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FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.

ABSTRACT: The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fatty acids by fatty acid desaturase 2 (FADS2). Genetic depletion and ectopic expression experiments show FADS2 is a key determinant of cellular sensitivity to ferroptosis. Inhibiting FADS2 markedly enhances HCV replication, whereas the ferroptosis-inducing compound erastin alters conformation of the HCV replicase and sensitizes it to direct-acting antiviral agents targeting the viral protease. Our results identify FADS2 as a rate-limiting factor in ferroptosis, and suggest the possibility of pharmacologically manipulating the ferroptosis pathway to attenuate viral replication.

SUBMITTER: Yamane D

PROVIDER: S-EPMC8913804 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.

Yamane Daisuke D Hayashi Yuri Y Matsumoto Moe M Nakanishi Hiroki H Imagawa Haruka H Kohara Michinori M Lemon Stanley M SM Ichi Ikuyo I

Cell chemical biology 20210913 5

The metabolic oxidative degradation of cellular lipids severely restricts replication of hepatitis C virus (HCV), a leading cause of chronic liver disease, but little is known about the factors regulating this process in infected cells. Here we show that HCV is restricted by an iron-dependent mechanism resembling the one triggering ferroptosis, an iron-dependent form of non-apoptotic cell death, and mediated by the non-canonical desaturation of oleate to Mead acid and other highly unsaturated fa ...[more]

PMID: 34520742

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Project description:Rationale: Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive. Methods: The omental conditioned medium (OCM) was established to imitate the omental or ascites microenvironment. Mass spectrometry, RT-qPCR, IHC, and western blot assays were applied to evaluate human fatty acid desaturases expressions and activities. Pharmaceutical inhibition and genetic ablation of SCD1/FADS2 were performed to observe the oncogenic capacities. RNA sequencing, lipid peroxidation, cellular iron, ROS, and Mito-Stress assays were applied to examine ferroptosis. OvCa patient-derived organoid and mouse model of peritoneal metastases were used to evaluate the combined effect of SCD1/FADS2 inhibitors with cisplatin. Results: We found that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), were aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) was positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, cancer stem cell (CSC) formation and reduced platinum resistance. Inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular/mitochondrial redox balance and subsequently, iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived OvCa cells. Conclusions: Combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC peritoneal metastases.

Dataset Information

FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.

Publications

FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication.

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