Journal of Clinical & Experimental Pathology
Open Access

Necroptosis is an intriguing event that arises inside the complex mechanism of cellular life and death which is positioned at the crossroads between apoptosis and necrosis. Necroptosis represents a regulated form of cell death with implications spanning from physiological development to pathological conditions. Necroptosis, a term coined relatively recently, refers to a programmed form of necrosis regulated by molecular pathways distinct from those governing apoptosis. Necroptosis is an inflammatory mechanism of cell death that is distinguished by cellular swelling, organelle rupture, and the consequent release of Damage-Associated Molecular Patterns (DAMPs). The activation of Receptor-Interacting Protein Kinase 1 (RIPK1) is usually the conventional mechanism of necroptosis, resulting in the creation of a multi-protein complex known as the necrosome. This complex involves the phosphorylation of mixed lineage kinase domain-like protein, which facilitates its translocation to the plasma membrane. There, it carries out membrane disruption, a characteristic feature of necroptotic cell death.

Necroptosis frequently begins when death receptors from the Tumor Necrosis Factor (TNF). Trimerization of TNFR1 occurs upon ligand interaction, attracting adaptor proteins such RIPK1 and TNF Receptor-Associated Death Domain (TRADD). When caspase-8 function is reduced or inhibited, RIPK1 participates in complex IIb, a cytoplasmic complex, where it combines with Receptor Interacting Serine/Threonine Kinase 3 (RIPK3) to start necroptotic signaling. Necroptotic and apoptotic pathways interact intricately, highlighting the regulatory interplay that affects decisions on how to dispose of individual cells. The regulation of necroptosis involves a delicate interplay of activators and inhibitors, dictating the threshold for cellular commitment to this form of programmed cell death. Phosphorylation emerges as a pivotal post-translational modification governing the activity of key players within the necroptotic cascade. For instance, the phosphorylation status of RIPK1 serves as a critical determinant of cell fate, with dephosphorylation favoring apoptosis through the formation of the apoptotic complex IIa. Conversely, RIPK3 phosphorylation potentiates necroptotic signaling by facilitating the recruitment and activation of MLKL. Additionally, cellular factors such as Cylindromatosis (CYLD) and caspase-8 exert fine-tuned control over necroptotic initiation, either by deubiquitinating RIPK1 or by cleaving RIPK1 and RIPK3 to prevent necrosome formation.

While necroptosis is often portrayed in the context of pathological cell death, accumulating evidence highlights its physiological significance in various biological processes. During embryonic development, necroptosis contributes to tissue remodeling and morphogenesis, ensuring proper organ formation. Moreover, in the immune system, necroptosis serves as a mechanism for eliminating virus-infected cells and modulating inflammatory responses, thereby strengthening host defense mechanisms against microbial invaders. These physiological roles underscore the nuanced interplay between necroptosis and cellular homeostasis. Conversely, dysregulated necroptosis underpins the pathogenesis of numerous diseases, ranging from neurodegenerative disorders to inflammatory conditions. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, aberrant necroptotic signaling exacerbates neuronal damage and contributes to disease progression. Similarly, in ischemic injury and inflammatory bowel diseases, necroptosis amplifies tissue damage and perpetuates inflammatory cascades, culminating in organ dysfunction.

Pharmacological interventions targeting key regulators of necroptosis has potential therapeutic strategies for mitigating disease severity and restoring tissue integrity. Given its involvement in diverse pathological contexts, targeting necroptosis has emerged as a promising avenue for therapeutic intervention. Small molecule inhibitors targeting RIPK1 and RIPK3 have shown efficacy in preclinical models of inflammatory diseases and ischemic injury, highlighting the therapeutic potential of modulating necroptotic signaling. Moreover, the repurposing of existing drugs with antinecroptotic properties offers a cost-effective approach for expedited clinical translation. However, the complex regulatory network governing necroptosis necessitates meticulous optimization of therapeutic strategies to minimize off-target effects and ensure efficacy. Necroptosis is an immersing example of programmed cell death that has a strong connection with the process of physiological development and pathological advancement. It is important as a therapeutic target and a topic for scientific research because of its complex roles in health and disease, molecular foundations, and regulatory dynamics.