Background: Systemic lupus erythematosus (SLE) is a high incidence, chronic and systemic autoimmune disease in women of childbearing age. It is characterized by a large number of autoantibodies in the body, multiple organ involvement, repeated recurrence and remission. The clinical manifestations are complex and heterogeneous, and it is easy to cause damage to important organs such as kidney, blood and nervous system [1]. Glucocorticoids and immunosuppression are still the main drugs for SLE treatment. The listing of biological agents has brought new hope for the treatment of SLE patients. However, there are still some problems in the treatment of SLE, such as low compliance rate of low disease activity status and high recurrence rate [2]. There are still unmet medical needs for SLE treatment.

Objectives: To investigate whether STAT1 (Signal transducer and activator of transcription 1) can accelerate CD4 ⁺ T cellular senescence by upregulating Map1s lactylation, thereby promoting the occurrence and development of systemic lupus erythematosus (SLE).

Methods: First, we screened a Bulk RNA dataset (GSE97263) of peripheral blood CD4 ⁺ T cells from SLE patients from the GEO database to screen differentially expressed genes. Next, GSEA enrichment, GO enrichment, KEGG enrichment, network analysis of differential genes using online database STRING, and hub genes were calculated using cytoscape. STAT1 expression and senescent markers in CD4 ⁺ T cells in peripheral blood of SLE patients and lymph nodes of Pristane-induced SLE mice was validated by quantificational real-time-PCR and western blot. Detection of lactylation of T cells in mouse lymph nodes by modified omics. The interplay between STAT1 and Map1s lactylation during cellular senescence was elucidated in vitro.

Results: The results showed that 790 genes were up-regulated and 217 genes were down-regulated in CD4 ⁺ T cells of SLE patients compared with healthy controls. We found a set of genes related to senescence, and then performed GSEA enrichment, and found that these gene sets were up-regulated in the SLE group. GO analysis found that the biological processes enriched in CD4 ⁺ T cells of SLE patients included inflammatory response, chemokine-mediated signaling pathways, innate and adaptive immune responses, etc. In addition, the enriched pathways include cell cycle, cell senescence, etc. Among the top 10 hub genes, STAT1 is the only protein strongly associated with cell senescence. STAT1 was upregulated in senescent CD4 ⁺ T cells in SLE patients and mice. The expression level of STAT1 was positively correlated with the severity of SLE. Map1s lactylation levels significantly increased in CD4 ⁺ T cells of Pristane-induced SLE mice. Lactylation enhancers, such as rotenone, enhanced the pro-senescence capabilities of STAT1, whereas treatment with sodium dichloroacetate, a lactylation inhibitor, damaged the facilitated effects of STAT1 to cellular senescence. LC-MS/MS analysis and CO-IP indicated that STAT1 might directly bind to the delactylase HDAC1. The interaction between HDAC1 and Map1s decreased under senescent conditions in vitro. Whereas, silencing STAT1 can increase the affinity between Map1s and HDAC1, reducing the level of lactylation.

Conclusion: Our results revealed that STAT1 promoted CD4 ⁺ T cellular senescence in SLE through upregulating the lactylation of Map1s and accelerating the incidence and development of SLE.

REFERENCES: [1] Hoi A, Igel T, Mok C C, et al. Systemic lupus erythematosus[J]. Lancet, 2024,403(10441):2326-2338.

[2] Lazar S, Kahlenberg J M. Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches[J]. Annu Rev Med, 2023,74:339-352.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.