bioRxiv : the preprint server for biology最新文献

{"title":"Outdoor Air Pollution, Perivascular Space Morphology, and Cognition in Preadolescence.","authors":"Jessica Morrel, Kirthana Sukumaran, Carinna Torgerson, Michael Rosario, Haoyu Lan, Joel Schwartz, Jiu-Chiuan Chen, Jeiran Choupan, Megan M Herting","doi":"10.1101/2025.09.26.678867","DOIUrl":"10.1101/2025.09.26.678867","url":null,"abstract":"<p><strong>Background: </strong>Ambient air pollution exposure is associated with structural brain differences and poorer cognition in children; however, mechanisms of toxicity remain unclear. Perivascular spaces (PVS), key for brain waste clearance, may play a role in the neurotoxicity of air pollution. This study explored associations between air pollution exposure, PVS morphology, and cognition in preadolescents.</p><p><strong>Methods: </strong>We analyzed cross-sectional Adolescent Brain Cognitive Development^SM (ABCD) Study^® data from 6,949 9-10-year-old participants. Annual average exposures to PM_2.5, O₃, NO₂, and 15 PM_2.5 components were estimated using spatiotemporal models mapped to residential addresses. PVS count and volume were derived from T1w and T2w MRI, and cognition was estimated using NIH Toolbox scores. Linear mixed-effects models examined independent associations between air pollution, PVS, and cognition; weighted quantile sum regression assessed co-exposure effects of PM_2.5 mixtures.</p><p><strong>Findings: </strong>Linear models revealed that exposures to Zn, NH₄ ⁺, and Br were positively associated with PVS count in several regions. Higher PVS count in five key regions was associated with poorer cognitive performance across several NIH Toolbox domains. Higher Ca, Zn, and NH₄ ⁺ exposures were associated with poorer cognition (P_FDR < 0.01). Higher frontal lobe PVS count mediated the association between Zn exposure and poorer total cognition (P < 0.01). Co-exposure models revealed that PM_2.5 mixtures were associated with higher temporal and cingulate PVS count, and poorer working memory and crystallized intelligence (P < 0.01).</p><p><strong>Interpretation: </strong>Outdoor air pollution was associated with higher PVS count and reduced cognition, suggesting that brain clearance may be a novel mechanism linking pollution to neurodevelopmental harm in preadolescents.</p><p><strong>Funding: </strong>This work was supported by the National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS) (Grant Nos. R01ES032295 and R01ES031074 [to MMH]; T32ES013678 [to JM]; P30ES07048 [to JM and MAR]; 3P30ES000002-55S [to MAR]), National Institute of Mental Health (NIMH) (Grant RF1MH123223 [to JC]), National Institute of Neurological Disorders and Stroke (Grant R01NS128486 [to JC]), and EPA grants (Grant Nos. 83587201 and 83544101 [to JS]).</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In-situ</i> glial cell-surface proteomics identifies pro-longevity factors in <i>Drosophila</i>.","authors":"Madeline P Marques, Bo Sun, Ye-Jin Park, Tyler Jackson, Tzu-Chiao Lu, Yanyan Qi, Erin Harrison, Miranda C Wang, Kartik Venkatachalam, Omar Moussa Pasha, Amogh Varanasi, Dominique Kiki Carey, D R Mani, Jonathan Zirin, Mujeeb Qadiri, Yanhui Hu, Norbert Perrimon, Steven A Carr, Namrata D Udeshi, Liqun Luo, Jiefu Li, Hongjie Li","doi":"10.1101/2025.09.26.678810","DOIUrl":"10.1101/2025.09.26.678810","url":null,"abstract":"<p><p>Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in <i>Drosophila</i>, which enabled us to fully profile cell-surface proteomes <i>in-situ</i>, preserving native cell-cell interactions that would otherwise be omitted using traditional proteomics methods. Applying this platform to young and old flies, we investigated how glial cell-surface proteomes change during aging. We identified candidate genes predicted to be involved in brain aging, including several associated with neural development and synapse wiring molecules not previously thought to be particularly active in glia. Through a functional genetic screen, we identified one surface protein, DIP-β, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We further performed whole-head single-nucleus RNA-seq, and revealed that DIP-β overexpression mainly impacts glial and fat cells. We also found that glial DIP-β overexpression was associated with improved cell-cell communication, which may contribute to the observed lifespan extension. Our study is the first to apply <i>in-situ</i> cell-surface proteomics to glial cells in <i>Drosophila</i>, and to identify DIP-β as a potential glial regulator of brain aging.