>). The <i>ugg1</i>Δ, <i>mns1</i>Δ, <i>mns101</i>Δ, and <i>mns1</i>Δ<i>101</i>Δ mutants showed alterations in <i>N</i>-glycan profiles, defective cell surface organization, decreased survival in host cells, and varying degrees of reduced <i>in vivo</i> virulence. The <i>ugg1</i>Δ strain exhibited severely impaired extracellular secretion of capsular polysaccharides and virulence-related enzymes. Comparative transcriptome analysis showed the upregulation of protein folding, proteolysis, and cell wall remodeling genes, indicative of induced endoplasmic reticulum stress. However, no apparent changes were observed in the expression of genes involved in protein secretion or capsule biosynthesis. Additionally, extracellular vesicle (EV) analysis combined with proteomic analysis showed significant alterations in the number, size distribution, and cargo composition of EVs in <i>ugg1</i>Δ. These findings highlight the essential role of the functional ERQC system for cellular fitness under adverse conditions and proper EV-mediated transport of virulence factors, which are crucial for the full fungal pathogenicity of <i>C. neoformans</i>.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of <i>Leishmania donovani</i>.","authors":"Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee","doi":"10.7554/eLife.102857","DOIUrl":"10.7554/eLife.102857","url":null,"abstract":"<p><p>The management of <i>Leishmania donovani</i> (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reliable protein-protein docking with AlphaFold, Rosetta, and replica exchange.","authors":"Ameya Harmalkar, Sergey Lyskov, Jeffrey J Gray","doi":"10.7554/eLife.94029","DOIUrl":"10.7554/eLife.94029","url":null,"abstract":"<p><p>Despite the recent breakthrough of AlphaFold (AF) in the field of protein sequence-to-structure prediction, modeling protein interfaces and predicting protein complex structures remains challenging, especially when there is a significant conformational change in one or both binding partners. Prior studies have demonstrated that AF-multimer (AFm) can predict accurate protein complexes in only up to 43% of cases (Yin et al., 2022). In this work, we combine AF as a structural template generator with a physics-based replica exchange docking algorithm to better sample conformational changes. Using a curated collection of 254 available protein targets with both unbound and bound structures, we first demonstrate that AF confidence measures (pLDDT) can be repurposed for estimating protein flexibility and docking accuracy for multimers. We incorporate these metrics within our ReplicaDock 2.0 protocol to complete a robust in silico pipeline for accurate protein complex structure prediction. AlphaRED (AlphaFold-initiated Replica Exchange Docking) successfully docks failed AF predictions, including 97 failure cases in Docking Benchmark Set 5.5. AlphaRED generates CAPRI acceptable-quality or better predictions for 63% of benchmark targets. Further, on a subset of antigen-antibody targets, which is challenging for AFm (20% success rate), AlphaRED demonstrates a success rate of 43%. This new strategy demonstrates the success possible by integrating deep learning-based architectures trained on evolutionary information with physics-based enhanced sampling. The pipeline is available at https://github.com/Graylab/AlphaRED.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers.","authors":"Robert G Stewart, Matthew James Marquis, Sooyeon Jo, Brandon J Harris, Aman S Aberra, Verity Cook, Zachary Whiddon, Vladimir Yarov-Yarovoy, Michael Ferns, Jon T Sack","doi":"10.7554/eLife.99410","DOIUrl":"10.7554/eLife.99410","url":null,"abstract":"<p><p>KvS proteins are voltage-gated potassium channel subunits that form functional channels when assembled into heteromers with Kv2.1 (<i>KCNB1</i>) or Kv2.2 (<i>KCNB2</i>). Mammals have 10 KvS subunits: Kv5.1 (<i>KCNF1</i>), Kv6.1 (<i>KCNG1</i>), Kv6.2 (<i>KCNG2</i>), Kv6.3 (<i>KCNG3</i>), Kv6.4 (<i>KCNG4</i>), Kv8.1 (<i>KCNV1</i>), Kv8.2 (<i>KCNV2</i>), Kv9.1 (<i>KCNS1</i>), Kv9.2 (<i>KCNS2</i>), and Kv9.3 (<i>KCNS3</i>). Electrically excitable cells broadly express channels containing Kv2 subunits and most neurons have substantial Kv2 conductance. However, whether KvS