Seema Kumari, Sudhir Kumar Rai
In this study, we examined the effect of hydrogen peroxide (H₂O₂) on AaAtg4. Functioning as a cysteine protease, AaAtg4 directly interacts with the AaAtg8 ubiquitin-like protein and is indispensable for AaAtg8 processing and autophagosome formation, with its enzymatic activity modulated by oxidative cues. H₂O₂ differentially impacts AaAtg4 activity, phosphorylation, binding with AaAtg8, AaAtg8 lipidation/delipidation, and autophagy. H₂O₂ has biphasic effects on AaAtg4. Moderate H₂O₂ levels enhance AaAtg4 activity and autophagy, whereas excessive H₂O₂ suppresses both, revealing a threshold-dependent redox regulation. Furthermore, AaAtg4 interacts with the stress-responsive mitogen-activated protein kinase AaHog1, which modulates its phosphorylation under conditions less conducive to autophagy and thus, reinforces a dynamic signaling axis.
Reactive oxygen species (ROS) are produced during metabolism through mitochondrial oxidative phosphorylation and NADPH oxidase activity. In cancer, ROS exhibit a paradoxical, concentration-dependent dual role. At low to moderate levels, ROS promote tumor cell survival, EMT, and metastasis, and at high levels, ROS overwhelm antioxidant defenses and induce regulated cell death (RCD); ferroptosis, autophagy, apoptosis, and immunogenic cell death (ICD) have emerged as significant ROS-dependent targets in cancer therapy. This review summarizes recent advances in ROS-controlled ferroptosis, autophagy, apoptosis, and ICD, emphasizing the roles of the GPX4/SLC7A11, AMPK/mTORC1/Beclin-1, Bcl-2/Bax/cytochrome c, and damage-associated molecular pattern (DAMP)-mediated signal cascade, their crosstalk, and therapeutic potential for targeting tumor redox vulnerabilities.