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EpiFoundation: A Foundation Model for Single-Cell ATAC-seq via Peak-to-Gene Alignment.","authors":"Juncheng Wu, Changxin Wan, Zhicheng Ji, Yuyin Zhou, Wenpin Hou","doi":"10.1101/2025.02.05.636688","DOIUrl":"10.1101/2025.02.05.636688","url":null,"abstract":"<p><p>Foundation models exhibit strong capabilities for downstream tasks by learning generalized representations through self-supervised pre-training on large datasets. While several foundation models have been developed for single-cell RNA-seq (scRNA-seq) data, there is still a lack of models specifically tailored for single-cell ATAC-seq (scATAC-seq), which measures epigenetic information in individual cells. The principal challenge in developing such a model lies in the vast number of scATAC peaks and the significant sparsity of the data, which complicates the formulation of peak-to-peak correlations. To address this challenge, we introduce EpiFoundation, a foundation model for learning cell representations from the high-dimensional and sparse space of peaks. EpiFoundation relies on an innovative cross-modality pre-training procedure with two key technical innovations. First, EpiFoundation exclusively processes the non-zero peak set, thereby enhancing the density of cell-specific information within the input data. Second, EpiFoundation utilizes dense gene expression information to supervise the pre-training process, aligning peak-to-gene correlations. EpiFoundation can handle various types of downstream tasks, including cell-type annotation, batch correction, and gene expression prediction. To train and validate EpiFoundation, we curated MiniAtlas, a dataset of 100,000+ single cells with paired scRNA-seq and scATAC-seq data, along with diverse test sets spanning various tissues and cell types for robust evaluation. EpiFoundation demonstrates state-of-the-art performance across multiple tissues and diverse downstream tasks.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A neural geometry for forelimb proprioception in the cervical spinal cord.","authors":"Tejapratap Bollu, Martyn Goulding","doi":"10.1101/2025.09.26.678887","DOIUrl":"https://doi.org/10.1101/2025.09.26.678887","url":null,"abstract":"<p><p>Precise, real-time somatosensory feedback is essential for coordinated movement. While the anatomy and physiology of these sensory pathways is well described, their neural code and its construction remains unclear. Here we show that neurons in the cervical spinal cord generate a precise neural representation of the forelimb's kinematic state using muscle and tendon sensory afferent inputs. We identify two classes of movement responsive neurons - the first encodes speed, position and direction of the limb, while the second exhibits precise firing at specific limb positions or grid-like firing patterns that tile space. Their composite population activity is constrained to a low dimensional manifold that is an ordered representation of the position and velocity of the limb. Ablating muscle and tendon sensory afferents, but not cutaneous sensory afferents, disrupts this neural manifold. Moreover, transient perturbations of muscle and tendon afferents in freely moving mice reaching to spatial targets cause end-point errors as predicted by the deficits in the neural code. Our findings demonstrate that spinal networks, one synapse from the periphery, perform the complex computations necessary to represent forelimb movement.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long Noncoding RNAs Preserve Pancreatic Cancer Identity and Resist Cell Fate Conversion.","authors":"Dmytro Grygoryev, Seung-Won Lee, Connor Mitchell Frankston, Shauna Rakshe, Mark Berry, Alex Hirano, Taelor Ekstrom, Elise Manalo, Julien Tessier, Marilynn Chow-Castro, Jason Link, Dove Keith, Brett C Sheppard, Suzanne Fei, Terry Morgan, Helen E Remotti, Wenli Yang, Emma Furth, Sudhir Thakurela, Rosalie C Sears, Jungsun Kim","doi":"10.1101/2025.06.25.661419","DOIUrl":"10.1101/2025.06.25.661419","url":null,"abstract":"<p><p>The Yamanaka factors (OCT4, SOX2, KLF4, and MYC; OSKM) can rejuvenate aging phenotypes in somatic cell types by resetting the epigenetic landscape. Curiously, most solid tumor cells remain largely resistant to reprogramming despite their well-documented plasticity, and the underlying mechanisms are unclear. Here, we combined genomic profiling and in vivo assays to investigate OSKM-mediated reprogramming of pancreatic ductal adenocarcinoma (PDAC). In the initial stages, we found that cancer-specific genes were refractory while mesodermal/ECM programs, normally silenced by PRC2, were aberrantly upregulated. A CRISPR interference screen for OSKM reprogramming coupled with functional analyses revealed that suppression of cancer-associated long noncoding RNAs (lncRNAs) erased malignant epithelial programs, restored tumor suppressor activity, and impaired tumorigenicity in vivo. We further identified that ATXN7L3-AS1 lncRNA sustains the PDAC malignant identity through its association with active epithelial oncogenic programs and poised PRC2-targeted developmental genes, thereby supporting both plasticity and memory. Thus, by exploring why cancer cells are resistant to reprogramming, we identify lncRNAs as gatekeepers of malignant identity, suggesting that targeting lncRNAs could be a generalizable therapeutic strategy in treating solid tumors.