👤 Heng-Huei Lin

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Also published as: Ai-Hsuan Lin, Aifu Lin, Ailong Lin, Aiping Lin, Aizhen Lin, Alexander Lin, Alexander P Lin, Ann Lin, Bei Lin, Bencheng Lin, Bi-Yun Lin, Biaoyang Lin, Bichun Lin, Bihua Lin, Bin Lin, Binbin Lin, Bing-Biao Lin, Bing-Jin Lin, Bing-Xue Lin, Bing-Yao Lin, Bingbing Lin, Bingqi Lin, Bo Lin, Bo-Wen Lin, Bode Lin, Bonnie Lin, Boxu Lin, Brian Leei Lin, Brian Lin, Bridget M Lin, C H Lin, C T Lin, C Y Lin, Cai-Xia Lin, Caiyu Lin, Chang Lin, Chang-Ching A Lin, Changchun Lin, Changpo Lin, Chao Lin, Chao-Chieh Lin, Chao-Feng Lin, Chao-Hsiung Lin, Chaohui Lin, Charles P Lin, Chen Lin, Chen-Yong Lin, Cheng Lin, Cheng-Chieh Lin, Cheng-Li Lin, Cheng-Yen Lin, Chengping Lin, Chengqi Lin, Chengyuan Lin, Chenquan Lin, Chi-Hung Lin, Chi-Shiuan Lin, Chi-Ying Lin, Chia-Chin Lin, Chia-Hao Lin, Chia-Ho Lin, Chia-Hsin Lin, Chia-Hung Lin, Chia-Liang Lin, Chia-Yu Lin, Chiao-Huang Lin, Chiao-Mei Lin, Chien-Ju Lin, Chien-Wei Lin, Chien-Yu Lin, Chih-Chun Lin, Chih-Hsun Lin, Chih-Ming Lin, Chih-Pei 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Han Lin, Han-Huei Lin, Hang Lin, Hang-Yan Lin, Hanyu Lin, Hao Lin, Hao-Yu Lin, Haochang Lin, Haocheng Lin, Haodong Lin, Haoyi Lin, Haoyu Lin, He Lin, Heng Lin, Henghui Lin, Hening Lin, Hong Lin, Hongcheng Lin, Hongchun Lin, Honghuang Lin, Hongkun Lin, Hongsheng Lin, Hongyan Lin, Hsiao-Yun Lin, Hsien-Chih Lin, Hsin-Ti Lin, Hsing-Pei Lin, Hsiu-Chu Lin, Hua Lin, Huanhuan Lin, Hui Lin, Hui-Hsuan Lin, Hui-Ju Lin, Hui-Kuan Lin, Hui-Ping Lin, Hui-Ru Lin, Hui-Yan Lin, Hui-Yi Lin, Huijuan Lin, Huilan Lin, Huimei Lin, Huisheng Lin, Hung-Chih Lin, Hung-Ju Lin, Hung-Jung Lin, I-Ching Lin, I-Jung Lin, I-Ling Lin, Jake Lin, James A Lin, Jamie S Lin, Jane-Ming Lin, Jeng-Feng Lin, Jia Lin, Jia-Bin Lin, Jia-Feng Lin, Jia-Li Lin, Jia-Qi Lin, Jiabin Lin, Jiacheng Lin, Jiaheng Lin, Jiahui Lin, Jiajing Lin, Jiali Lin, Jiamao Lin, Jiamei Lin, Jian-Yu Lin, JianMin Lin, Jiandie D Lin, Jiandie Lin, Jianfei Lin, Jiang Lin, Jianhao Lin, Jianhua Lin, Jianhui Lin, Jianjian Lin, Jiantao Lin, Jianwei Lin, Jianyin Lin, Jiaqi Lin, Jiaqian Lin, Jiaquan Lin, Jiarui Lin, Jiatong Lin, Jiayang Lin, Jiayi Lin, Jiayuh Lin, Jie Lin, Jie Ming Lin, Jieye Lin, Jieying Lin, Jijin Lin, Jim Jr-Min Lin, Jin Lin, Jin'e Lin, Jin-Ru Lin, Jinchuan Lin, Jing Lin, Jing-Ping Lin, Jing-Ying Lin, Jing-Yu Lin, Jinghan Lin, Jingmei Lin, Jingyu Lin, Jingyuan Lin, Jinlong Lin, Jinxiu Lin, Jinzhong Lin, Jiu Lin, Jiuann-Huey Ivy Lin, Jiunn-Lee Lin, Jiyan Lin, Jo-Yu Lin, Joanne Lin, Johnson Lin, Jue Lin, Juin-Han Lin, Jun-Ming Lin, Junjian Lin, Junnan Lin, Junyi Lin, Kai Lin, Kai-Hsin Lin, Kai-Min Lin, Kai-Yan Lin, Kai-Yen Lin, Kang Lin, Kashuai Lin, Katia Lin, Ke Lin, Ke-Shin Lin, Kejian Lin, Keng-Hung Lin, Kim Y Lin, Kimberly Y Lin, Kongying Lin, Kuan-Hung Lin, Kuang Lin, L Lin, L Y Lin, Lanyan Lin, Le-Hang Lin, Lei Lin, Leilei Lin, Lezhen Lin, Li An Lin, Li Lin, Li-An Lin, Li-Ching Lin, Li-E Lin, Li-Fen Lin, Li-Ling Lin, Li-Rong Lin, Li-Song Lin, Lian-Yu Lin, Liang-Chun Lin, Liang-Tzung Lin, Lihao Lin, Lijin Lin, Liling Lin, Limei Lin, Lin Lin, Ling Lin, Ling-Li Lin, Liping Lin, Lisong Lin, Liwen Lin, Lizhong Lin, Lizhu Lin, Long Lin, Long-Yau Lin, Lu Lin, Luping Lin, M Lin, Manjie Lin, Mao-Shin Lin, Mao-Tsun Lin, Mary Grace Lin, Mei-Chi Lin, Meifang Lin, Meizhen Lin, Meng-Fei Lin, Meng-Wei Lin, Mengsha Lin, Mengxin Lin, Mengyao Lin, Miao Lin, Miao-Chong Joy Lin, Min Lin, Min-Huan Lin, Min-Jie Lin, Min-Rou Lin, Ming-Der Lin, Ming-Hong Lin, Ming-Huei Lin, Ming-Tai Lin, Ming-Wei Lin, Mingkuan Lin, Mingmei Lin, Mingqun Lin, Mingrui Lin, Mingxing Lin, Mingying Lin, Monica Lin, Nan Lin, Nancy U Lin, Nianwei Lin, Ning Lin, Ning-Ning Lin, Ningning Lin, Pei Lin, Pei-Chin Lin, Pei-Lin Lin, Pei-Yi Lin, Peijia Lin, Peng Lin, Peng-Chan Lin, Pengfei Lin, Penghui Lin, Ping Lin, Pingping Lin, Po-Han Lin, Qi Lin, Qian Lin, Qianmeng Lin, Qiannan Lin, Qiao Lin, Qiao-Hong Lin, Qiaoxuan Lin, Qichang Lin, Qin Lin, Qing Lin, Qinghua Lin, Qingling Lin, Qingqing Lin, Qingxiang Lin, Qinlu Lin, Qiong Lin, Qiongfen Lin, Qitai 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articles

Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.

Joshua K Meisner, Aaron Renberg, Eric D Smith +29 more · 2025 · Circulation · added 2026-04-24
Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rar Show more
Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity. Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10 Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM. Show less
📄 PDF DOI: 10.1161/CIRCULATIONAHA.124.069398
MYBPC3

Genetic Testing Practices and Pathological Assessments in Patients With End-stage Heart Failure Undergoing Heart Transplantation and Left Ventricular Assist Device Use.

Elizabeth Silver, Alessia Argiro, Sarah S Murray +7 more · 2025 · Journal of cardiac failure · Elsevier · added 2026-04-24
Genetic cardiomyopathies (CMs) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. H Show more
Genetic cardiomyopathies (CMs) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. However, genetic testing practices are understudied in patients with ESHF. This single-center, retrospective study included consecutive patients with ESHF who underwent heart transplantation (HT) or left ventricular assist device (LVAD) implantation between 2018 and 2023. Data, including genetic testing and pathology reports, were collected from the electronic medical records. Analyses of demographic and clinical characteristics were stratified by genetic-testing completion and the presence of clinically actionable variants. Logistic regression was performed to evaluate for associations between histology findings and genetic variants. A total of 529 adult patients (mean age 57 years) were included in the study and were predominantly male (79%, 422/529) and non-white (61%, 322/529). Genetic testing was performed in 54% (196/360) of patients with either nonischemic or mixed CMs. A clinically actionable result was identified in 36% (70/196) of patients, of whom only 43% (30/70) had genetic counselor referrals. The most common genetic variants were TTN (32%, 24/75), MYBPC3 (13%, 10/75) and TTR (11%, 8/75). Clinically actionable variants were identified in patients with known heart failure precipitators such as alcohol use. In multivariable analysis, the presence of interstitial fibrosis, specifically diffuse, on pathology was significantly associated with a clinically actionable variant (aOR 2.29, 95% CI [1.08-4.86]; P = 0.03). Patients with ESHF and with nonischemic or mixed CM who were undergoing advanced therapies had low uptakes of genetic services, including testing and counselors, despite high burdens of genetic disease. Pathology findings such as interstitial fibrosis may provide insight into genetic etiology. The underuse of services suggests a need for implementation strategies to improve uptake. Show less
no PDF DOI: 10.1016/j.cardfail.2024.09.015
MYBPC3

Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway.

Qian Li, Yang Ang, Qing-Qing Zhou +15 more · 2025 · Journal of pharmaceutical analysis · Elsevier · added 2026-04-24
Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treat Show more
Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation. Show less
no PDF DOI: 10.1016/j.jpha.2024.101039
MYO19

Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration.

Yu-Fan Chen, Chien-Wei Lee, Yi-Shuan J Li +8 more · 2025 · Experimental & molecular medicine · Nature · added 2026-04-24
Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poo Show more
Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration. Show less
no PDF DOI: 10.1038/s12276-025-01467-4
NR1H3

Protective functions of liver X receptor α on calcified aortic valve: involvement of regulating endoplasmic reticulum-mediated osteogenic differentiation.

