Abstract:
Ferroptosis is an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and oxidative damage to cellular and organelle membranes. Because lysosomes are membrane-bound organelles that are particularly susceptible to oxidative injury, ferroptosis-associated membrane damage may compromise lysosomal integrity and promote lysosomal membrane permeabilization (LMP). As lysosomes are essential for autophagic degradation, such membrane destabilization may further disrupt autophagic homeostasis. However, whether ferroptosis contributes to curcumin-induced LMP and autophagic dysfunction remains unclear. In this study, we investigated the relationship among ferroptosis, LMP, and autophagic dysfunction in human H1299 lung cancer cells exposed to curcumin. Curcumin markedly increased intracellular reactive oxygen species (ROS), particularly superoxide (O?•?), and induced mitochondrial membrane depolarization. These effects were substantially attenuated by the superoxide scavenger MnTBAP and antioxidants, including N- acetylcysteine (NAC), glutathione (GSH), and dithiothreitol (DTT), indicating a critical role for oxidative stress. Curcumin also increased LC3-I/II expression and GFP-LC3 puncta formation, whereas the expression of the autophagy-related proteins ATG5, ATG7, and Beclin-1 was decreased, suggesting disruption of autophagic processing. In parallel, curcumin induced progressive LMP, which was markedly attenuated by MnTMPyP and NAC, demonstrating that lysosomal membrane destabilization was ROS dependent. Because ferroptosis is closely
associated with oxidative membrane injury and lysosomal regulation, we further examined whether ferroptotic signaling mediated curcumin-induced lysosomal damage. However, pharmacological inhibition of ferroptosis failed to prevent curcumin-induced LMP or substantially rescue cell viability. These findings indicate that, although curcumin induces oxidative stress and membrane-associated alterations potentially compatible with ferroptotic signaling, ferroptosis is not a major mediator of its lysosomal effects. Collectively, curcumin induces ROS-dependent LMP and disrupts autophagic homeostasis in H1299 lung cancer cells through a mechanism largely independent of ferroptosis. These findings distinguish curcumin- induced lysosomal and autophagic dysfunction from canonical ferroptotic cell death and identify a ROS–lysosome–autophagy axis underlying curcumin-induced cellular stress.
