Transcriptional Regulatory Network Analysis Uncovers Modular Gene Control and Potential Key Regulators in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) arises from the interplay of metabolic overload, inflammation, and structural remodeling, yet the transcriptional mechanisms coordinating these processes remain incompletely defined. Here, we combined differential expression profiling of human hiPSC-derived cardiomyocytes exposed to diabetic conditions with literature-curated transcription factor target interactions to reconstruct a comprehensive transcriptional regulatory subnetwork for DCM. Topological and functional analyses revealed transcriptional reprogramming organized into six modules spanning metabolic, inflammatory, hypoxic, fibrotic, and hormonal programs. Established DCM-associated regulators (e.g., FOS, JUN, STAT3, and MYC) ranked among the highest-centrality hubs. Added to this group is ESR1, whose role in estrogen signaling is well established, yet whose function as a high-centrality hub within a DCM has not previously been recognized. In contrast, TRPS1, HBP1, and NFIA operated as a secondary tier of locally acting regulators, highlighting a multilayered and modular regulatory architecture. Network-derived predictions were experimentally validated in a type 2 diabetes mouse model, where ESR1 and STAT6 were significantly downregulated and TRPS1 and HBP1 were upregulated in diabetic hearts, providing supportive evidence for cross-species concordance of a subset of regulatory signatures. Together, our results outline the modular structure of a curated DCM regulatory subnetwork and highlight candidate regulators that motivate future functional perturbation studies and biomarker-focused validation in diabetic cardiac disease.