Lishan Zeng, Xin Chen, Kai Kang +12 more · 2025 · Cardiovascular research · Oxford University Press · added 2026-04-24
Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade and is predicted to continue rising in the future. Thi Show more
Effective therapeutic drugs for calcific aortic valve disease (CAVD) are lacking, although its incidence has been increasing over the past decade and is predicted to continue rising in the future. This study aimed to explore the role and potential mechanisms of liver X receptor α (LXRα) in CAVD, which offers a promising approach for treating CAVD. Osteogenic stimulation was performed following which a substantial downregulation of LXRα was observed in human calcific aortic valves and valvular interstitial cells. Further functional investigations revealed that silencing LXRα exacerbated calcification both in vitro and in vivo. We showed that LXRα suppressed the protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4 pathway, which controls endoplasmic reticulum stress (ERS) and promotes osteogenic differentiation, thereby slowing the course of CAVD. Our research offers fresh perspectives on how LXRα controls the pathophysiology of CAVD via regulating ERS. The findings suggest that targeting LXRα is a potential treatment strategy for treating aortic valve calcification. Show less
no PDF DOI: 10.1093/cvr/cvaf044
NR1H3

Multi-omics and Mendelian randomization study explores potential therapeutic targets for meningiomas.

Yongxue Li, Lihao Lin, Wenhui Zhang +3 more · 2025 · Discover oncology · Springer · added 2026-04-24
Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficientl Show more
Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficiently abundant. Therefore, we explored potential therapeutic targets for meningiomas by integrating genomic and proteomic data. We integrated meningioma data from the UK Biobank and Finnish databases and subsequently explored potential therapeutic targets for meningiomas through multi-omics data using bioinformatics techniques and Mendelian randomization. These targets were finally evaluated using phenotype-wide association group analysis. We found that BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 can be potential therapeutic targets for meningiomas. This study provides evidence and explores the biological significance of BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 as potential therapeutic targets for meningiomas, providing new insights into the development of targeted therapy for meningiomas. Show less
no PDF DOI: 10.1007/s12672-025-03318-0
NRXN3

Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.

Tzu-Lin Lee, Wen-Chi Shen, Ya-Chun Chen +9 more · 2025 · Autophagy · Taylor & Francis · added 2026-04-24
Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion Show more
Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Show less
no PDF DOI: 10.1080/15548627.2024.2395799
PIK3C3

CSRNP1 Promotes Apoptosis and Mitochondrial Dysfunction via ROS-Mediated JNK/p38 MAPK Pathway Activation in Hepatocellular Carcinoma.

Huihui Shi, Lei Chen, Juan Huang +6 more · 2025 · Oncology research · added 2026-04-24
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mech Show more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 ( A six-gene prognostic model was established, comprising downregulated genes ( Show less
no PDF DOI: 10.32604/or.2025.068737
POC5

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

Anneke T Vulto-van Silfhout, Ingrid M Jazet, Suzanne Yzer +41 more · 2025 · Genetics in medicine : official journal of the American College of Medical Genetics · Elsevier · added 2026-04-24
A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim t Show more
A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies. Show less
no PDF DOI: 10.1016/j.gim.2025.101513
POC5

Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.

Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff +122 more · 2025 · Nature communications · Nature · added 2026-04-24
Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L DeMeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael LeNoir, Changwei Li, Loic Le Marchand, Merry-Lynn N McDonald, Caitlin P McHugh, Alanna C Morrison, Take Naseri, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice Show less
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data fr Show more
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10 Show less
no PDF DOI: 10.1038/s41467-025-58420-2
POC5

Case Report: Pediatric AML with

Qiang Yao, Xiaoyong Chen, Meizhu Luo +2 more · 2025 · Frontiers in oncology · Frontiers · added 2026-04-24
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibitin Show more
We report a diagnostically challenging case of acute myeloid leukemia (AML) in a 2-year-9-month-old boy, presenting with diarrhea and pancytopenia. Bone marrow aspiration revealed 90% blasts exhibiting cup-like nuclei and azurophilic granules, morphologically mimicking acute promyelocytic leukemia (APL).However, immunophenotyping was inconsistent with classic APL, showing positivity for CD33 and cytoplasmic myeloperoxidase (cMPO) but negativity for CD34 and HLA-DR. Molecular analysis was negative for the canonical PML::RARA fusion but identified a rare Show less
no PDF DOI: 10.3389/fonc.2025.1683005
RAB21

Uncovering the role of RNA binding proteins in colorectal cancer through single-cell transcriptomic analysis.

