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.© 2023. The Author(s).