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| Open AccessOrthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia subgroup carrying 3q26 abnormalities. Here, pan-histone deacetylase inhibitors are identified as potent repressors of EVI1 and PA2G4 as a druggable target.
- Matteo Marchesini
- , Andrea Gherli
- & Giovanni Roti
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Article
| Open AccessTargeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.
- Harim I. Won
- , Samuel Zinga
- & Junhao Zhu
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Article
| Open AccessMultimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88
Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis. Here, the authors show that the honey-bee derived PrAMPs Api137 and Api88 inhibit bacterial ribosomes through multiple mechanisms, promising for drug development.
- Simon M. Lauer
- , Maren Reepmeyer
- & Ralf Hoffmann
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Article
| Open AccessCRISPR-dCas13d-based deep screening of proximal and distal splicing-regulatory elements
Here the authors develop Splice-RUSH, a high-throughput screening method to map both proximal and distal splicing-regulatory sequences in a native sequence context. These sequences can also be targeted by ASOs to modulate splicing.
- Yocelyn Recinos
- , Dmytro Ustianenko
- & Chaolin Zhang
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Article
| Open AccessGalectin-3 impairs calcium transients and β-cell function
Galectin-3, mainly produced and secreted by macrophages, is elevated in diabetes. Here, the authors show that galectin-3 directly interacts with voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and blocks calcium transients and subsequent insulin secretion.
- Qian Jiang
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessIdentifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers
Circulating proteins are a potential source of cancer biomarkers. Here, the authors assessed 2,074 circulating proteins and used Mendelian randomisation to compare with the risk of 9 common cancer types across multiple GWAS cohorts and identified key considerations with respect to the potential for adverse effects of altering cancer-risk proteins that inform their utility in cancer prevention.
- Karl Smith-Byrne
- , Åsa Hedman
- & Anders Mälarstig
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| Open AccessThe antimicrobial fibupeptide lugdunin forms water-filled channel structures in lipid membranes
The fibupeptide lugdunin has shown activity against antibiotic-resistant bacteria. Here, authors disclose its mechanism of action in lipid membranes and demonstrate that it assembles into nanotubes facilitating the translocation of monovalent cations.
- Dominik Ruppelt
- , Marius F. W. Trollmann
- & Claudia Steinem
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Article
| Open AccessSNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
| Open AccessFibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto
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Article
| Open AccessDrug target prediction through deep learning functional representation of gene signatures
Large-scale OMICs investigations of biological systems can be used to predict functional relationships between compounds, genes and proteins. Here, the authors develop a deep learning-based approach that significantly increases the number of high-quality compound-target predictions relative to existing methods.
- Hao Chen
- , Frederick J. King
- & Yingyao Zhou
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Article
| Open AccessTargeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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Article
| Open AccessCDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver
Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.
- Alexander J. Hu
- , Wei Li
- & Miaofen G. Hu
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Article
| Open AccessArtesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessReaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.
- Stanley C. Xie
- , Yinuo Wang
- & Leann Tilley
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Article
| Open AccessElucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Mycoplanecins show promising activity against tuberculosis. Here, the authors identify and study mycoplanecins’ biosynthesis, antibacterial effects, and binding mechanism to DnaN, suggesting potential for fighting multidrug-resistant tuberculosis.
- Chengzhang Fu
- , Yunkun Liu
- & Rolf Müller
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Article
| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessA biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ
Unbiased chemical biology strategies for direct readout of small molecule protein interactomes provide advantages over target-focused approaches. Here, the authors describe the BioTAC system, a network-scale small molecule guided proximity labeling platform, to rapidly identify ligand-target interactomes.
- Andrew J. Tao
- , Jiewei Jiang
- & Fleur M. Ferguson
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Article
| Open AccessCurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Article
| Open AccessEvaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
Proteomics of blood samples is a promising avenue for cancer diagnosis. Here, the authors conduct Mendelian randomisation analysis of protein levels across multiple cohorts, and identify 5 proteins that show promise as biomarkers for the long-term risk of breast cancer, and as potential drug targets.
- Anders Mälarstig
- , Felix Grassmann
- & Åsa K. Hedman
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| Open AccessA large meta-analysis identifies genes associated with anterior uveitis
Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.
