Qingwen Tao

In recent years, PANoptosis has garnered increasing attention for its potential to promote inflammation. Nevertheless, several issues, including resistance to conventional treatment and immune evasion, correlate with inflammation in the tumor microenvironment. Controlled by the assembly of NLRP12‐, ZBP1‐, AIM2‐, and RIPK1‐PANoptosome, the newly discovered programmed cell death PANoptosis simultaneously manifests the characteristics of apoptosis, necroptosis, and pyroptosis. This review summarizes the multifaceted characteristics and the molecule determining PANoptosis sensitivity within the microenvironment. It examines the immunomodulatory function of PANoptosis in the tumor microenvironment, including how immune cells mediate PANoptosis in tumor cells and how tumor cells leverage PANoptosis to evade immune response and promote immunosupression. The crucial role of PANoptosis in immune remodeling suggests promising therapeutic strategies for tumors, such as immunotherapy and combination therapy. The induction of PANoptosis may establish a positive feedback loop that promotes immune activation and has a potential to remodel the immunosuppressive TME. Future strategies is expected to provide new directions for more precise, personalized cancer treatment.

Galectin‐9 (Gal9) is a type of animal lectin that binds terminal β‐galactosides and is involved in immunoregulatory functions. Clinically, Gal9 levels are positively correlated with disease activity in systemic autoimmune diseases, and it acts as a modulator of inflammation. Gal9 regulates inflammation and T cell‐mediated immune responses, and it can induce apoptosis and autophagy. Intracellularly, Gal9 regulates metabolic signaling pathways and glycosyltransferases. Extracellularly, Gal9 modulates immune polarization and promotes cell–cell interactions by binding to various receptors on immune cells. This review summarizes the multifaceted effects and underlying mechanisms of Gal9 in autoimmune diseases. Given its critical role in tissue inflammation and organ‐specific damage in autoimmune diseases, we discuss the current limitations of treatment and the challenges of clinical translation.

Objective: Primary Sjögren’s syndrome (pSS) is a highly heterogeneous autoimmune disease. Previous studies have suggested that rheumatoid factor (RF)-positive patients appear to have a higher incidence of systemic involvement. However, the underlying mechanisms remain unclear. This study aims to elucidate the potential biological mechanisms through single-cell RNA sequencing (scRNA-seq). Methods: Peripheral blood mononuclear cells from 3 healthy controls, 6 RF-negative (RF ^- ) pSS patients, and 6 RF-positive (RF ⁺ ) pSS patients were subjected to scRNA-seq. Subsequent analyses included pathway enrichment analysis, trajectory analysis, cell-cell communication analysis, and B cell receptor (BCR) and T cell receptor (TCR) repertoire profiling. Potential differences were further validated by flow cytometry. Results: Analysis of B cell subsets revealed a significantly increased proportion of plasma cells in RF ⁺ patients, and differential gene expression analysis indicated enhanced pathways related to antibody production, clonal expansion, and type I interferon activation. In T-cell subsets, the RF ⁺ group showed a notably higher proportion of CD8 ⁺ T cells, which exhibited stronger cytotoxicity and activation of interferon signaling. In contrast, mucosal-associated invariant T (MAIT) cells demonstrated activated interferon signaling but were present at a lower proportion compared to the RF ^- group. Cell–cell communication analysis revealed strengthened crosstalk between B cells and T cells in the RF ⁺ group. Pseudo-time trajectory analysis further indicated that in RF ⁺ patients, both plasma cells and CD8 ⁺ T cells exhibited a developmental skew toward a terminally differentiated state. Additionally, both BCR and TCR repertoire analyses indicated RF ⁺ and RF ^- patients exhibiting distinct patterns in clonal distribution and frequency. Flow cytometry further validated the increased proportion of CD8 ⁺ T cells and the decreased proportion of MAIT cells in the peripheral blood of RF ⁺ pSS patients. Conclusion: The RF status in pSS patients is closely associated with specific immune cell profiles. RF ⁺ patients exhibit more active plasma cell responses, enhanced CD8 ⁺ T-cell cytotoxicity and interferon responses, as well as heightened interferon signaling yet reduced proportion of MAIT cells. RF status serves as a key stratification marker for immune heterogeneity in pSS patients, providing new insights for understanding disease mechanisms and developing targeted therapeutic strategies.

