Classical swine fever virus utilizes stearoyl-CoA desaturase 1-mediated lipid metabolism to facilitate viral replication

Viral infections can significantly alter cellular lipid metabolism by modulating key rate-limiting Enzymes, including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and Acetyl-CoA Carboxylase (ACC). Our previous study revealed the pivotal role of FASN in lipid droplet (LD) synthesis and the promotion of classical swine fever virus (CSFV) replication. However, the roles of the Other two key Enzymes in CSFV Infection remain unexplored. In this study, we screened a library of 96 lipid metabolism-targeted compounds and identified an Antiviral inhibitor of SCD1, a rate-limiting enzyme in monounsaturated fatty acid synthesis, that inhibits CSFV replication. Suppressing SCD1 activity through inhibitors or small interfering RNA knockdown reduces CSFV proliferation. However, this suppression is reversed by adding SCD1 active products (oleic acid/palmitoleic acid [OA/PA]), highlighting the essential role of SCD1 in CSFV proliferation. Mechanistically, CSFV non-structural protein p7 interacts with SCD1 and recruits it to the viral replication complex (VRC) during Infection. Importantly, CSFV Infection activates the endoplasmic reticulum stress pathway IRE1α/XBP1, which positively regulates SCD1 expression, leading to increased production of triglyceride (TG) and LDs and subsequently enhancing CSFV replication. In summary, our study elucidates the critical role of SCD1 in the CSFV life cycle and highlights its potential as an Antiviral target for developing new therapies against Flaviviridae.IMPORTANCEUnderstanding the virus's pathogenesis within the host is essential for advancing Antiviral therapeutics and vaccine development. Previous studies have demonstrated that classical swine fever virus (CSFV) leverages host lipid metabolic rate-limiting Enzymes, such as fatty acid synthase (FASN), to support viral replication. This study identified stearoyl-CoA desaturase 1 (SCD1), a key enzyme in monounsaturated fatty acid biosynthesis, as a novel regulator of CSFV replication. Mechanistically, the viral non-structural protein p7 mediates the recruitment of SCD1 to the endoplasmic reticulum (ER), facilitating the formation of viral replication complexes (VRCs). Additionally, our findings showed that viral Infection activated the ER stress pathway IRE1α/XBP1, which upregulated SCD1 expression and promoted the synthesis of triglycerides (TG) and lipid droplets (LDs). This study provides insights into the metabolic reprogramming triggered by viral Infection to support replication and underscores the intricate crosstalk between ER stress and lipid metabolism during CSFV Infection. These findings have significant implications for identifying novel Antiviral targets against CSFV.

IRE1α/XBP1; classical swine fever virus (CSFV); lipid metabolism; stearoyl-CoA desaturase 1 (SCD1).