Over the past two decades, increasing attention has been devoted to regulated forms of cell death that occur independently of apoptosis. Among these, necroptosis and ferroptosis exhibit a necrotic-like morphology, yet are defined by distinct molecular and biochemical signatures. Both pathways have attracted considerable interest due to growing evidence implicating them in the pathogenesis of a wide range of acute and chronic disorders. Notably, the simultaneous engagement of multiple regulated necrosis pathways has been reported in many disease contexts, highlighting the limitations of single-target therapeutic approaches. In this light, the design of multi-target-directed ligands, that is, embracing a polypharmacological strategy, has emerged as a promising direction for development of future therapies. In this review, we propose the concept of NecroFerrins, a class of small molecules that simultaneously inhibit necroptosis and ferroptosis. Within this class, we identify RIPROStatins as a distinct subclass of RIPK1 inhibitors that additionally possess radical-trapping antioxidant activity. The objective of this review is also to stimulate translational research on complex diseases using polypharmacological drugs acting as necrosis inhibitors.

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.