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and classification of ion-channels across the tree of life provide functional insights into understudied CALHM channels.","authors":"Rahil Taujale, Sung Jin Park, Nathan Gravel, Saber Soleymani, Rayna Carter, Kennady Boyd, Sarah Keuning, Zheng Ruan, Wei Lü, Natarajan Kannan","doi":"10.1101/2025.02.10.637530","DOIUrl":"10.1101/2025.02.10.637530","url":null,"abstract":"<p><p>The ion channel (IC) genes encoded in the human genome play fundamental roles in cellular functions and disease and are one of the largest classes of druggable proteins. However, limited knowledge of the diverse molecular and cellular functions carried out by ICs presents a major bottleneck in developing selective chemical probes for modulating their functions in disease states. The wealth of sequence data available on ICs from diverse organisms provides a valuable source of untapped information for illuminating the unique modes of channel regulation and functional specialization. However, the extensive diversification of IC sequences and the lack of a unified resource present a challenge in effectively using existing data for IC research. Here, we perform integrative mining of available sequence, structure, and functional data on 419 human ICs across disparate sources, including extensive literature mining by leveraging advances in large language models to annotate and curate the full complement of the \"channelome\". We employ a well-established orthology inference approach to identify and extend the IC orthologs across diverse organisms to above 48,000. We show that the depth of conservation and taxonomic representation of IC sequences can further be translated to functional similarities by clustering them into functionally relevant groups, which can be used for downstream functional prediction on understudied members. We demonstrate this by delineating co-conserved patterns characteristic of the understudied family of the Calcium Homeostasis Modulator (CALHM) family of ICs. Through mutational analysis of co-conserved residues altered in human diseases and electrophysiological studies, we show that these evolutionarily-constrained residues play an important role in channel gating functions. Thus, by providing new tools and resources for performing large comparative analyses on ICs, this study addresses the unique needs of the IC community and provides the groundwork for accelerating the functional characterization of dark channels for therapeutic intervention.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Imaging for Intraindividual Investigation of the Reward Response.","authors":"Matthew Mattoni, Shenghan Wang, Cooper J Sharp, Thomas M Olino, David V Smith","doi":"10.1101/2025.09.26.678878","DOIUrl":"10.1101/2025.09.26.678878","url":null,"abstract":"<p><p>The reliance of fMRI research on between-person comparisons is limited by low test-retest reliability and inability to explain within-person processes. Intraindividual studies are needed to understand how changes in brain functioning relate to changes in behavior. Here, we present open data and analysis of a novel intensively sampled fMRI study, the Night Owls Scan Club. This precision imaging dataset includes 44 sessions acquired across four participants at a roughly biweekly rate. In each session, participants completed multiple reward-related tasks and mood and alertness ratings, and mood induction behavioral manipulation. In this study, we examined how the reward response reflects between-person or within-person variance. Test-retest-reliability of the reward response was very low and not explained my measurement error, suggesting little utility for between-person comparisons. At an intraindividual level, the mood induction showed small increases in the reward anticipation response. Additionally, mood and alertness explained notable intraindividual variance of the reward response, including as much as 31% for one participant. Overall, results suggest that BOLD activation to reward tasks - and likely other fMRI tasks - is more appropriate for within-person study than between-person study, highlighting a need for intensive longitudinal neuroimaging designs.