- Sahar Gelfman
- , Arden Moscati
- & Giovanni Coppola
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Article
| Open AccessTelomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes
The RNA component telomerase (TERC) has a critical non-canonical role in the formation of the myeloid lineage. Here, the authors show aptamers that mimic the behaviour of the entire TERC molecule in myelopoiesis activation.
- Elena Martínez-Balsalobre
- , Jesús García-Castillo
- & María L. Cayuela
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Article
| Open AccessChronic cough relief by allosteric modulation of P2X3 without taste disturbance
P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
- Chang-Run Guo
- , Zhong-Zhe Zhang
- & Ye Yu
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| Open AccessPharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
TANK-binding kinase-1 (TBK1) and its homologue IκB kinase-ε (IKKε) are critical in the induction of the interferon response and the response to infection by pathogens. Here the authors show that pharmacological targeting of TBK1 AND IKKε reduces the immunopathology seen in a murine model of SARS-COV-2 infection.
- Tomalika R. Ullah
- , Matt D. Johansen
- & Michael P. Gantier
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| Open AccessIdentification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets
In this work, the authors mapped putative interactions between protein domains encoded by the SARS-CoV-2 and intrinsically disordered regions of the human proteome. From the data, peptides with antiviral properties targeting Nsp9 and Nsp16 were identified.
- Filip Mihalič
- , Caroline Benz
- & Ylva Ivarsson
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Article
| Open AccessCis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
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| Open AccessAuranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
- Wenjing Yan
- , Yongwang Zhong
- & Shengyun Fang
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Article
| Open AccessIdentification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1
The authors identify a small molecule inhibitor targeting the ssDNA-binding function of T. brucei Replication Protein A1 without affecting the host ortholog. They confirm the key residue in TbRPA1 involved in the species-specific selectivity of the chemical probe.
- Aditi Mukherjee
- , Zakir Hossain
- & Hee-Sook Kim
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| Open AccessSequence-based drug design as a concept in computational drug design
Conventional structure-based drug design pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, the authors report a sequence-to-drug concept that discovers drug-like small molecule modulators directly from protein sequences.
- Lifan Chen
- , Zisheng Fan
- & Mingyue Zheng
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| Open AccessHidden modes of DNA binding by human nuclear receptors
Nuclear receptors (NR) are drug-responsive master regulators. Here, authors map DNA binding profiles of all human NRs. Their MinSeq Find algorithm identifies masked NR binding sites in genomes and maps ~10% of orphan SNPs linked to numerous diseases.
- Devesh Bhimsaria
- , José A. Rodríguez-Martínez
- & Aseem Z. Ansari
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Article
| Open AccessTargeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1
Understanding the cellular target of hit compounds from phenotypic screens presents a major challenge yet is essential in the development of chemical probes. Here, the authors reveal the target of Hedgehog Pathway Inhibitor-1, by converting it to a bifunctional degrader, to be BET bromodomains.
- Meropi Bagka
- , Hyeonyi Choi
- & Sascha Hoogendoorn
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Article
| Open AccessDprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.
- Katherine A. Abrahams
- , Sarah M. Batt
- & Gurdyal S. Besra
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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| Open AccessEmpowering drug off-target discovery with metabolic and structural analysis
The authors present a workflow integrating metabolic perturbations with protein structural analysis to identify drug off-targets, demonstrating how combining machine learning methods with mechanistic analyses can benefit off-target identification.
- Sourav Chowdhury
- , Daniel C. Zielinski
- & Eugene I. Shakhnovich
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| Open AccessSystematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research
Chemical probes and their correct use are essential for accurate and robust data. Here, authors show that only 4% of analyzed publications used chemical probes in line with recommendations. This indicates that the best practice with chemical probes is yet to be implemented in research.
- Jayden Sterling
- , Jennifer R. Baker
- & Lenka Munoz
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Article
| Open AccessA first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi
Hsp110 chaperones play important roles in protein homeostasis in eukaryotes. Here, the authors identify a small compound that inhibits fungal Hsp110s as well as the growth and viability of the pathogenic fungus Candida albicans, supporting Hsp110s as targets for development of new antifungal drugs.
- Liqing Hu
- , Cancan Sun
- & Qinglian Liu
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| Open AccessLow complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.
- Einav Tayeb-Fligelman
- , Jeannette T. Bowler
- & David S. Eisenberg
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| Open AccessCorrection of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy
In a double homozygous mouse model of myotonic dystrophy type 1, Hu et al. use antisense oligonucleotide correction of myotonia to induce a therapeutic shift from an overabundance of oxidative muscle fibers to mechanically stronger glycolytic fibers.
