Reactive oxygen species (ROS) are typically elevated at inflammatory sites due to the influx of large numbers of neutrophils and other myeloid cells that produce high levels of oxygen free radicals as microbicidal agents. Reactive oxygen intermediates are also generated as a byproduct of cellular metabolism, due to mitochondrial damage, exposure to toxins or radiation, and are also frequently increased during inflammatory reactions. However, although oxidative stress is often implicated as an initiator or amplifier of inflammation, particularly in the context of cancer, how reactive oxygen modulates inflammatory signalling remains poorly understood. Here we discuss the diversity of pathways and molecules implicated in promoting or suppressing inflammation in response to ROS. As we shall see, reactive oxygen has been reported to influence inflammatory outputs through direct effects on phosphatases that regulate nuclear factor kappa B (NF-κB) activation, through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) or hypoxia-inducible factor (HIF)-1 transcription factors that can directly or indirectly promote inflammatory gene expression, by provoking DNA damage leading to activation of the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)/stimulator of interferon genes (STING) pathway, or through promoting assembly of inflammasomes. Thus, there are a multitude of routes by which ROS can influence inflammatory responses. How reactive oxygen promotes inflammation in specific contexts is likely to be influenced by several factors, including the source of ROS, whether intracellular or extracellular, the responding cell type, as well as the extent of deviation from normal homeostatic setpoints. Understanding how reactive oxygen shapes inflammation has important implications for therapeutic intervention in multiple disease states.

Ferroptosis is an iron-dependent form of programmed cell death defined by the lethal accumulation of lipid peroxides. Accumulating evidence indicates that ferroptosis plays a critical role in a wide range of pathological processes, including tumor progression, ischemia-reperfusion injury, and neurodegenerative diseases. The key determinants of cellular susceptibility to ferroptosis are the homeostasis of iron and lipid metabolism, whose maintenance relies heavily on the precise regulation of inter-organelle communication networks. In this review, we focus on the spatial biology of ferroptosis regulation. From three core dimensions, iron homeostasis modulation, lipid metabolism remodeling, and redox balance maintenance, we systematically dissect the mechanisms by which signal crosstalk and functional coordination among multiple organelles (lysosomes, endoplasmic reticulum, mitochondria, plasma membrane, nucleus, lipid droplets, Golgi apparatus, and peroxisome) govern ferroptosis initiation, signal amplification, and cellular defense responses. Comprehensive elucidation of this multi-organellar coordinated regulatory network will not only advance our fundamental understanding of ferroptosis execution but also provide a holistic perspective for the development of organelle-targeted therapeutic strategies against human diseases.