Mengxin Lin, Zongqi Weng, Yuyuan Lin +6 more · 2025 · Scientific reports · Nature · added 2026-04-24
Colorectal cancer (CRC) is a globally prevalent malignancy associated with high mortality rates. Despite the existence of various treatment modalities, the prognosis for CRC remains relatively poor. T Show more
Colorectal cancer (CRC) is a globally prevalent malignancy associated with high mortality rates. Despite the existence of various treatment modalities, the prognosis for CRC remains relatively poor. This study aims to explore the role of RNA-binding proteins (RBPs) in CRC progression and their potential as prognostic biomarkers and therapeutic targets. We first identified 166 prognosis-related RBPs, including LIN28B, PPARGC1A, RBM47, and AFF3, by performing univariate Cox regression analysis on bulk transcriptomic and clinical data from The Cancer Genome Atlas (TCGA). Next, single-cell RNA sequencing data from normal, adenoma, and CRC tissues of four patients were analyzed to determine cell type-specific expression patterns of RBPs. Ten upregulated RBPs (HSPB1, RBM47, HMGN2, BRD2, BST2, RBM6, YBX3, CANX, PLEC, and RNASET2) were identified as CRC-associated. Among them, HSPB1, RBM47, HMGN2, BRD2, BST2, and PLEC were predominantly expressed in epithelial cell subsets, whereas RNASET2, RBM6, YBX3, and G3BP2 showed higher expression in T cell subpopulations. Aberrant expression of these RBPs was significantly associated with clinical features such as age, cancer stage, and overall survival ( The online version contains supplementary material available at 10.1038/s41598-025-29678-9. Show less
no PDF DOI: 10.1038/s41598-025-29678-9
RBM6

Hsa_circ₀₀₈₁₁₁₁ promotes the proliferation and metastasis of non-small cell lung cancer by regulating IGF2BP2-mediated stability of Slug mRNA.

Wenjun Tang, Junnv Xu, Shu Lin +4 more · 2025 · Experimental cell research · Elsevier · added 2026-04-24
Previous researches have indicated the oncogenic effect of circCOL1A2 in several cancers, such as tongue squamous cell carcinoma, gastric cancer, and colorectal cancer. Regrettably, the functions and Show more
Previous researches have indicated the oncogenic effect of circCOL1A2 in several cancers, such as tongue squamous cell carcinoma, gastric cancer, and colorectal cancer. Regrettably, the functions and mechanisms of circCOL1A2 in lung cancer, a disease with the highest global incidence and mortality rates and with 85 % of cases classified as non-small cell lung cancer (NSCLC), remain largely unexplored. Hsa_circ₀₀₈₁₁₁₁ (circCOL1A2) was identified from GSE236879 dataset of Gene Expression Omnibus (GEO) database. Its expression was validated in 37 paired samples of cancerous and adjacent normal tissues from NSCLC patients, as well as in cell lines. The function of hsa_circ₀₀₈₁₁₁₁ was analyzed using CCK-8, Matrigel transwell, Western blot, and immunofluorescence assays in vitro, and by conducting subcutaneous xenograft experiments in mouse. The underlying mechanisms were explored using bioinformatics analysis, RNA pull-down experiments, and RNA immunoprecipitation. High expression of hsa_circ₀₀₈₁₁₁₁ was observed in NSCLC tissues and cell lines. This was positively correlated with the TNM stage and lymph node metastasis of NSCLC patients. Hsa_circ₀₀₈₁₁₁₁ overexpression promoted the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of NSCLC cells. Conversely, its downregulation showed the opposite effects. In vivo studies revealed that silencing hsa_circ₀₀₈₁₁₁₁ inhibited tumor growth, EMT, and MMP9 expression in tumor tissues. Mechanically, hsa_circ₀₀₈₁₁₁₁ enhanced Slug mRNA stability by interacting with the RNA-binding protein IGF2BP2. Taken together, hsa_circ₀₀₈₁₁₁₁ is an oncogenic circRNA that promotes NSCLC malignancy by regulating IGF2BP2-mediated Slug mRNA stability. Hsa_circ₀₀₈₁₁₁₁ has the potential to be a diagnostic and therapeutic target for NSCLC. Show less
no PDF DOI: 10.1016/j.yexcr.2025.114685
SNAI1

CXCR4-LASP1-G9a-SNAIL axis drives NEPC transdifferentiation via induction of EMT and downregulation of REST.

Liangliang Liu, Itzel Astiazarán Rascón, Dong Lin +15 more · 2025 · Cell genomics · Elsevier · added 2026-04-24
Phenotypic switching is an emerging driver of cancer treatment resistance, yet early signals regulating this process remain unclear. Here, using longitudinal single-cell RNA sequencing, we mapped diff Show more
Phenotypic switching is an emerging driver of cancer treatment resistance, yet early signals regulating this process remain unclear. Here, using longitudinal single-cell RNA sequencing, we mapped differentiation trajectories in the LTL331 prostate adenocarcinoma patient-derived xenograft (PDX) model undergoing neuroendocrine prostate cancer (NEPC) transformation post castration. Our analyses identified a key differentiation node marked by epithelial-mesenchymal transition (EMT) and repressor element-1 silencing transcription factor (REST) downregulation driven by the CXCR4-LASP1-G9a-SNAIL axis. Mechanistically, CXCR4 activation promotes nuclear translocation of LASP1 that links G9a and SNAIL via SH3/proline-rich motif and LIM/SNAG domain interactions, enabling SNAIL-mediated REST repression via promoter E-box motifs. Inhibition of CXCR4 or G9a reversed LTL331R NEPC cells toward a luminal androgen receptor-active phenotype. CXCR4-targeted radioligands enabled both imaging and inhibition of NEPC tumors in vivo. These findings highlight the CXCR4-LASP1-G9a-SNAIL axis as a key regulator of epigenetic and transcriptional reprogramming in NEPC transdifferentiation and support its therapeutic targeting in aggressive NEPC. Show less
no PDF DOI: 10.1016/j.xgen.2025.100916
SNAI1

STAT3-mediated upregulation of TRIM6 promotes hepatocellular carcinoma invasion through the DDX58-Snail1 axis.

