PANoptosis as a Therapeutic Target for COVID-19

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has sparked a global pandemic with extensive spread, posing a severe threat to public health due to its high mortality rate in severe cases. The continuous emergence of variants with enhanced immune evasion capabilities, coupled with the prolonged and debilitating symptoms of Long Coronavirus Disease (Long COVID) such as intermittent dyspnea, persistent fatigue, and cognitive impairment (brain fog), has become a major global concern. The pathogenesis of COVID-19 is a complex interplay of direct viral cytotoxicity and an overwhelming secondary inflammatory response in the host, with the latter being a key driver of immune homeostasis disruption. Accumulating evidence indicates that PANoptosis, an integrated programmed cell death process involving the crosstalk and coordinated activation of apoptosis, pyroptosis, and necroptosis, is closely linked to the cytokine storm syndrome triggered by SARS-CoV-2 infection. As a critical mediator of various infectious diseases, PANoptosis plays a pivotal role in regulating the balance between viral clearance and pathological inflammation. This review specifically targets SARS-CoV-2, adopting a "basic mechanism-molecular regulation-therapeutic target-clinical translation" framework. We elaborate on SARS-CoV-2-induced PANoptosis mechanisms, including its constituent cell death pathways and contributions to cytokine storms. By dissecting the intricate regulatory networks between PANoptosis and interferon (IFN) signaling during viral infection, this work aims to identify potential therapeutic targets and provide novel insights for the development of effective strategies to mitigate severe COVID-19 and its long-term sequelae.