Key result
STING or SPHK1 inhibition reduces cardiac inflammation and improves function in viral myocarditis.
Why the study?
Stimulator of interferon genes (STING) is increasingly implicated in cardiovascular inflammation, but its precise role and downstream molecular mechanisms in coxsackievirus B3 (CVB3)-induced viral myocarditis remain unclear.
Does pharmacological inhibition of STING or SPHK1 reduce cardiac inflammation and dysfunction in a mouse model of CVB3-induced viral myocarditis?
Does pharmacological inhibition of STING or SPHK1 reduce cardiac inflammation and dysfunction in a mouse model of CVB3-induced viral myocarditis?
STING promotes CVB3-induced viral myocarditis by upregulating SPHK1 via STAT1::STAT2, identifying the STING-SPHK1 axis as a potential therapeutic target to alleviate myocardial inflammation and injury.
STING modulation may merit preclinical testing in viral myocarditis; leaves open any clinical role pending human data.
Background/Introduction Viral myocarditis is an inflammatory heart disease caused by viral infections such as coxsackievirus B3 (CVB3), often affecting young adults and contributing to sudden cardiac death. Stimulator of interferon genes (STING), a central component of innate immunity, is increasingly implicated in cardiovascular inflammation. However, its precise role and downstream mechanisms in CVB3-induced myocarditis remain unclear. Purpose To investigate the role of STING in CVB3-induced viral myocarditis and identify its downstream molecular mechanisms. Methods CVB3-induced myocarditis was modeled in mice. Transcriptomic and multi-omics analyses were performed to identify potential downstream effectors of STING. Pharmacological inhibition studies in vivo and mtDNA-stimulated THP-1 macrophages in vitro were used to validate the STING–SPHK1 axis through molecular and functional assays. Results STING signaling was markedly activated in CVB3-induced myocarditis and macrophages, and its inhibition reduced cardiac inflammation and improved cardiac function. CVB3-induced cardiomyocyte injury led to mitochondrial DNA (mtDNA) release, activating STING mainly in macrophages. Multi-omics analysis revealed sphingosine kinase 1 (SPHK1) as a downstream STING target, transcriptionally upregulated by the STAT1::STAT2 transcriptional complex. In vivo SPHK1 inhibition similarly attenuated myocardial inflammation and dysfunction. SPHK1 knockdown in mtDNA-stimulated macrophages decreased reactive oxygen species production, mitochondrial damage, and mtDNA release, suppressing STING activation and cytokine production. Conclusion(s) STING promotes CVB3-induced viral myocarditis by upregulating SPHK1 via STAT1::STAT2. This signalling axis amplifies macrophage-mediated inflammation and myocardial injury. Targeting STING or SPHK1 alleviates disease severity, highlighting a previously unrecognized proinflammatory amplification loop and suggesting potential therapeutic strategies for viral myocarditis.
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Wang et al. (2026) studied CVB3-induced acute viral myocarditis. Pharmacological inhibition of STING or SPHK1, and SPHK1 knockdown was evaluated on Cardiac inflammation, cardiac function, and STING-SPHK1 signaling activation. Pharmacological inhibition of STING or its downstream target SPHK1 reduced cardiac inflammation and improved cardiac function in mice with CVB3-induced viral myocarditis.
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