Jolkinolide B Activates Mitophagy to Exhibit Antipancreatic Cancer Activity and Alleviate Cognitive Deficits in Alzheimer's Disease.

Dysfunctional mitophagy leads to the pathological accumulation of damaged mitochondria, which is closely associated with the development of human diseases such as cancer and Alzheimer's disease. The identification of safer and more effective mitophagy regulators may provide a novel approach for treating mitochondrial diseases. Covalent-binding drugs have attracted substantial attention due to their high specificity, selectivity, and low resistance potential. In this study, we demonstrated that the natural epoxide compound jolkinolide B (JB) specifically induces mitophagy both in vitro and in vivo. Mass spectrometry analysis confirmed that JB directly binds to the outer mitochondrial membrane translocase protein TOM40, leading to autophagic cell death in pancreatic cancer. As a mitophagy enhancer, JB also ameliorates mitochondrial dysfunction and mitigates cognitive deficits in the 5×FAD mouse model of Alzheimer's disease. The findings indicate that JB selectively targets mitochondria to enhance mitophagy while exhibiting minimal toxicity in pancreatic cancer and Alzheimer's disease mouse models, highlighting its potential as a therapeutic agent for mitochondrial diseases.