African swine fever virus A151R downregulates cGAS-STING-mediated IFN-β production by promoting lipid peroxidation through ferritinophagy-induced ferroptosis
Abstract The African swine fever virus (ASFV) has been reported to cause oxidative damage and inhibit IFN-β production. However, the precise mechanisms through which ASFV-induced lipid peroxidation modulates the innate immune response remain to be elucidated. Here, we investigated the regulatory mec...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-06-01
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| Series: | Cellular and Molecular Life Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00018-025-05732-7 |
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| Summary: | Abstract The African swine fever virus (ASFV) has been reported to cause oxidative damage and inhibit IFN-β production. However, the precise mechanisms through which ASFV-induced lipid peroxidation modulates the innate immune response remain to be elucidated. Here, we investigated the regulatory mechanism underlying ASFV A151R-induced lipid peroxidation and ferroptosis in restricting IFN-β production The results demonstrated that A151R negatively inhibited IFN-β production via the cGAS-STING pathway by facilitating ROS accumulation, lipid peroxidation, and the carbonylative modification of STING. Concurrently, the translocation of STING from the ER to the Golgi, the generation of GSH, and the system xc−/GSH/GPX4 axis were impaired. However, GPX4 activation ameliorated lipid peroxidation mediated by A151R. Importantly, A151R facilitated NCOA4 mediated ferritinophagy. The downregulation of NCOA4 suppressed ferroptosis and lipid peroxidation, upregulated GPX4 expression, and attenuated ferroptosis. GPX4 activation abolished A151R-induced protein carbonylation, subsequently activating the TBK1-IRF3 pathway and enhancing the transcription of IFN-β and ISGs. Consistent with the in vitro findings, ASFV infection significantly reduced GPX4 and FTH levels in porcine lungs and spleens. Pharmacological inhibition of ferroptosis and knockdown of A151R in ASFV enhanced the transcription of INF-β and ISGs, reduced lipid peroxidation, and restored the expression of GPX4. Overall, our study reveals a novel mechanism whereby ASFV A151R induces STING carbonylation and triggers ferritinophagy-induced ferroptosis, thereby impairing cGAS-STING-mediated antiviral immunity. This work establishes a new paradigm for understanding ferritinophagy-driven ferroptosis and provides mechanistic insights into ASFV immune evasion strategies. |
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| ISSN: | 1420-9071 |