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ⁹-THC Impairment.","authors":"Anthony English, David Marcus, Khushi Yadav, Yassin Elkhouly, Allan Levy, Victoria Corbit, Maddie Ask, Anika Scedberg, Jordan Poces-Ball, Fleur Uittenbogaard, Rayna Simons, Ilana Witten, Larry Zweifel, Benjamin Land, Nephi Stella, Michael R Bruchas","doi":"10.1101/2025.09.26.678874","DOIUrl":"10.1101/2025.09.26.678874","url":null,"abstract":"<p><p>How Δ⁹-tetrahydrocannabinol (THC) impairs natural behaviors in mice remains unknown. We developed a video-monitored behavioral platform with machine learning classifiers to unravel discrete changes in natural mouse behaviors. THC infusion into the medial prefrontal cortex (mPFC) disrupted walking kinematic features characteristic of impairment responses. THC predominantly increased mPFC GABAergic activity preceding walk initiation shifting the mPFC excitatory/inhibitory (E/I) balance. Pose-defined closed loop photo-stimulation of mPFC GABAergic neurons demonstrated that THC exacerbates selected parameters of motor impairment. Surprisingly, THC also induced a time locked, movement-induced, transient potentiation of mPFC endocannabinoid (eCB) release and ensuing CB₁R-mediated synaptic inhibition. Here we establish that THC-modifies mPFC E/I balance to excitation via dynamic changes in eCB release which acts to induce behavioral impairment.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of Sex Differences in the Whole Brain White Matter Using Diffusion MRI Tractography and Suprathreshold Fiber Cluster Statistics.","authors":"Fan Zhang, Jarrett Rushmore, Yijie Li, Suheyla Cetin-Karayumak, Yang Song, Weidong Cai, Carl-Fredrik Westin, James J Levitt, Nikos Makris, Yogesh Rathi, Lauren J O'Donnell","doi":"10.1101/2025.09.27.679006","DOIUrl":"10.1101/2025.09.27.679006","url":null,"abstract":"<p><p>Sex-specific characteristics demonstrate a substantial influence on the human brain white matter, suggesting distinct brain structural connectivity patterns between females and males. Diffusion MRI (dMRI) tractography is an important tool in assessing white matter connectivity and brain tissue microstructure across different populations. Whole brain white matter analysis using dMRI tractography for group statistical comparison is a challenging task due to the large number of white matter connections. In this work, we study whole-brain white matter connectivity differences between females and males using dMRI tractography. We study a large cohort of 707 healthy adult subjects from the Human Connectome Project Young Adult dataset. By applying a well-established fiber clustering pipeline and a suprathreshold fiber cluster statistical method, we evaluated tracts in the cerebral cortex, as well as those connecting to regions such as the cerebellum, which have been relatively less studied using dMRI tractography. We identified several tracts that differed significantly between females and males in terms of their fractional anisotropy and/or mean diffusivity. These included several deep white matter tracts (e.g., arcuate fasciculus, corticospinal tract, and corpus callosum) that have been previously shown to have sex differences, as well as superficial white matter tracts in the frontal lobe. However, there were relatively few cortical association tracts that exhibited significant sex differences. We also identified cerebellar tracts with sex differences. Finally, correlation analysis revealed that these white matter differences were linked to a range of neurobehavioral measures, with the strongest and most consistent associations observed for motor function. Overall, these findings provide characterizations of sex differences in the white matter and indicate that the circuits underlying motor function may be an important focus of future work on sex differences in the human brain.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPP1R3G Deletion Blocks RIPK1-Mediated Apoptosis and Necroptosis in Doxorubicin-Induced Cardiotoxicity.","authors":"Xueling Ma, Ken Chen, Zhigao Wang","doi":"10.1101/2025.09.26.678784","DOIUrl":"https://doi.org/10.1101/2025.09.26.678784","url":null,"abstract":"<p><p>Cardiotoxicity is a major limitation of cancer chemotherapy, exemplified by doxorubicin (DOX), yet its underlying mechanisms remain incompletely defined. Here, we identify Protein Phosphatase 1 Regulatory Subunit 3G (PPP1R3G) as a critical amplifier of DOX-induced cardiotoxicity. We show that DOX activates both apoptosis and necroptosis in vitro. Mechanistically, DOX first induces p38-dependent inhibitory phosphorylation of receptor-interacting protein kinase 1 (RIPK1), providing a transient brake on cell death. PPP1R3G facilitates the removal of inhibitory phosphorylation, thereby permitting RIPK1 activation, oligomerization, and downstream apoptotic signaling. Activated RIPK1 further promotes mitochondrial DNA (mtDNA) release, which induces IFN-β-mediated ZBP1 expression and establishes a positive feedback loop that amplifies late-stage necroptosis. Genetic ablation of Ppp1r3g suppresses both apoptosis and necroptosis in cardiomyocytes, attenuates inflammatory cytokine production, and protects mice from DOX-induced cardiac injury and mortality. These findings delineate a PPP1R3G-RIPK1 axis that converts an early protective phosphorylation checkpoint into sustained death signaling and identify PPP1R3G as a potential therapeutic target for cardioprotection.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}