Yiqiao Wang, Jie Wang, Shihao Huang +7 more · 2025 · Scientific reports · Nature · added 2026-04-24
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, driven by complex molecular mechanisms that remain inadequately understood. Among these, the ubiquitin-proteasome Show more
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, driven by complex molecular mechanisms that remain inadequately understood. Among these, the ubiquitin-proteasome system plays a crucial role in regulating protein stability and function, with E3 ubiquitin ligases emerging as key players in cancer progression. Here, we identify Tripartite Motif-containing 6 (TRIM6), an E3 ubiquitin ligase, as a critical regulator of HCC metastasis. We demonstrate that TRIM6 is significantly upregulated in HCC tissues and correlates with poor overall survival. Mechanistically, we uncover that STAT3 directly regulates TRIM6 by binding to its promoter and enhancing its transcription. Functionally, TRIM6 promotes epithelial-mesenchymal transition (EMT) and cell invasion by upregulating the key EMT transcription factor Snail1. Importantly, we reveal that TRIM6 interacts with and ubiquitinates DDX58 (RIG-I), leading to its proteasomal degradation. The degradation of DDX58 by TRIM6 alleviates its inhibitory effects on Snail1, thereby facilitating EMT and enhancing the invasive potential of HCC cells. These findings establish the STAT3-TRIM6-DDX58-Snail1 axis as a pivotal pathway in HCC progression, offering novel insights into the molecular underpinnings of HCC metastasis and highlighting TRIM6 as a potential therapeutic target and prognostic biomarker in HCC. Show less
no PDF DOI: 10.1038/s41598-025-96548-9
SNAI1

POU6F2 promotes liver metastasis of gastric adenocarcinoma by dual mechanism of transcriptional upregulation of SNAI1 and IGF2/PI3K/AKT signaling-induced conversion of hepatic stellate cells into cancer-associated fibroblasts.

Chunxiao Yang, Zhiqing Gao, Ruiming Tang +16 more · 2025 · British journal of cancer · Nature · added 2026-04-24
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells ( Show more
Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC. Show less
no PDF DOI: 10.1038/s41416-025-03017-1
SNAI1

Cyclic increase in the histamine receptor H1-ADAM9-Snail/Slug axis as a potential therapeutic target for EMT-mediated progression of oral squamous cell carcinoma.

Yi-Fang Ding, Kuo-Hao Ho, Wei-Jiunn Lee +8 more · 2025 · Cell death & disease · Nature · added 2026-04-24
The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor Show more
The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor H1 (HRH1) was reported to be overexpressed in several cancer types, but its specific functional implications in oral squamous cell carcinoma (OSCC) predominantly remain unexplored. Our findings indicate that dysregulated high levels of HRH1 were correlated with lymph node (LN) metastasis and poor prognoses in OSCC patients. We identified a disintegrin and metalloprotease 9 (ADAM9) as a critical downstream target of HRH1, promoting protumorigenic and prometastatic characteristics both in vitro and in vivo. Molecular investigations revealed that the cyclic increase in the HRH1-ADAM9-Snail/Slug axis promoted progression of the epithelial-to-mesenchymal transition (EMT). Clinical analyses demonstrated significant correlations of HRH1 expression with ADAM9 and with EMT-related markers, with elevated ADAM9 also associated with LN metastasis in OSCC patients. Regarding therapeutic aspects, we discovered that activated STAT3 acts as a compensatory pathway for the long-term HRH1 signaling blockade in OSCC cells. Combining inhibition of HRH1 and STAT3 using their respective inhibitors or short hairpin (sh)RNAs enhanced the tumor-suppressive effects compared to HRH1 inhibition/depletion alone in OSCC cells and a xenograft model. In summary, HRH1 has emerged as a valuable biomarker for predicting OSCC progression, and combined targeting of HRH1 and STAT3 may represent a promising strategy for preventing OSCC progression. Show less
no PDF DOI: 10.1038/s41419-025-07507-1
SNAI1

Programmed cell death protein 5 inhibits hepatocellular carcinoma progression by inducing pyroptosis through regulation of TGF-β/Smad2/3/Snail pathway.