Primary Sjögren's disease (pSjD) confers a markedly elevated risk for developing CVD, an important contributor to mortality in this population. This study was designed to identify factors associated with CVD in pSjD and to develop a classification model. In this cross-sectional analysis of pSjD individuals (2013-2023), multivariable logistic regression was used to identify CVD-related factors. A classification model was constructed with variable selection via LASSO regression and the Boruta algorithm. Among 734 patients with pSjD, 192 (26.2%) had CVD. Age (odds ratio [OR]: 1.06, P < 0.001), body mass index (BMI; OR: 1.14, P < 0.001), triglyceride-glucose (TyG) index (OR: 3.49, P < 0.001), and positive anti-Ro52 status (OR: 1.58, P = 0.022) were independent correlates of CVD in pSjD. Moreover, age, BMI, and TyG index showed a trend of gradually increasing CVD risk in patients with pSjD (P < 0.05). A five-variable classification model incorporating age, BMI, TyG index, anti-Ro52 antibody, and corrected QT interval was developed to identify CVD status. Good discrimination (area under the curve: 0.768), proper calibration, and clinical applicability were observed for this model. Its performance remained robust upon internal validation and testing in the test set (area under the curve: 0.753 and 0.821). The TyG index and anti-Ro52 antibody serve as significant factors associated with prevalent CVD in patients with pSjD. A novel classification model that integrates these biomarkers with age, BMI, and corrected QT interval showed good performance and generalizability, and may provide a practical tool for identifying cardiovascular status in this population.

Objective: To investigate the clinical and immunological features of primary Sjögren’s disease (pSjD) patients with anti-centromere protein B (CENP-B) antibody positivity and to evaluate its prognostic significance. Methods: This ambispective cohort study included 1,222 patients with pSjD from the China–Japan Friendship Hospital between February 2014 and February 2023, with follow-up through February 2024. Patients were categorized into anti-CENP-B positive and negative groups based on serum testing. Clinical characteristics, immunological features, and outcomes were compared between groups. A subgroup analysis compared patients with isolated CENP-B positivity to those with additional autoantibodies. Statistical analyses were conducted using SPSS 26.0 and R 4.2.3, including descriptive statistics, univariate tests, and Kaplan-Meier survival analysis. Results: In this study, 100 patients (8.2%) were positive for anti-CENP-B antibody, while 1,122 patients (91.8%) were negative. Compared with the negative group, positive patients were older, more often female, and have higher rates of xerostomia and Raynaud’s phenomenon, but lower frequency of dyspnea. They showed lower platelet counts, higher aspartate aminotransferase, gamma glutamyl transferase, lactate dehydrogenase, total bilirubin, and lower estimated glomerular filtration rate, with reduced frequencies of elevated Immunoglobulin (Ig) G, but increased IgM levels and slightly lower EULAR Sjögren’s Syndrome Disease Activity Index scores. Among anti-CENP-B positive patients, those with isolated anti-CENP-B positivity had milder immunologic abnormalities than those with concomitant autoantibodies. Among patients with available LSGB data, focal lymphocytic infiltration counts were higher in the anti-CENP-B-positive group. Anti-CENP-B positivity was not significantly associated with mortality, cancer, or interstitial lung disease. Conclusion: Anti-CENP-B positivity in pSjD may identify a different baseline serological and clinical profile, characterized by relatively milder immunologic abnormalities and lower disease activity. However, its prognostic and clinical significance remains uncertain and requires further validation.

