Redox signaling in the pathogenesis of human disease and the regulatory role of autophagy

Aberrant cell death signaling and oxidative stress are implicated in myriad of human pathological states such as neurodegenerative, cardiovascular, metabolic and liver diseases, as well as drug-induced toxicities. While regulated cell death and mild oxidative stress are essential during normal tissue homeostasis, deregulated signaling can trigger massive depletion in a particular cell type and/or damage tissues and impair organ function with deleterious consequences that manifest as disease states. If regeneration cannot restore tissue homeostasis, the severity of the disease correlates with the extent of cell loss. Cell death can be executed via multiple modalities such as apoptosis, necrosis, pyroptosis, necroptosis and ferroptosis, depending on cell autonomous mechanisms (e.g., reactive oxygen species production, calcium overload and altered proteostasis) and/or non-cell autonomous processes (e.g., environmental stress, irradiation, chemotherapeutic agents, inflammation and pathogens). Accordingly, the inhibition of aberrant cell death and oxidative stress together with activation of autophagy, a regulated self-degradation process, are progressively emerging as relevant cytoprotective strategies to sustain homeostasis. In this review, we summarize the current literature on the crosstalk between cellular redox state and cell fate signaling, specifically from the standpoint of autophagy and its role in the maintenance of tissue/organ homeostasis via regulating oxidative stress and the potential implications for the design of novel therapeutic strategies.