Yiqiao Wang, Shihao Huang, Yangbai Cai +5 more · 2025 · Biochimica et biophysica acta. Molecular basis of disease · Elsevier · added 2026-04-24
Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcin Show more
Programmed cell death protein 5 (PDCD5) is involved in apoptosis and is regarded as a tumor suppressor in various tumors. However, its role and underlying molecular mechanisms in hepatocellular carcinoma (HCC) remain unclear. PDCD5-overexpressing cell and xenograft tumor models were developed. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, wound healing, Transwell, flow cytometry, immunohistochemistry, and hematoxylin-eosin staining were employed to explore the effects of PDCD5 on HCC cell behaviors and tumor growth. The enzyme-linked immunosorbent assay and western blot were used to detect pyroptosis-related marker levels. The molecular mechanisms underlying PDCD5's role in HCC were investigated through transcriptome sequencing and coimmunoprecipitation. SRI-011381, a TGF-β signaling activator, was applied to evaluate the impact of PDCD5 in modulating the TGF-β/Smad2/3/Snail pathway. PDCD5 expression was reduced in HCC cells. Overexpression of PDCD5 inhibited HCC cell proliferation, migration, invasion, and xenograft tumor growth. Additionally, PDCD5 overexpression promoted apoptosis and pyroptosis, with corresponding increases in inflammatory factors and Caspase-1, GSDMD, and NLRP3 protein levels. Mechanistically, PDCD5 bound to receptor-regulated Smads (Smad2/3), inhibiting the TGF-β pathway. Treatment with the TGF-β pathway activator SRI-011381 significantly counteracted the inhibitory effects of PDCD5 overexpression on HCC progression. Our findings suggest that PDCD5 impedes the progression of HCC by promoting pyroptosis via regulation of TGF-β/Smad2/3/Snail pathway, which could be a possible therapeutic target for HCC. Show less
no PDF DOI: 10.1016/j.bbadis.2025.167696
SNAI1

ANGPTL3 overcomes sorafenib resistance via suppression of SNAI1 and CPT1A in liver cancer.

Yang-Hsiang Lin, Cheng-Yi Chen, Hsiang-Cheng Chi +3 more · 2025 · Translational oncology · Elsevier · added 2026-04-24
Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is resp Show more
Liver cancer, encompassing hepatocellular carcinoma (HCC) and hepatoblastoma, the latter of which primarily occurs in early childhood, is the most common malignant tumor arising from liver and is responsible for a significant number of cancer-related deaths worldwide. Targeted drugs have been used for anti-liver cancer treatment in the advanced stage, while their efficacy is greatly compromised by development of drug resistance. Drug resistance is a complicated process regulated by intrinsic and extrinsic signals and has been associated with poorer prognosis in cancer patients. In the current study, online available dataset analysis uncovered that angiopoietin-like protein 3 (ANGPTL3) manifested lower expression in sorafenib-resistant liver cancer cell lines. Additionally, ANGPTL3 was downregulated in HCC tissues, with its expression positively correlated with good prognosis. Functionally, ectopic expression of ANGPTL3 re-sensitized sorafenib-resistant cells, enhancing the sorafenib-induced reduction in cell viability and migration by suppressing zinc finger protein SNAI1 (SNAI1) expression and the protein stability of carnitine O-palmitoyltransferase 1, liver isoform (CPT1A). Clinical correlation analysis revealed that ANGPTL3 was negatively associated with SNAI1 expression. In conclusion, we identify a novel association between ANGPTL3, SNAI1 and CPT1A on sorafenib therapeutic response. Targeting ANGPTL3/SNAI1/CPT1A axis may serve as a therapeutic approach to improve prognosis of liver cancer patients with sorafenib resistance. Show less
no PDF DOI: 10.1016/j.tranon.2024.102250
SNAI1

FAM189A2 activates Hippo signaling pathway by abrogating WWP2-mediated LATS1 ubiquitination, to inhibit the glycolysis and proliferation processes of lung adenocarcinoma.

Bingyu Chen, Xuezhu Rong, Yuheng Feng +5 more · 2025 · Journal of translational medicine · BioMed Central · added 2026-04-24
Metabolic abnormalities have become a prominent hallmark of malignant tumor and play a crucial role in the occurrence and development of lung adenocarcinoma (LUAD). however, the underlying mechanism i Show more
Metabolic abnormalities have become a prominent hallmark of malignant tumor and play a crucial role in the occurrence and development of lung adenocarcinoma (LUAD). however, the underlying mechanism involved this process is still far from being fully elucidated. In this study, we aimed to explore the essential factors regulating the glycolysis and proliferation process in LUAD. Bioinformation and immunohistochemistry were applied to screen and verify the expression pattern of the vital factors in LUAD. A series of biological function assays, including Cell Counting Kit 8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridine‌ (EdU), seahorse assays and nude mouse transplantation tumor assays, were performed to demonstrate the impact of the family with sequence similarity 189 member A2 (FAM189A2) on the glycolysis and proliferation process in LUAD. Co-immunoprecipitation, immunofluorescence and dual-luciferase reporter gene and RT-qPCR were used to verify the FAM129A2 and the WW domains of E3 ubiquitin ligase (WWP2) interaction, as well as the influence of their combination on large tumour suppressor-1 (LATS1) ubiquitination level and Hippo signaling pathway activity. FAM189A2 was weakly expressed in the cytoplasm of LUAD, and associated with the poor prognosis of patients. FAM189A2 overexpression inhibited the glycolysis and proliferation processes of LUAD cells in vitro. Meanwhile, both the processes were enhanced following FAM189A2 knockdown. Mechanistically, FAM189A2 was identified to interact with WWP2 through its own PPxY motifs, hence weakened the WWP2-LATS1 affinity and inhibited the WWP2-mediated LATS1 ubiquitination, which ultimately resulted in a reduced yes-associated protein (YAP) nuclear translocation. In addition, Verteporfin (Hippo pathway inhibitor) or YAP knockdown could eliminate the biological effects of promoting proliferation and glycolysis in LUAD cells caused by FAM189A1 silence. FAM189A2 can be considered as a potential diagnostic and prognostic marker associated with LUAD, and suppresses the proliferation and glycolytic metabolism of LUAD cells via WWP2-LATS1-YAP signaling, which will provide a corresponding theoretical foundation for the development of small molecule inhibitors. Show less
no PDF DOI: 10.1186/s12967-025-07526-8
WWP2

The Ubiquitination and Degradation of SH2B3 Mediated by MEF2A/WWP2 Axis Restores Microglial Homeostasis to Alleviate Cerebral Microvascular Endothelial Cell Injury in Ischemic Stroke.