Objective: To assess the impact of sex on mortality and malignancy in patients with primary Sjögren’s disease (pSD). Methods: This ambispective cohort study included 1,182 pSD patients (1,025 women and 157 men) from the China–Japan Friendship Hospital between 2014–2023 and followed through 2024. Survival outcomes were estimated via Kaplan–Meier curves, and SMRs were calculated. Independent risk factors were identified via multivariate Cox regression, followed by stepwise Cox, sex-stratified and interaction analyses. Results: During follow-up, 125 deaths (10.6%) and 33 malignancies (2.8%) occurred, both of which were more common in men (log–rank tests, P < 0.001). Overall mortality was markedly higher in men (25.5%, SMR = 4.79) than in women (8.3%, SMR = 2.42). Male sex was independently associated with higher risk of mortality (HR = 1.998, P = 0.004) and cancer incidence (HR = 3.799, P = 0.001). Sex-stratified analyses revealed distinct death–associated factors: interstitial lung disease (ILD), pulmonary infection and ischemic stroke were independently associated with mortality in men, whereas older age, low C3, elevated C-reactive protein and total bilirubin (TBIL) levels were associated with mortality in women. With respect to cancer, longer disease duration, lymphadenopathy, lymphocytopenia, elevated TBIL and hypochloremia were independently associated with cancer risk in women, whereas no variables showed an independent association with cancer risk among men. Interaction analyses demonstrated additive interactions between male sex and elevated ESSDAI scores, as well as male sex and concomitant ILD, in relation to mortality. Conclusion: Compared with women, men with pSD presented greater risks and distinct risk profiles of death and malignancy. Moreover, male sex was independently associated with adverse outcomes and acted as an important effect modifier, highlighting the need for sex-specific risk stratification and clinical management. Trial registration: This ambispective cohort study was registered in the Clinical Trial Registry (ID: NCT06528197) on June 27, 2024 and conducted in accordance with the Declaration of Helsinki.

Rheumatoid arthritis (RA) is a complex and highly disabling chronic autoimmune disease. As the disease progresses, patients often develop complications such as joint destruction and cardiovascular diseases, posing significant threats to human health. Celastrol, a major bioactive compound extracted from the traditional Chinese herb Tripterygium wilfordii Hook. f., exhibits potent immunomodulatory and anti-inflammatory properties. However, the specific mechanisms underlying its protective effects against bone destruction in RA remain poorly understood. To elucidate its potential therapeutic mechanisms, this study retrieved three gene expression datasets—GSE55235, GSE93777, and GSE200815—from the Gene Expression Omnibus (GEO) database. The primary molecular targets of celastrol were obtained from the HERB and TCMSP platforms. Functional mechanisms associated with these targets were explored using gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Furthermore, molecular docking, immune infiltration analysis, and single-cell RNA sequencing analysis were employed to investigate the role of key target genes. In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5 , AGTR1 , ALOX5 , CTSB , MMP3 , MMP9 , MYC , TNF , ITGA4 , ITGB7 , MMP1 , MMP13 , and PPARG . Among these, ALOX5 was found to significantly promote MMP3 protein expression, based on which a regulatory model with high predictive power was constructed. GSVA analysis revealed that the TNF-NFκB pathway was significantly activated in RA and exhibited a strong positive correlation with ALOX5 expression. Further experimental analysis demonstrated that knockdown of ALOX5 and its shared transcription factor with MMP2 resulted in a significant downregulation of both genes and inhibition of TNF-NFκB pathway activity. Single-cell transcriptomic analysis showed that ALOX5 was predominantly expressed in macrophages, and the AddModuleScore of celastrol-targeted genes in this cell type was significantly higher than in other cell types, suggesting that macrophages may serve as key effector cells in celastrol-mediated treatment of RA. Celastrol might attenuate RA bone destruction by inhibiting the expression of the ALOX5 gene in macrophages, thereby suppressing the activation of the NF-κB pathway and subsequently reducing the production of matrix metalloproteinases.