Isopimaric acid derived from Torreya nucifera blocks autophagy and mitophagy to sensitize colon cancer cells to nutrient starvation

Autophagy and Mitophagy are essential survival mechanisms that enable Cancer cells to adapt to metabolic stress, particularly during nutrient deprivation. Therefore, targeting these pathways presents a promising therapeutic strategy. Thus, this study aimed to investigate the potential of isopimaric acid (IPA), a diterpenoid compound derived from Torreya nucifera, to disrupt autophagy-related processes in colon Cancer cells. Notably, IPA treatment promoted the accumulation of autophagosomes, as indicated by increased LC3-II and p62 protein levels, suggesting an inhibition of autophagic flux rather than an enhancement of initiation. Further analysis revealed that IPA impaired lysosomal function and blocked autophagosome degradation. IPA also suppressed Mitophagy by downregulating key regulators, including PINK1 and Parkin, resulting in mitochondrial dysfunction and the accumulation of Reactive Oxygen Species (ROS). Particularly, IPA was non-toxic under nutrient-rich conditions but induced significant cell death under serum starvation conditions. To our knowledge, these findings are the first to show that IPA selectively induces apoptotic cell death in nutrient-deprived colon Cancer cells by disrupting both late-stage Autophagy and PINK1/Parkin-mediated Mitophagy. Furthermore, this research establishes the development of innovative therapeutic strategies that specifically target metabolic stress and combination therapy.