USP30 Knockdown Drives Mitophagy and Suppresses Pyroptosis in Heart Failure by Activating the PINK1/Parkin Pathway

Nov 30, 2025International heart journal

Reducing USP30 boosts damaged mitochondria removal and lowers inflammatory cell death in heart failure by activating the PINK1/Parkin pathway

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Abstract

USP30 knockdown improved cardiac function and mitophagy while repressing pyroptosis in heart failure models.

USP30 is expressed abundantly in models of oxygen-glucose deprivation and heart failure.
Knockdown of USP30 in cell models enhanced cell viability and mitophagy.
USP30 knockdown reduced levels of key proteins associated with cell death and inflammation.
Inhibition of mitophagy or knockdown of PINK1 negated the beneficial effects of USP30 knockdown.
USP30 may regulate mitophagy and pyroptosis through the PINK1/Parkin pathway during heart failure.

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This study probed into the mechanism of USP30 in mitophagy and pyroptosis during heart failure (HF).A cell model was constructed with oxygen-glucose deprivation (OGD), and an HF rat model was generated by permanently ligating the left anterior descending branch of the left coronary artery. Loss-of-function experiments were carried out with the use of si-USP30 and si-PINK1. Cell viability was assessed using MTT, and cell death was measured by LDH release. Mitophagy was analyzed using immunofluorescence double staining, mitochondrial membrane potential (MMP) changes were detected by JC-1, and ROS levels were measured using specific kits. WB was performed to detect autophagy markers LC3II/I and p62, pyroptosis-related proteins NLRP3, active-caspase-1, GSDMD-N, and PINK1/Parkin protein expression. The inflammatory cytokines IL-18 and IL-1β were measured by ELISA. Histological changes and fibrosis in heart tissue were observed by H&E and Masson staining.USP30 was expressed abundantly in OGD-induced H9C2 cells and HF rats. USP30 knockdown enhanced viability, mitophagy, MMP, and LC3II/I but reduced death, NLRP3, p62, active-caspase-1, and GSDMD-N protein expression, and ROS, IL-1β, and IL-18 levels in OGD-treated H9C2 cells. PINK1 knockdown or mitophagy inhibition abolished the effects of USP30 knockdown on mitophagy and pyroptosis in OGD-treated H9C2 cells. Additionally, USP30 knockdown improved cardiac function and mitophagy while repressing pyroptosis in HF rats.In summary, USP30 controls mitophagy and pyroptosis in HF by mediating the PINK1/Parkin pathway.

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USP30 Knockdown Drives Mitophagy and Suppresses Pyroptosis in Heart Failure by Activating the PINK1/Parkin Pathway

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