- Ningyan Hu
- , Eunjoo Kim
- & Thurman M. Wheeler
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| Open AccessNemacol is a small molecule inhibitor of C. elegans vesicular acetylcholine transporter with anthelmintic potential
Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.
- Sean Harrington
- , Jacob Pyche
- & Peter J. Roy
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Article
| Open AccessP2X3 receptor antagonism attenuates the progression of heart failure
Despite medications, heart failure worsens with time with many patients dying within five years of diagnosis. Here the authors show that blocking purinergic receptors in the carotid body stops heart failure progression, improves its function, reduces sleep apneas and systemic inflammation in male rats.
- Renata M. Lataro
- , Davi J. A. Moraes
- & Julian F. R. Paton
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessPredicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network
Cryptic pockets enable targeting of proteins currently considered undruggable because they lack pockets in their ground state structures. Here, the authors develop a graph neural network that accurately predicts cryptic pockets in static structures by training using molecular simulation data alone.
- Artur Meller
- , Michael Ward
- & Gregory R. Bowman
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Article
| Open AccessTargeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression
Cutaneous hyperpigmented lesions, including nevi, are populated by senescent melanocytes. Here the authors provide evidence for a novel strategy based on combining inhibition of the BCL-2 and MCL1 anti-apoptotic pathways that selectively eliminates senescent melanocytes in culture and in vivo.
- Jaskaren Kohli
- , Chen Ge
- & Marco Demaria
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Article
| Open AccessTargeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis
Psoriasis is an inflammatory disease which has proven difficult to cure. Prof. Honglin Wang’s team describes L-menthol for treating models of psoriasis and uncovers the dysfunctional HES1- IGBP1-PP6 axis in psoriasis pathology by using L-menthol as a probe.
- Zhikai Wang
- , Yang Sun
- & Honglin Wang
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Article
| Open AccessRegulation of bone homeostasis by MERTK and TYRO3
The TAM family of receptor tyrosine kinases exerts pleiotropic functions in health and disease. Here, the authors show that TAM receptors control osteoblastic bone formation and identified MERTK as a novel target for bone anabolic therapy and mitigation of bone metastasis including its associated osteolytic bone disease
- Janik Engelmann
- , Jennifer Zarrer
- & Sonja Loges
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Article
| Open AccessTargeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction
Therapeutic interference with the immune response after myocardial infarction holds the potential to close a clinically relevant gap. Here, the authors show that inhibition of a cardiomyocyte-specific ADAM10 / CX3CL1 axis improves post infarction survival and cardiac function by attenuating neutrophil-mediated myocardial damage.
- Erik Klapproth
- , Anke Witt
- & Ali El-Armouche
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Article
| Open AccessIdentifying antibiotics based on structural differences in the conserved allostery from mitochondrial heme-copper oxidases
Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.
- Yuya Nishida
- , Sachiko Yanagisawa
- & Yasunori Shintani
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Article
| Open AccessNon-classical ferroptosis inhibition by a small molecule targeting PHB2
Ferroptosis is a promising therapeutic target for a variety of diseases, but a majority of known ferroptosis inhibitors belong to either antioxidants or iron chelators. Here, the authors discover a new non-classical small molecule inhibitor that is a PHB2 binder and show it ameliorates liver damage in an acute liver injury model.
- Wei Yang
- , Bo Mu
- & Shengyong Yang
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Article
| Open AccessPEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis
Currently, there is a lack of effective drugs for the treatment of pulmonary fibrosis. Here, the authors reveal a novel role of PEAR1 in fibroblast activation and demonstrate that activating PEAR1 by monoclonal antibodies might be a promising therapeutic approach for pulmonary fibrosis.
- Yan Geng
- , Lin Li
- & Xuemei Fan
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Article
| Open AccessCancer cell survival depends on collagen uptake into tumor-associated stroma
Collagen can be a metabolic source to fuel cancer growth. Here the authors show that cell surface protein TEM8 mediates the binding and uptake of collagen in stromal cells and these cells processed the collagen to glutamine, providing an alternative energy source for tumour cells to grow.
- Kuo-Sheng Hsu
- , James M. Dunleavey
- & Brad St. Croix