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July 2, 2026Open Access

Molecular mechanisms of erectile dysfunction in type 1 and type 2 diabetic rats: a multiomics approach

Key Points

This study aims to uncover the molecular mechanisms of erectile dysfunction in type 1 and type 2 diabetic models.
Establishment of type 2 diabetes mellitus-related erectile dysfunction rat model
Multiomics approach integrating transcriptomic analysis and machine learning techniques
Validation of findings through quantitative polymerase chain reaction and Western blot.
Identified 141 shared differentially expressed genes between T1DM-ED and T2DM-ED models, enriched in key signaling pathways.
Downregulation of proteins linked to inflammation and survival signaling—including periostin, elastin, and collagen—suggested a impaired ECM environment.
Increased macrophage infiltration and enhanced apoptosis indicated a pathological state affecting erectile function.

Abstract

Erectile dysfunction (ED) is a prevalent complication of both type 1 and type 2 diabetes mellitus (DM), but the shared molecular mechanisms underlying this complication remain unclear. This study employed an integrative multiomics approach to identify conserved pathways in diabetic ED. A type 2 diabetes mellitus-related erectile dysfunction (T2DM-ED) rat model was established and validated functionally. Transcriptomic analysis of cavernous tissue identified differentially expressed genes (DEGs), which were cross-referenced with a public type 1 diabetes mellitus-related erectile dysfunction (T1DM-ED) dataset, revealing 141 shared DEGs enriched in extracellular matrix (ECM)–receptor interaction, focal adhesion, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt), and advanced glycation end products (AGE)–receptor for advanced glycation end products (RAGE) signaling. Machine learning prioritized five consistently downregulated hub genes (periostin POSTN , elastin ELN , collagen type VI alpha 3 chain COL6A3 , collagen type V alpha 2 chain COL5A2 , and secreted protein acidic and rich in cysteine SPARC ), as validated by quantitative polymerase chain reaction (qPCR) and Western blot. Their encoded proteins (periostin, elastin, collagen VI, collagen V, and SPARC) were significantly suppressed. Further analysis revealed downregulation of the expression of the focal adhesion kinase (FAK)–PI3K–Akt survival pathway and brain-derived neurotrophic factor (BDNF) and increased apoptosis (cleaved caspase-3) and CD68 + macrophage infiltration. Single-cell RNA sequencing (scRNA-seq) mapping localized these hub genes to stromal and neural cells. These findings reveal a pathological microenvironment of ECM imbalance, impaired survival signaling, and inflammation, which are common to both diabetic ED subtypes. We conclude that macrophage-driven inflammation and ECM disruption converge to inhibit FAK–PI3K–Akt signaling, accelerating structural and functional decline. This inflammatory–ECM signaling axis represents a promising therapeutic target for diabetic ED.

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