The Janus Face of Oxidative Stress and Hydrogen Sulfide: Insights into Neurodegenerative Disease Pathogenesis

Abstract

Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H₂S), a versatile gasotransmitter, exhibits a similarly "Janus-faced" nature, acting as a potent antioxidant and cytoprotective molecule at physiological concentrations, but becoming detrimental when dysregulated. This review explores the dual roles of oxidative stress and H₂S in normal cellular physiology and pathophysiology, focusing on neurodegenerative disease progression. We highlight potential therapeutic opportunities for targeting redox and sulfur-based signaling systems in neurodegenerative diseases by elucidating the intricate balance between these opposing forces.

Keywords: Janus face; hydrogen sulfide (H2S); neurodegenerative diseases; neuroinflammation; oxidative stress; redox signaling.

Figure 1

The Janus face of oxidative stress. This diagram illustrates the dual role of oxidative stress in cellular physiology and neurodegenerative disease pathogenesis, depicting a balance scale between physiological and pathological states. On the left, excessive ROS accumulation contributes to neurodegeneration through inflammation, neuronal apoptosis, mitochondrial dysfunction, and energy deficits, exacerbated by environmental and biological stressors such as heavy metals, radiation, smoking, and metabolic disorders. In contrast, the right side highlights the protective role of controlled ROS levels in cellular signaling, immune response, and mitochondrial homeostasis, supported by endogenous and dietary antioxidants. An inset diagram at the top-center illustrates ROS sources, including mitochondria, NADPH oxidase, peroxisomes, and the endoplasmic reticulum. This figure encapsulates the “Janus face” of oxidative stress, where moderate ROS levels maintain homeostasis, while excessive ROS drive neurodegeneration. The visual framework underscores the intricate interplay of oxidative stress, redox signaling, and neurodegenerative disease mechanisms.

Figure 2

The “Janus face” of hydrogen sulfide (H₂S) in neurodegenerative disease pathogenesis, emphasizing its dual role in physiological and pathological conditions. Excessive or diminished H₂S levels, as shown on the left side, contribute to neurodegeneration by promoting inflammation, oxidative stress, lipid peroxidation, mitochondrial dysfunction, and energy deficits, which are similar to the effects of reactive oxygen species (ROS). This imbalance is depicted in a damaged brain with signs of inflammation, tissue degeneration, and neuronal cell death. Conversely, the right side represents optimal H₂S levels that support physiological homeostasis by exerting anti-inflammatory effects, enhancing vascular function, modulating redox balance, and promoting neuroprotection. The figure also highlights key enzymatic sources of H₂S—cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST)—which regulate H₂S production. The interplay between ROS, oxidative stress, and lipid peroxidation underscores the necessity of maintaining balanced H₂S levels to prevent neurodegeneration and support brain health, making H₂S a crucial target for therapeutic interventions.