Background Systemic lupus erythematosus (SLE) is characterised by a chronic type I interferon (IFN) signature whose epigenetic basis remains incompletely defined. Histone H3 lysine 9 dimethylation (H3K9me2) is a key repressive mark that can shape DNA-methylation landscapes and antiviral responses.

Methods Naïve CD4⁺ T cells were purified from 29 adults with SLE and 15 healthy donors. Genome-wide distributions of H3K9me2 and, for comparison, H3K27me3 were mapped by Cleavage Under Targets and Tagmentation (CUT&Tag). Targeted chromatin immunoprecipitation-qPCR and quantitative RT-PCR validated findings at canonical interferon-stimulated genes (ISGs). Pharmacological rescue was tested ex-vivo with ribavirin (RBV) ± the G9a inhibitor BIX01294. Therapeutic relevance was assessed in NZB/W-F1 lupus-prone mice treated with RBV (50–250 mg kg⁻¹, i.p., twice weekly for 20 weeks).

Results CUT&Tag revealed a pronounced, genome-wide reduction of H3K9me2—but not H3K27me3—in SLE T cells, which segregated cases from controls by principal-component analysis. H3K9me2 loss was most evident across ISG loci and inversely correlated with ISG mRNA expression. In vitro, RBV restored H3K9me2 at ISG regions and repressed ISG transcripts; both effects were abrogated by G9a inhibition, implicating G9a-dependent dimethylation. In NZB/W-F1 mice, RBV dose-dependently reduced proteinuria, diminished renal immune-complex deposition, and normalised splenic CD4⁺ T-cell ISG expression, mirroring ex-vivo epigenetic rescue.

Conclusions Loss of H3K9me2 is a selective epigenetic lesion that sustains the type I IFN signature in SLE. Pharmacological reinstatement of this mark with ribavirin reverses aberrant ISG activation and ameliorates lupus nephritis in vivo, highlighting H3K9me2 restoration as a tractable therapeutic strategy for IFN-high SLE.

The authors have declared no competing interest.

This work was supported by JSPS KAKENHI Grant Numbers JP19164142 and JP17K17940.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee/Institutional Review Board of Kyushu University Hospital gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The raw sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE274177.