subunits contribute to these conductances has not been clear, leaving the physiological roles of KvS subunits poorly understood. Here, we identify that two potent Kv2 inhibitors, used in combination, can distinguish conductances of Kv2/KvS heteromers and Kv2-only channels. We find that Kv5, Kv6, Kv8, or Kv9-containing channels are resistant to the Kv2-selective pore-blocker RY785 yet remain sensitive to the Kv2-selective voltage sensor modulator guangxitoxin-1E (GxTX). Using these inhibitors in mouse superior cervical ganglion neurons, we find predominantly RY785-sensitive conductances consistent with channels composed entirely of Kv2 subunits. In contrast, RY785-resistant but GxTX-sensitive conductances consistent with Kv2/KvS heteromeric channels predominate in mouse and human dorsal root ganglion neurons. These results establish an approach to pharmacologically distinguish conductances of Kv2/KvS heteromers from Kv2-only channels, enabling investigation of the physiological roles of endogenous KvS subunits. These findings suggest that drugs which distinguish KvS subunits could modulate electrical activity of subsets of Kv2-expressing cell types.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optogenetic control of a GEF of RhoA uncovers a signaling switch from retraction to protrusion.","authors":"Jean de Seze, Maud Bongaerts, Benoit Boulevard, Mathieu Coppey","doi":"10.7554/eLife.93180","DOIUrl":"10.7554/eLife.93180","url":null,"abstract":"<p><p>The ability of a single protein to trigger different functions is an assumed key feature of cell signaling, yet there are very few examples demonstrating it. Here, using an optogenetic tool to control membrane localization of RhoA nucleotide exchange factors (GEFs), we present a case where the same protein can trigger both protrusion and retraction when recruited to the plasma membrane, polarizing the cell in two opposite directions. We show that the basal concentration of the GEF prior to activation predicts the resulting phenotype. A low concentration leads to retraction, whereas a high concentration triggers protrusion. This unexpected protruding behavior arises from the simultaneous activation of Cdc42 by the GEF and sequestration of active RhoA by the GEF PH domain at high concentrations. We propose a minimal model that recapitulates the phenotypic switch, and we use its predictions to control the two phenotypes within selected cells by adjusting the frequency of light pulses. Our work exemplifies a unique case of control of antagonist phenotypes by a single protein that switches its function based on its concentration or dynamics of activity. It raises numerous open questions about the link between signaling protein and function, particularly in contexts where proteins are highly overexpressed, as often observed in cancer.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of head and body orientations in the macaque superior temporal sulcus is stronger for upright bodies.","authors":"Yordanka Zafirova, Rufin Vogels","doi":"10.7554/eLife.105714","DOIUrl":"10.7554/eLife.105714","url":null,"abstract":"<p><p>The neural processing of faces and bodies is often studied separately, despite their natural integration in perception. Unlike prior research on the neural selectivity for either head or body orientation, we investigated their interaction in macaque superior temporal sulcus (STS) using a monkey avatar with diverse head-body orientation angles. STS neurons showed selectivity for specific combinations of head-body orientations. Anterior STS (aSTS) neurons enabled more reliable decoding of head-body configuration angles compared to middle STS neurons. Decoding accuracy in aSTS was lowest for head-body angle pairs differing only in sign (e.g. head-body orientation difference of ±90° relative to the anatomical midline), and highest for aligned (0°) head-body orientations versus those with maximum angular difference. Inverted bodies showed diminished decoding of head-body orientation angle compared to upright bodies. These findings show that aSTS integrates head and body orientation cues, revealing configuration-specific neural mechanisms, and advance our understanding of social perception.