USP30-AS1 functions as a post-transcriptional amplifier of interferon signalling to drive autoimmune pathogenesis.

Interferon (IFN) signalling is essential for antiviral defence yet pathogenic in autoimmunity, however, the mechanisms orchestrating this duality remain poorly defined. Here, we identify USP30-AS1, a cytoplasmic long non-coding RNA (lncRNA) induced by type I IFN, as a pivotal post-transcriptional amplifier of innate immunity. We demonstrate that USP30-AS1 selectively enhances the mRNA stability of nucleic acid sensors. Moreover, USP30-AS1 preferentially stabilizes the majority of AU-rich element (ARE)-containing interferon-stimulated gene (ISG) mRNAs. USP30-AS1 executes this function independently of its antisense partner, USP30. The deletion of USP30-AS1 impaired IFN-β-mediated antiviral defence and suppressed pro-inflammatory cytokine production. Consistent with its role in amplifying immune responses, USP30-AS1 was markedly upregulated in human autoimmune diseases characterised by dysregulated IFN signalling, including systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Thus, our work unveils USP30-AS1 as a key regulator that fine-tunes the stability of nucleic acid sensors and ARE-containing immune transcripts, providing a direct mechanistic link between IFN signalling and post-transcriptional gene regulation. These findings establish USP30-AS1 as a critical rheostat for immune homeostasis and a promising therapeutic target for IFN-associated diseases.