Diabetic cardiomyopathy as a disorder of proteostatic maladaptation: context-dependent ubiquitin-specific protease networks

Figures

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  FIGURE 1. Conceptual framework: diabetic stress, proteostatic disturbance and USP-dependent remodeling in DCM. Diabetic stressors, including hyperglycaemia, lipotoxicity, insulin resistance, advanced glycation end-products (AGEs) and reactive oxygen species (ROS), disturb myocardial protein homeostasis through ubiquitination imbalance, deubiquitinase (DUB) dysregulation, impaired ubiquitin-proteasome system (UPS) activity and altered autophagy. USPs act on this disturbed proteostatic landscape through three mechanistic modes: protein stabilization, ubiquitin-chain editing, and signaling-complex remodeling. USP-dependent substrate regulation in turn links proteostatic failure to five interconnected pathological modules, mitochondrial dysfunction and metabolic remodeling, inflammation and inflammatory cell death, ferroptosis and redox injury, autophagy impairment and defective proteostasis, and fibrotic remodeling, which converge on diastolic dysfunction, systolic dysfunction, arrhythmia and heart failure. This framework reframes DCM as a disorder of metabolic stress-driven proteostatic maladaptation in which USPs function as nodal regulators rather than peripheral modifiers.

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  FIGURE 2. Evidence-resolved USP-substrate network in diabetic cardiomyopathy. (A) Experimentally supported USP-substrate axes are mapped onto major pathological processes in DCM. Green denotes predominantly protective axes, red denotes predominantly injurious axes, and amber denotes bidirectional or context-dependent regulation. Question marks identify unresolved direct substrates or ubiquitin-linkage information. USP7 illustrates substrate-dependent bidirectionality through the injurious USP7-PGC1β axis and the protective USP7-NRF2/GPX4 axis. The USP24 autophagy pathway is represented as direct stabilization of TRAF6 followed by TRAF6-dependent Beclin-1 ubiquitination and degradation. (B) Cell type-resolved evidence. Most direct DCM evidence derives from cardiomyocytes, whereas USP33 provides direct endothelial-specific evidence through the ATG7-FIS1 pathway. Direct substrate-resolved USP evidence in cardiac fibroblasts and immune cells remains limited in non-ischemic DCM. The previous stage-specific panel was removed because temporal dominance of individual USP axes has not been directly established experimentally.

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  FIGURE 3. Potential translational directions for USP-substrate modulation in diabetic cardiomyopathy. (A) Hypothesis-generating axis-level intervention concepts based on currently reported USP-substrate relationships in diabetic cardiomyopathy (DCM). Predominantly injurious programs include USP14-VDAC1, USP24-associated ferroptotic and autophagy-disruptive signaling, USP38-ACAD11 and USP7-PGC1β. USP7 is highlighted as a context-dependent regulator because USP7-PGC1β promotes maladaptive metabolic remodeling, whereas USP7-NRF2 supports GPX4-dependent ferroptosis resistance, illustrating the rationale for substrate-selective rather than whole-enzyme modulation. Potentially protective programs include USP28-PPARα/Mfn2, USP13-NLRP3, USP20-p62/STING, H2S-dependent USP8-Parkin signaling, endothelial USP33-ATG7/FIS1 and USP18-associated Notch1/FOXC2 signaling. These intervention concepts remain preclinical and should not be interpreted as therapeutically validated strategies in DCM. (B) Key prerequisites for future translational evaluation, including validation of disease-relevant USP-substrate axes in human diabetic myocardium, demonstration of cardiac and cell type-specific target engagement,…