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing.","authors":"Madeline M Keenen, Liheng Yang, Huan Liang, Veronica J Farmer, Rizban E Worota, Rohit Singh, Amy S Gladfelter, Carolyn B Coyne","doi":"10.7554/eLife.101170","DOIUrl":"10.7554/eLife.101170","url":null,"abstract":"<p><p>The syncytiotrophoblast (STB) is a multinucleated cell layer that forms the outer surface of human chorionic villi. Its unusual structure, with billions of nuclei in a single cell, makes it difficult to resolve using conventional single-cell methods. To better understand STB differentiation, we performed single-nucleus and single-cell RNA sequencing on placental tissue and trophoblast organoids (TOs). Single-nucleus RNA-seq was essential for capturing STB populations, revealing three nuclear subtypes: a juvenile subtype co-expressing CTB and STB markers, one enriched in oxygen sensing genes, and another in transport and GTPase signaling. Organoids grown in suspension culture (STBout) showed higher expression of STB markers, hormones, and a greater proportion of the transport-associated nuclear subtype while TOs grown with an inverted polarity (STBin) exhibited a higher proportion of the oxygen sensing nuclear subtype. Gene regulatory analysis identified conserved STB markers, including the chromatin remodeler RYBP. Although RYBP knockout did not impair fusion, it downregulated CSH1 and upregulated oxygen-sensing genes. Comparing STB expression in first trimester, term, and TOs revealed shared features but context-dependent variability. These findings establish TOs as a robust platform to model STB differentiation and nuclear heterogeneity, providing insight into the regulatory networks that shape placental development and function.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase transition of WTAP regulates m⁶A modification of interferon-stimulated genes.","authors":"Sihui Cai, Jie Zhou, Xiaotong Luo, Chenqiu Zhang, Shouheng Jin, Jian Ren, Jun Cui","doi":"10.7554/eLife.100601","DOIUrl":"10.7554/eLife.100601","url":null,"abstract":"<p><p><i>N</i>⁶-methyladenosine (m⁶A) is the most prevalent modification of mRNA which controls diverse physiological processes. Although m⁶A modification has been reported to regulate type I interferon (IFN) responses by targeting the mRNA of IFN-β and the interferon-stimulated genes (ISGs), the detailed mechanism of how m⁶A methyltransferase complex (MTC) rapidly responds to conduct the modification on nascent mRNA during IFN-β stimulation remains largely unclear. Here, we demonstrate that WTAP, the adaptor protein of m⁶A MTC, undergoes dephosphorylation-regulated phase transition from aggregates to liquid-like condensates under IFN-β stimulation, thereby mediating m⁶A modification of a subset of ISGs to restrict their expression. The phase transition of WTAP promotes the interaction with nucleus-translocated transcription factor STAT1, recruits MTC to the promoter regions of ISGs and directs the co-transcriptional m⁶A modification on ISG mRNAs. Collectively, our findings reveal a novel regulatory role of WTAP phase transition in manipulating signaling pathways and fine-tuning immune response by orchestrating dynamic m⁶A modification through the cooperation of transcription factors and MTC. Our findings unveil a novel mechanism by which WTAP phase transition controls immune homeostasis via transcription factor-MTC-driven dynamic m⁶A modification, thereby proposing a potential therapeutic target for alleviating immune dysregulation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Household clustering and seasonal genetic variation of <i>Plasmodium falciparum</i> at the community-level in The Gambia.","authors":"Marc-Antoine Guery, Sukai Ceesay, Sainabou Drammeh, Fatou K Jaiteh, Umberto D'Alessandro, Teun Bousema, David J Conway, Antoine Claessens","doi":"10.7554/eLife.103047","DOIUrl":"10.7554/eLife.103047","url":null,"abstract":"<p><p>Understanding the genetic diversity and transmission dynamics of <i>Plasmodium falciparum</i>, the causative agent of malaria, is crucial for effective control and elimination efforts. In some endemic regions, malaria is highly seasonal with no or little transmission during up to 8 mo, yet little is known about how seasonality affects the