PROTAC-Mediated Degradation of Class I HDACs by JPS016 Alleviates Septic Cardiomyopathy via Mitophagy-Driven Exopher Formation and Mitochondrial Quality Control.

Septic cardiomyopathy (SCM) is a severe complication of sepsis with limited targeted treatment options, largely due to mitochondrial dysfunction in cardiomyocytes. Exophers, extracellular vesicles responsible for removing damaged mitochondria, represent a newly recognized mechanism of mitochondrial quality control, yet their upstream regulation remains unclear. This study tested the hypothesis that targeted degradation of Class I histone deacetylases (HDACs) using a PROTAC compound, JPS016, could alleviate SCM by promoting mitophagy-dependent exopher formation. An in vitro SCM model was established in HL-1 cardiomyocytes treated with lipopolysaccharide (LPS), and the effects of JPS016 on mitochondrial homeostasis, HDAC degradation, histone modifications, mitophagy, and exopher production were assessed using molecular and imaging techniques. JPS016 treatment significantly enhanced cell viability, reduced mitochondrial damage, and increased both histone acetylation and lactylation. Mechanistically, JPS016 activated the PINK1/Parkin mitophagy pathway and markedly increased the formation of exophers. Pharmacological inhibition experiments demonstrated that mitophagy, rather than general autophagy, was essential for exopher biogenesis and the protective effect of JPS016. These findings identify HDAC degradation as a novel upstream regulator of exopher-mediated mitochondrial clearance and support the therapeutic potential of PROTAC-based interventions in SCM.