Si-Xian Lin, Chenglong Shi, Lei Zhao +6 more · 2025 · Neurochemical research · Springer · added 2026-04-24
Ischemic stroke (IS) is a severe disease. The altered activation states of microglia play important roles in IS. In present study, a total of 125 C57BL/6 mice was used (N = 6 per group). Middle cerebr Show more
Ischemic stroke (IS) is a severe disease. The altered activation states of microglia play important roles in IS. In present study, a total of 125 C57BL/6 mice was used (N = 6 per group). Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were performed for in vivo and in vitro model construction. The infarct size was detected using TTC staining. The nerve injury was evaluated by a neurological deficit score. OGD-treated brain microvascular endothelial cells (BMECs) were co-cultured with BV2 cells. Cell viability was determined by CCK-8 assay, and the apoptosis rate was identified by flow cytometry analysis. Transendothelial electronic resistance (TEER) of the cells was measured by TEER measurement. Molecular interactions were analyzed using dual-luciferase reporter gene, ChIP, and Co-IP assays. All in vitro experiments were conducted with three replicates, and each experiment was performed in triplicate. We found that Src Homology 2B Adaptor Protein 3 (SH2B3) was overexpressed in the cerebral cortex tissues of MCAO treated mice (P < 0.01), and BMECs co-cultured with BV-2 cells under OGD conditions (P < 0.01). SH2B3 knockdown or Myocyte Enhancer Factor 2 A (MEF2A) overexpression reduced infarct size and improved neurological function in MCAO mice. SH2B3 knockdown enhanced OGD-treated cell viability (P < 0.05), inhibited cell apoptosis (P < 0.05) in BMECs, and ameliorated BBB (P < 0.01). Moreover, SH2B3 knockdown changed the activation status of microglia. MEF2A promoted the transcriptional activation of WW Domain Containing E3 Ubiquitin Protein Ligase 2 (WWP2) and WWP2 promoted the ubiquitination and degradation of SH2B3. SH2B3 overexpression reversed the effects of MEF2A overexpression on microglia states, BMECs injury and BBB function. In summary, MEF2A promoted the ubiquitination-mediated degradation of SH2B3 via transcription up-regulating WWP2, then changed the activation status of microglia, thus ameliorating BMEC injury, and finally ameliorating IS injury. Show less
no PDF DOI: 10.1007/s11064-025-04406-x
WWP2

ADCY3: the pivotal gene in classical ketogenic diet for the treatment of epilepsy.

Mingxing Lin, Jiayin Gong, Luyan Wu +5 more · 2024 · Frontiers in cellular neuroscience · Frontiers · added 2026-04-24
Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, t Show more
Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, the exact therapeutic mechanism of the ketogenic diet for epilepsy remains unclear. This study investigates the molecular mechanisms of the ketogenic diet in regulating fatty acid metabolism and activating the ADCY3-initiated cAMP signaling pathway to enhance neuronal inhibition and thereby treat epilepsy. Meta-analysis reveals that the ketogenic diet is superior to the conventional diet in treating epilepsy. Animal experiments demonstrate that the ketogenic diet is more effective than the conventional diet in treating epilepsy, with the best results achieved using the classic ketogenic diet. Transcriptome sequencing analysis identifies six essential genes, among which ADCY3 shows increased expression in the ketogenic diet. In vivo experiments confirm that the activation of the cAMP-PKA signaling pathway by ADCY3 enhances neuronal inhibition and improves epilepsy control. Clinical observations indicate that the ketogenic diet improves patient epilepsy episodes by regulating the ADCY3-initiated cAMP signaling pathway. Show less
📄 PDF DOI: 10.3389/fncel.2024.1305867
ADCY3

Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.

Tristan C Dinsmore, Jamie Liu, Jiayuan Miao +5 more · 2024 · Angewandte Chemie (International ed. in English) · Wiley · added 2026-04-24
The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite su Show more
The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP-1 receptor (GLP-1R) and dual agonists of GLP-1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase-4 (DPP4), that catalyzes rapid removal of the two N-terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza-amino acids, that are bioisosteric replacements for α-amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza-amino acid can populate the same conformational space that GLP-1 adopts when bound to the GLP-1R. The insertion of an aza-amino acid at the second position from the N-terminus in semaglutide and in a dual agonist of GLP-1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling. Show less
no PDF DOI: 10.1002/anie.202410237
GIPR

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

Ajit Regmi, Eitaro Aihara, Michael E Christe +22 more · 2024 · Cell metabolism · Elsevier · added 2026-04-24
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, an Show more
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state. Show less
no PDF DOI: 10.1016/j.cmet.2024.05.010
GIPR

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Hongyu Liu, Huimin Xiao, Sufen Lin +4 more · 2024 · Frontiers in pharmacology · Frontiers · added 2026-04-24
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skel Show more
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms. Show less
📄 PDF DOI: 10.3389/fphar.2024.1372399
GIPR

An imbalanced GLP-1R/GIPR co-agonist peptide with a site-specific N-terminal PEGylation to maximize metabolic benefits.