parasite population genetics. Here, we conducted a longitudinal study over 2.5 y on 1516 participants in the Upper River Region of The Gambia. With 425 <i>P. falciparum</i> genetic barcodes genotyped from asymptomatic infections, we developed an identity by descent (IBD) based pipeline and validated its accuracy against 199 parasite genomes sequenced from the same isolates. Genetic relatedness between isolates revealed a very low inbreeding level, suggesting continuous recombination among parasites rather than the dominance of specific strains. However, isolates from the same household were sixfold more likely to be genetically related compared to those from other villages, suggesting close transmission links within households. Seasonal variation also influenced parasite genetics, with most differentiation occurring during the transition from the low transmission season to the subsequent high transmission season. Yet chronic infections presented exceptions, including one individual who had a continuous infection by the same parasite genotype for at least 18 mo. Our findings highlight the burden of asymptomatic chronic malaria carriers and the importance of characterizing the parasite genetic population at the community-level. Most importantly, 'reactive' approaches for malaria elimination should not be limited to acute malaria cases but be broadened to households of asymptomatic carriers.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12113269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular feature-based classification of retroperitoneal liposarcoma: a prospective cohort study.","authors":"Mengmeng Xiao, Xiangji Li, Fanqin Bu, Shixiang Ma, Xiaohan Yang, Jun Chen, Yu Zhao, Ferdinando Cananzi, Chenghua Luo, Li Min","doi":"10.7554/eLife.100887","DOIUrl":"10.7554/eLife.100887","url":null,"abstract":"<p><strong>Background: </strong>Retroperitoneal liposarcoma (RPLS) is a critical malignant disease with various clinical outcomes. However, the molecular heterogeneity of RPLS was poorly elucidated, and few biomarkers were proposed to monitor its progression.</p><p><strong>Methods: </strong>RNA sequencing was performed on a training cohort of 88 RPLS patients to identify dysregulated genes and pathways using clusterProfiler. The GSVA algorithm was utilized to assess signaling pathway levels in each sample, and unsupervised clustering was employed to distinguish RPLS subtypes. Differentially expressed genes (DEGs) between RPLS subtypes were identified to construct a simplified dichotomous clustering via nonnegative matrix factorization. The feasibility of this classification was validated in a separate validation cohort (n=241) using immunohistochemistry (IHC) from the REtroperitoneal SArcoma Registry (RESAR). The study is registered with https://clinicaltrials.gov/ under number NCT03838718.</p><p><strong>Results: </strong>Cell cycle, DNA damage and repair, and metabolism were identified as the most aberrant biological processes in RPLS, enabling the division of RPLS patients into two distinct subtypes with unique molecular signatures, tumor microenvironment, clinical features, and outcomes (overall survival [OS] and disease-free survival [DFS]). A simplified RPLS classification based on representative biomarkers (LEP and PTTG1) demonstrated high accuracy (area under the curve [AUC]>0.99), with patients classified as LEP+ and PTTG1-, showing lower aggressive pathological composition ratio and fewer surgery times, along with better OS (HR = 0.41, p<0.001) and DFS (HR = 0.60, p=0.005).</p><p><strong>Conclusions: </strong>Our study provided an ever-largest gene expression landscape of RPLS and established an IHC-based molecular classification that was clinically relevant and cost-effective for guiding treatment decisions.</p><p><strong>Funding: </strong>This work was supported by grants from the Beijing Municipal Science and Technology Project (Z191100006619081), National Natural Science Foundation of China (82073390), and Young Elite Scientists Sponsorship Program (2023QNRC001). The study sponsors had no role in the design and preparation of this manuscript.</p><p><strong>Clinical trial number: </strong>NCT03838718.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}