Inhibiting ACSL1-Related Ferroptosis Restrains Murine Coronavirus Infection

Abstract

Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.

PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia

“…Beatty et al 49 recently reported that ACSL1 promotes conjugated linoleic acids incorporation into neutral lipids, leading to ferroptosis by increasing lipid peroxidation. Another study has shown that triacsin C inhibits ACSL1 to prevent ferroptosis and protects mice from MHV‐A59 infection 50 . Here, it was demonstrated that both GSK3368715 treatment and PRMT1‐knockout induced ACSL1 messenger RNA and protein expression in two AML cell lines.…”

Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis

“…Epstein-Barr virus dynamically sensitizes B cells to ferroptosis for latency ( 56 ). In addition, a number of human enteroviruses and coronaviruses induce ferroptosis via acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) ( 57 ), and murine coronavirus can trigger ferroptosis through ACSL1 ( 58 ). Moreover, oxidative stress and lipid peroxidation leading to exacerbated inflammation and tissue damage have been considered important in the pathogenesis of different viruses ( 59 ).…”

Liproxstatin‑1 induces cell cycle arrest, apoptosis, and caspase‑3/GSDME‑dependent secondary pyroptosis in K562 cells

“…Different types of RCD occasionally share the same upstream molecules; accordingly, crosstalk between RCD pathways is inevitable. Ferroptosis is an iron-dependent form of RCD, and differs from apoptosis by excessive lipid peroxidation, lack of glutathione, and inactivation of caspase-3 (50,51). However, a recent study demonstrated that the ER stress-mediated CHOP-PUMA pathway was associated with the interaction between apoptosis and ferroptosis (52).…”