Xuan Xia, Qianmeng Lin, Zhan Zhou +1 more · 2024 · iScience · Elsevier · added 2026-04-24
Glycemic and body weight control gained from GLP-1R agonists remains an unmet need for diabetes and obesity treatment, leading to the development of GLP-1R/GIPR co-agonists. An imbalance in GLP-1R/GIP Show more
Glycemic and body weight control gained from GLP-1R agonists remains an unmet need for diabetes and obesity treatment, leading to the development of GLP-1R/GIPR co-agonists. An imbalance in GLP-1R/GIPR agonism may extensively maximize the glucose- and weight-lowering effects. Hence, we prepared a potent and imbalanced GLP-1R/GIPR co-agonist, and refined its action time through a site-specific N-terminal PEGylation strategy. The pharmacological efficacy of these resulting long-acting co-agonists was interrogated both Show less
📄 PDF DOI: 10.1016/j.isci.2024.109377
GIPR

Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G

Zhaotong Cong, Fenghui Zhao, Yang Li +9 more · 2024 · Cell discovery · Nature · added 2026-04-24
Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-li Show more
Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with G Show less
📄 PDF DOI: 10.1038/s41421-024-00649-0
GIPR

Association of obesity and menarche SNPs and interaction with environmental factors on precocious puberty.

Peng Xue, Jianfei Lin, Jingyi Tang +6 more · 2024 · Pediatric research · Nature · added 2026-04-24
Obesity is an important cause for the precocious or early puberty. However, the association between obesity-related loci and the risk of precocious puberty as well as the effect of gene-environment in Show more
Obesity is an important cause for the precocious or early puberty. However, the association between obesity-related loci and the risk of precocious puberty as well as the effect of gene-environment interaction are unclear, especially in the Chinese children population. This was a case-control study using baseline data from two cohorts and hospital cases in China. 15 SNPs loci and several environmental factors were included in the analysis of 1201 participants. Chi-square test and logistic regression were used to analyze the association between SNPs and precocious puberty. Additionally, exploratory factor analysis was conducted on 13 environmental variables, and then to explore their interaction with genes on precocious puberty. The effect allele C of rs571312, and G of rs12970134 MC4R were associated with precocious puberty in girls with obesity. Regarding the gene-environment interaction, we found that when girls were in the high socioeconomic status, the rs571312 (OR: 3.996; 95% CI: 1.694-9.423) and rs12970134 (OR: 3.529; 95% CI: 1.452-8.573) risk genotypes had a greater effect on precocious puberty. The obesity risk gene polymorphisms MC4R rs571312 and rs12970134 were associated with precocious puberty in Chinese girls with obesity, and girls with risk genotypes and high socioeconomic status should be given extra attention. This is the first study that identified the association between rs571312 and rs12970134 of MC4R gene and precocious puberty in Chinese children. We found that when girls were in the high socioeconomic status, the risk genotypes of rs571312 and rs12970134 had a greater effect on precocious puberty. The results of this study have great public health implications. It is recommended that girls who are in high socioeconomic status and have a high genetic risk for early sexual maturity should closely monitor their pubertal development and consider early intervention strategies. Show less
📄 PDF DOI: 10.1038/s41390-024-03168-6
MC4R

CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.

Youwen Yuan, Kangli Li, Xueru Ye +12 more · 2024 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activit Show more
Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders. Show less
📄 PDF DOI: 10.1073/pnas.2310711121
ADCY3

Multi-Omics Approaches Uncovered Critical mRNA-miRNA-lncRNA Networks Regulating Multiple Birth Traits in Goat Ovaries.

Weibing Lv, Ren An, Xinmiao Li +9 more · 2024 · International journal of molecular sciences · MDPI · added 2026-04-24
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptabili Show more
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptability. The ovary, as a key organ determining reproductive performance, is regulated by a complex transcriptional network involving numerous protein-coding and non-coding genes. However, the molecular mechanisms of the key mRNA-miRNA-lncRNA regulatory network in goat ovaries remain largely unknown. This study focused on the histology and differential mRNA/miRNA/lncRNA between Chuanzhong black goat (CBG, high productivity, multiple births) and Tibetan goat (TG, strong adaptability, single birth) ovaries. Histomorphological analysis showed that the medulla proportion in CBG ovaries was significantly reduced compared to TG. RNA-Seq and small RNA-Seq analysis identified 1218 differentially expressed (DE) mRNAs, 100 DE miRNAs, and 326 DE lncRNAs, which were mainly enriched in ovarian steroidogenesis, oocyte meiosis, biosynthesis of amino acids and protein digestion, and absorption signaling pathways. Additionally, five key mRNA-miRNA-lncRNA interaction networks regulating goat reproductive performance were identified, including Show less
📄 PDF DOI: 10.3390/ijms252212466
AKAP6