EN6

EN6 is a small-molecule covalent activator of the vacuolar H+-ATPase (V-ATPase), specifically targeting the ATP6V1A subunit of the complex. By binding to a specific cysteine residue (C277) within the ATP6V1A subunit, EN6 enhances V-ATPase activity and promotes lysosomal acidification, which in turn modulates the Ragulator-mTORC1 signaling pathway. In the context of reproductive biology and aging, EN6 has been investigated for its ability to restore lysosomal function in embryos from advanced maternal age (AMA) patients. This restoration facilitates the proper degradation of lactate dehydrogenase B (LDHB), leading to increased lactate levels and the promotion of histone H3 lysine 18 lactylation (H3K18lac). This metabolic-epigenetic restoration helps rescue zygotic genome activation (ZGA) defects and improves the developmental potential of AMA embryos. EN6 is primarily utilized as a chemical probe in research to study lysosomal acidification, autophagy, and nutrient sensing.