Hippo signaling-linked circulating microRNA networks are associated with cardiovascular disease in type 2 diabetes.
13 affiliations
- 1Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
- 2Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
- 3Department of Public Health Sciences, University of Miami, Miami, FL 33136, USA.
- 4Max Delbrück Center-Berlin Institute for Medical Systems Biology (MDC-BIMSB), Berlin 10115, Germany.
- 5Department of Medicine, Surgery and Neuroscience, University of Siena, Siena 53100, Italy.
- 6Department of Computer, Control and Management Engineering, Sapienza University of Rome, Rome 00161, Italy.
- 7Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy.
- 8Department of Life, Health and Health Professions Sciences, Link Campus University, Rome 00165, Italy.
- 9Laboratory of Preclinical and Translational Research, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, PZ 85028, Italy.
- 10Department of Radiological, Oncological & Pathological Sciences, Sapienza University of Rome, Rome 00161, Italy.
- 11Department of Systems Medicine, Tor Vergata University, Rome 00133, Italy.
- 12Department of Medicine, University of Padova, Padua 35121, Italy.
- 13Department of Biomedical Science, Consiglio Nazionale delle Ricerche, Rome 00185, Italy.
Abstract
Context
Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease (CVD). Circulating microRNAs (miRNAs) are promising biomarkers for patient stratification and may provide mechanistic insight into dysregulated pathways in T2D-associated CVD.Objective
This work aimed to identify circulating miRNA signatures in T2D patients with CVD (T2D-CVD) vs T2D patients without CVD using a novel network-based medicine approach.Methods
Patients (n = 110) were stratified into T2D and T2D-CVD groups based on the absence or presence of macrovascular complications. Circulating miRNAs, proinflammatory cytokines, and growth factors were profiled in a discovery cohort (n = 80) and confirmed in a validation cohort (n = 30). Differential expression, network-based approaches, and pathway enrichment analyses identified miRNA signatures, coexpression communities, hub miRNAs, and associated signaling pathways.Results
T2D-CVD patients showed a set of elevated inflammatory cytokines and circulating miRNAs. Particularly, 19 miRNAs were differentially expressed between T2D-CVD and T2D patients. Pathway enrichment of these miRNAs highlighted Hippo signaling together with transforming growth factor-β, mechanistic target of rapamycin, Wnt, and PI3K-Akt pathways. Network analysis identified a coexpression community of 34 miRNAs, including hub miRNAs let-7a-5p, miR-132-3p, and miR-1306-3p, all linked to Hippo signaling. Key miRNA interactions were validated, and differentially expressed and hub miRNAs both correlated with inflammatory mediators such as PAR-1, CXCL1, and NEMO, which are linked to Hippo pathway regulation.Conclusion
This study identified a network of circulating miRNAs associated with inflammatory cytokines and Hippo signaling pathway in T2D-CVD. These findings reveal novel molecular aspects of the systemic inflammation characterizing T2D-CVD and support the potential of Hippo-related circulating miRNAs as mechanistic biomarkers for cardiovascular risk in T2D.
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BibTeX
@article{besharat2026hippo,
title = {{Hippo signaling-linked circulating microRNA networks are associated with cardiovascular disease in type 2 diabetes.}},
author = {Zein Mersini Besharat and Sofia Trocchianesi and Giuseppina Emanuela Grieco and Tanja Milena Autilio and Caterina Alfano and Angela Dardano and Daniela Fignani and Elena Splendiani and Anna Citarella and Claudia Sabato and Zaira Spinello and Giuseppina Catanzaro and Agnese Po and Manuela Petti and Lorenzo Farina and Mary Anna Venneri and Davide Lauro and Gian Paolo Fadini and Francesco Dotta and Guido Sebastiani and Andrea Natali and Elisabetta Ferretti},
journal = {Journal of the Endocrine Society},
year = {2026},
month = oct,
doi = {10.1210/jendso/bvag229},
url = {https://europepmc.org/article/MED/42909870},
note = {CC BY},
}
RIS
TY - JOUR
TI - Hippo signaling-linked circulating microRNA networks are associated with cardiovascular disease in type 2 diabetes.
AU - Zein Mersini Besharat
AU - Sofia Trocchianesi
AU - Giuseppina Emanuela Grieco
AU - Tanja Milena Autilio
AU - Caterina Alfano
AU - Angela Dardano
AU - Daniela Fignani
AU - Elena Splendiani
AU - Anna Citarella
AU - Claudia Sabato
AU - Zaira Spinello
AU - Giuseppina Catanzaro
AU - Agnese Po
AU - Manuela Petti
AU - Lorenzo Farina
AU - Mary Anna Venneri
AU - Davide Lauro
AU - Gian Paolo Fadini
AU - Francesco Dotta
AU - Guido Sebastiani
AU - Andrea Natali
AU - Elisabetta Ferretti
PY - 2026
DA - 2026/10/14
JO - Journal of the Endocrine Society
DO - 10.1210/jendso/bvag229
UR - https://europepmc.org/article/MED/42909870
AB - Context Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease (CVD). Circulating microRNAs (miRNAs) are promising biomarkers for patient stratification and may provide mechanistic insight into dysregulated pathways in T2D-associated CVD.Objective This work aimed to identify circulating miRNA signatures in T2D patients with CVD (T2D-CVD) vs T2D patients without CVD using a novel network-based medicine approach.Methods Patients (n = 110) were stratified into T2D and T2D-CVD groups based on the absence or presence of macrovascular complications. Circulating miRNAs, proinflammatory cytokines, and growth factors were profiled in a discovery cohort (n = 80) and confirmed in a validation cohort (n = 30). Differential expression, network-based approaches, and pathway enrichment analyses identified miRNA signatures, coexpression communities, hub miRNAs, and associated signaling pathways.Results T2D-CVD patients showed a set of elevated inflammatory cytokines and circulating miRNAs. Particularly, 19 miRNAs were differentially expressed between T2D-CVD and T2D patients. Pathway enrichment of these miRNAs highlighted Hippo signaling together with transforming growth factor-β, mechanistic target of rapamycin, Wnt, and PI3K-Akt pathways. Network analysis identified a coexpression community of 34 miRNAs, including hub miRNAs let-7a-5p, miR-132-3p, and miR-1306-3p, all linked to Hippo signaling. Key miRNA interactions were validated, and differentially expressed and hub miRNAs both correlated with inflammatory mediators such as PAR-1, CXCL1, and NEMO, which are linked to Hippo pathway regulation.Conclusion This study identified a network of circulating miRNAs associated with inflammatory cytokines and Hippo signaling pathway in T2D-CVD. These findings reveal novel molecular aspects of the systemic inflammation characterizing T2D-CVD and support the potential of Hippo-related circulating miRNAs as mechanistic biomarkers for cardiovascular risk in T2D.
SN - 2472-1972
ER -