Acid sphingomyelinase inhibition as an antiviral strategy: mechanisms, functional inhibitors, and therapeutic potential against SARS-CoV-2 and beyond

The entry, replication, and egress processes of viruses depend on their ability to hijack host lipid metabolism. At the core of many viruses is the acid sphingomyelinase (ASM)–ceramide pathway: ASM hydrolyzes sphingomyelin into ceramide, creating ceramide-enriched platforms that cluster receptors and endocytic components to thereby facilitate viral attachment, fusion, and intracellular trafficking. This review will analyze evidence from various virus families, including coronaviruses, to show how ASM/ceramide regulation impacts viral infectivity. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), post-binding to the host cell, stimulates ASM activation to subsequently induce the ACE2/TMPRSS2 clusters that increase viral entry. Studies show that viral entry is blocked with ASM inhibitors. Beyond cell entry, ceramide functions as a key factor that promotes the formation of microvesicle particles (MVPs), which leads to the release of inflammatory mediators and viral components, thus creating a link between ASM activity with systemic inflammation and coagulopathy. We analyze functional inhibitors of ASM (FIASMs), which include multiple FDA-approved drugs that detach ASM from lysosomes to disrupt ceramide domains. FIASMs have been experimentally shown to block SARS-CoV-2 entry and ceramide-driven vesiculation in experimental models. Both observational clinical findings and initial research on FIASMs show promise. This review will evaluate both the advantages and limitations of the FIASM approach and provide recommendations for future studies on engineered vesicles as therapeutic decoys and biomarkers (sphingolipid signatures, vesicle cargo) for monitoring treatment success. The ASM–ceramide axis is a promising broad-spectrum host-directed antiviral pathway that has translational value for treating viral diseases beyond COVID-19.