Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-α–induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-κB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-β/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.

Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

Certified RNA reference materials are indispensable for assessing the reliability of RNA sequencing to detect intrinsically small biological differences in clinical settings, such as molecular subtyping of diseases. As part of the Quartet Project for quality control and data integration of multi-omics profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets between two samples, providing cross-platform and cross-laboratory ‘ground truth’. Investigation of the intrinsically subtle biological differences among the Quartet samples enables sensitive assessment of cross-batch integration of transcriptomic measurements at the ratio level. The Quartet RNA reference materials, combined with the ratio-based reference datasets, can serve as unique resources for assessing and improving the quality of transcriptomic data in clinical and biological settings.

Superoxide dismutase 2 (SOD2) is essential in radical scavenging, which balances the intracellular level of reactive oxygen species (ROS). The dysfunction of SOD2 is associated with increasing incidence of various human diseases, including cancer, neuron diseases, and myocardial defects. However, the connections between SOD2-mediated oxidative homeostasis and innate immune response remain unclear. In this study, we report that SOD2 is a crucial regulator of antiviral signaling. Depletion of SOD2 impairs RNA virus-induced type I interferon (IFN) and proinflammatory cytokine production, resulting in enhanced viral replication. Type I IFN production is highly sensitive to cellular level of ROS. SOD2 deficiency-mediated ROS accumulation potently inhibits RIG-I-like receptor (RLR)-induced innate immune responses through the regulation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor-3 activation. These findings uncover a novel role for SOD2 in regulating RLR-mediated antiviral innate immune signaling.

Dengue virus (DENV) is a mosquito-borne single-stranded RNA virus causing human disease with variable severity. The production of massive inflammatory cytokines in dengue patients has been associated with dengue disease severity. However, the regulation of these inflammatory responses remains unclear. In this study, we report that SIRT6 is a negative regulator of innate immune responses during DENV infection. Silencing of Sirt6 enhances DENV-induced proinflammatory cytokine and chemokine production. Overexpression of SIRT6 inhibits RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) mediated NF-κB activation. The sirtuin core domain of SIRT6 is required for the inhibition of NF-κB p65 function. SIRT6 interacts with the DNA binding domain of p65 and competes with p65 to occupy the Il6 promoter during DENV infection. Collectively, our study demonstrates that SIRT6 negatively regulates DENV-induced inflammatory response via RLR and TLR3 signaling pathways.

Comprehensive and in-depth research on the immunophenotype of septic patients remains limited, and effective biomarkers for the diagnosis and treatment of sepsis are urgently needed in clinical practice. Blood samples from 31 septic patients in the Intensive Care Unit (ICU), 25 non-septic ICU patients, and 18 healthy controls were analyzed using flow cytometry for deep immunophenotyping. Metagenomic sequencing was performed in 41 fecal samples, including 13 septic patients, 10 non-septic ICU patients, and 18 healthy controls. Immunophenotype shifts were evaluated using differential expression sliding window analysis, and random forest models were developed for sepsis diagnosis or prognosis prediction. Septic patients exhibited decreased proportions of natural killer (NK) cells and plasmacytoid dendritic cells (pDCs) in CD45⁺ leukocytes compared with non-septic ICU patients and healthy controls. These changes statistically mediated the association of Bacteroides salyersiae with sepsis, suggesting a potential underlying mechanism. A combined diagnostic model incorporating B.salyersia, NK cells in CD45⁺ leukocytes, and C-reactive protein (CRP) demonstrated high accuracy in distinguishing sepsis from non-sepsis (area under the receiver operating characteristic curve, AUC = 0.950, 95% CI: 0.811-1.000). Immunophenotyping and disease severity analysis identified an Acute Physiology and Chronic Health Evaluation (APACHE) II score threshold of 21, effectively distinguishing mild (n = 19) from severe (n = 12) sepsis. A prognostic model based on the proportion of total lymphocytes, Helper T (Th) 17 cells, CD4⁺ effector memory T (T_EM) cells, and Th1 cells in CD45⁺ leukocytes achieved robust outcome prediction (AUC = 0.906, 95% CI: 0.732-1.000), with further accuracy improvement when combined with clinical scores (AUC = 0.938, 95% CI: 0.796-1.000). NK cell subsets within innate immunity exhibit significant diagnostic value for sepsis, particularly when combined with B. salyersiae and CRP. In addition, T cell phenotypes within adaptive immunity are correlated with sepsis severity and may serve as reliable prognostic markers. This project was supported by the National Key R&D Program of China (2023YFC2307600, 2021YFA1301000), Shanghai Municipal Science and Technology Major Project (2023SHZDZX02, 2017SHZDZX01), Shanghai Municipal Technology Standards Project (23DZ2202600).