Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases

Abstract

Pyroptosis, apoptosis, and necroptosis are mainly programmed cell death (PCD) pathways for host defense and homeostasis. PANoptosis is a newly distinct inflammatory PCD pathway that is uniquely regulated by multifaceted PANoptosome complexes and highlights significant crosstalk and coordination among pyroptosis (P), apoptosis (A), and/or necroptosis(N). Although some studies have focused on the possible role of PANpoptosis in diseases, the pathogenesis of PANoptosis is complex and underestimated. Furthermore, the progress of PANoptosis and related agonists or inhibitors in disorders has not yet been thoroughly discussed. In this perspective, we provide perspectives on PANoptosome and PANoptosis in the context of diverse pathological conditions and human diseases. The treatment targeting on PANoptosis is also summarized. In conclusion, PANoptosis is involved in plenty of disorders including but not limited to microbial infections, cancers, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), ischemia-reperfusion, and organic failure. PANoptosis seems to be a double-edged sword in diverse conditions, as PANoptosis induces a negative impact on treatment and prognosis in disorders like COVID-19 and ALI/ARDS, while PANoptosis provides host protection from HSV1 or Francisella novicida infection, and kills cancer cells and suppresses tumor growth in colorectal cancer, adrenocortical carcinoma, and other cancers. Compounds and endogenous molecules focused on PANoptosis are promising therapeutic strategies, which can act on PANoptosomes-associated members to regulate PANoptosis. More researches on PANoptosis are needed to better understand the pathology of human conditions and develop better treatment.

Fig. 1. The PANoptosomes and brief molecular mechanisms of PANoptosis.

When encountering triggers like diverse microbial infections and altered cellular homeostasis, sensors including ZBP1, AIM2, RIPK1, and NLRP12 can interact and recruit several other molecules to form a PANoptosome, namely ZBP1-PANoptosome (ZBP1, NLRP3, ASC, caspase-1, caspase-6, caspase-8, RIPK1, and RIPK3), AIM2-PANoptosome (AIM2, Pyrin, ZBP1, ASC, caspase-1, caspase-8, FADD, RIPK1, and RIPK3), RIPK1-PANoptosome (RIPK1, RIPK3, NLRP3, ASC, caspase-1, and caspase-8), and NLRP12- PANoptosome (NLRP12, ASC, caspase-8, and RIPK3), respectively. These PANoptosomes further induce caspase-3/7 activation, GSDMD and GSDME cleavage, and MLKL phosphorylation, resulting in membrane pore formation and PANoptosis progression. In addition, these PANoptosomes can also be regulated by IRF1 under some conditions. With IAV infection or IFN plus KPT330, IRF1 contributes to ZBP1 expression and ZBP1-PANoptosome formation. Similarly, IRF1 is responsible for AIM2-PANoptosome activation under F. novicida infection. IRF1 acts as an upstream regulator of RIPK1-PANoptosome with TAKi plus LPS stimulation, and IRF1 mediates the form of NLRP12-PANoptosome when stimulated with heme plus PAMPs or TNF. Abbreviations: AIM2 absent in melanoma 2, ASC apoptosis-associated speck-like protein containing a caspase recruitment domain, CASP caspase, FADD Fas-associated death domain protein, GSDMD: gasdermin D, GSDMDE gasdermin E, IAV influenza A virus, IFN interferon, IRF1 Interferon regulatory factor 1, KPT330 a nuclear export inhibitor, LPS lipopolysaccharide, MLKL mixed lineage kinase domain-like pseudokinase, NLRP3 NLR family pyrin domain containing 3, NLRP12 NLR family pyrin domain containing 12, RIPK receptor-interacting serine/threonine-protein kinase, TNF tumor necrosis factor ZBP1 Z-DNA binding protein 1.

Fig. 2. The overview of PANoptosis in diseases.

PANoptosis is involved in diverse conditions, mainly including diverse infections (e.g. bacteria, viruses, fungi), cancers and tumorigenesis (e.g. digestive cancers, adrenocortical carcinoma, malignant melanoma), ischemia-reperfusion and organic injury (e.g. ALI/ARDS and heart failure), and ophthalmic diseases (e.g. diabetic retinopathy and acute ocular hypertension).