Targeting necroptosis: a promising avenue for respiratory disease treatment

Abstract

Respiratory diseases are a growing concern in public health because of their potential to endanger the global community. Cell death contributes critically to the pathophysiology of respiratory diseases. Recent evidence indicates that necroptosis, a unique form of programmed cell death (PCD), plays a vital role in the molecular mechanisms underlying respiratory diseases, distinguishing it from apoptosis and conventional necrosis. Necroptosis is a type of inflammatory cell death governed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like protein (MLKL), resulting in the release of intracellular contents and inflammatory factors capable of initiating an inflammatory response in adjacent tissues. These necroinflammatory conditions can result in significant organ dysfunction and long-lasting tissue damage within the lungs. Despite evidence linking necroptosis to various respiratory diseases, there are currently no specific alternative treatments that target this mechanism. This review provides a comprehensive overview of the most recent advancements in understanding the significance and mechanisms of necroptosis. Specifically, this review emphasizes the intricate association between necroptosis and respiratory diseases, highlighting the potential use of necroptosis as an innovative therapeutic approach for treating these conditions.

Keywords: Mixed-lineage kinase domain-like protein (MLKL); Necroptosis; RIPK3; Receptor-interacting serine/Threonine protein kinase 1 (RIPK1); Respiratory diseases.

Fig. 1

Regulation of necroptotic signalling. A Classical necroptotic pathways. Necroptosis begins with the activation of death receptors such as necrosis factor receptor (TNFR) 1, Fas, and TRAIL receptors, leading to the assembly of “complex I” on the cell membrane. This complex includes TRADD, RIP1, TRAF2/5, and cIAP1/2, acting as a crucial decision point between cell survival and death pathways. TRADD recruits RIP1 to TNFR1, while cIAP1/2 and TRAF2/5 promote RIP1 ubiquitination, stabilizing complex I and activating pathways like NF-κB and MAPK for cell survival. Upon RIP1 deubiquitination, complex IIa forms, involving FADD, TRADD, RIP3, and caspase 8, suppressing apoptosis under normal conditions. However, if caspase-8 is inactive, RIPK1-RIPK3 interaction leads to complex IIb formation, initiating MLKL phosphorylation and oligomerization, triggering necroptosis. B Non-classical necroptotic signaling. Toll-like receptor (TLR)3 and TLR4, activated by dsRNA and LPS respectively, trigger necroptosis directly through RHIM domain-mediated TRIF and RIPK3 association. Viral nucleic acids activate RHIM-containing ZBP1, inducing RIP3-MLKL-dependent necroptosis, independently of RIPK1. Interferon (IFN)-driven necroptosis involves JAK/STAT-dependent transcription. These pathways converge on MLKL activation, the necroptosis executor

Fig. 2

Necroptosis in chronic lung diseases. A Cigarette smoke induces necroptosis in alveolar epithelial cells in individuals with COPD. This process releases damage-associated molecular patterns (DAMPs), exacerbating inflammation and tissue damage, thereby contributing to disease progression. B Necroptosis in airway epithelial cells, neutrophils, and macrophages contributes to airway inflammation and hyperresponsiveness, thereby promoting the development of asthma. C In idiopathic pulmonary fibrosis, alveolar epithelial cells also undergo necroptosis, releasing DAMPs. This process induces an inflammatory response, promoting the progression of pulmonary fibrosis. D In pulmonary hypertension, necroptosis and subsequent HMGB1 release are reported to result in pulmonary vascular remodeling, although the role of mixed-lineage kinase domain-like protein (MLKL) in this process has not been conclusively determined

Fig. 3

Necroptosis plays a significant role in acute lung injury (ALI). A Lipopolysaccharide (LPS) exhibits dual effects: it activates RIPK3, triggering necroptosis via IGF and ZBP1, while also inducing mitochondrial damage through L-OPA and TREM-1, leading to upregulated FUNDC1 expression and further activation of RIPK3. B  Hyperbaric oxygen exposure directly initiates the RIPK1-RIPK3-MLKL pathway, culminating in necroptosis. C Kidney transplantation may cause pulmonary ischemia-reperfusion injury, elevating TNF-α and OPN release, thereby promoting necroptosis and worsening lung damage. D Ventilator-induced ALI (VILI) is linked to impaired FAO function, with FAO-dependent RIPK3-mediated necroptosis being a key pathogenic mechanism. E Sepsis-induced ALI results in elevated exosomal APN expression, inducing necroptosis in alveolar epithelial cells. F Cardiopulmonary bypass (CPB) exacerbates ALI by facilitating exosomal release of HMGB1 via the mtDNA/cGAS/STING pathway, promoting necroptosis

Fig. 4

Necroptosis in infectious pneumonia presents diverse mechanisms across different pathogens. A The envelope protein (E) of SARS-CoV-2 uniquely mediates necroptosis and inflammatory cytokine release via RIPK1, marking a distinct feature in COVID-19 pathogenesis. B Influenza A virus (IAV) employs Z-RNA to interact with ZBP1, initiating RIPK3-mediated necroptosis while also upregulating OPN expression, modulating necroptosis and immunity. C Respiratory syncytial virus (RSV) induces necroptosis through the RIPK1/RIPK3/MLKL pathway, with MLKL further promoting NETs formation, exacerbating airway inflammation. D Pseudomonas aeruginosa primarily triggers necroptosis via RIPK3, leading to lung inflammation and tissue damage. E Streptococcus pneumoniae triggers necroptosis via RIPK1/RIPK3/MLKL while inhibiting cell survival through NF-κB inhibition. F Staphylococcus aureus toxins target ADAM10, NLRP3, and CD11b or activate NLRC4, inducing immune cell necroptosis via the RIPK1/RIPK3/MLKL pathway, thus exacerbating respiratory diseases

Fig. 5

Necroptosis in pulmonary tuberculosis (TB). Necroptosis of macrophages plays a pivotal role in TB pathology. Key insights reveal the involvement of tuberculous necrosis toxin (TNT) in triggering necroptosis and the impact of NAD + depletion on its induction, thus influencing TB pathology. Additionally, focal adhesion kinase (FAK), signal regulatory proteinα (SIRPα), and cAMP response element-binding protein (CREB) are crucial in orchestrating immune responses to Mtb infection, particularly by inhibiting necroptosis and regulating cellular signaling pathways