VCPIP1 drives diabetic cardiomyopathy by deubiquitinating AMPKγ1 and preventing AMPKα-γ subunit assembly in cardiomyocytes.

Summary

This mechanistic study identifies VCPIP1 as a deubiquitinase that deubiquitinates AMPKγ1 (K63 at K234), disrupting AMPKα–γ assembly and impairing AMPK activation, thereby driving diabetic cardiomyopathy. Cardiomyocyte-specific VCPIP1 knockout mitigated cardiac injury in both T1D and T2D mouse models, positioning the VCPIP1–AMPKγ1 axis as a therapeutic target.

Key Findings

• VCPIP1 expression is elevated in diabetic hearts and localized to cardiomyocytes.
• Cardiomyocyte-specific VCPIP1 knockout ameliorates cardiac injury in both T1D and T2D mouse models.
• Ubiquitinome/interactome profiling identifies AMPKγ1 as a VCPIP1 substrate; VCPIP1 binds AMPKγ1 (CBS2) via UBX-L.
• VCPIP1 catalyzes K63-linked deubiquitination at AMPKγ1-K234 via catalytic C218, disrupting AMPKα–γ assembly and AMPKα2–LKB1 interaction.

Clinical Implications

While preclinical, inhibiting VCPIP1 or preserving AMPKα–γ assembly may restore AMPK signaling and mitigate DCM. The pathway could guide biomarker development and patient stratification based on cardiac VCPIP1/AMPKγ1 status.

Limitations

• Preclinical study; limited human validation beyond expression profiling.
• Potential off-target or compensatory effects of DUB modulation not fully characterized.

Future Directions

Develop selective VCPIP1 inhibitors or strategies to stabilize AMPKα–γ assembly; validate pathway activity and biomarkers in human DCM cohorts; test translational efficacy in large-animal models.