Songping Xie

Sepsis-associated acute lung injury (SALI) is characterized by disruption of the alveolar–capillary barrier, uncontrolled inflammation, oxidative stress, and impaired tissue repair. Ferroptosis and cellular senescence have emerged as potentially interacting stress-response programs that may jointly shape the progression of septic lung injury. Ferroptosis promotes epithelial and endothelial damage through iron-dependent lipid peroxidation, glutathione depletion, and impaired GPX4-mediated lipid repair. In parallel, senescence-associated remodeling may contribute to persistent cell-cycle arrest, senescence-associated secretory phenotype (SASP) production, endothelial dysfunction, and defective regenerative capacity. This review summarizes current evidence on the molecular and cellular crosstalk between ferroptosis and cellular senescence in SALI. Candidate regulatory intersections include context-dependent mitochondrial dysfunction, reactive oxygen species accumulation, iron dyshomeostasis, metabolic reprogramming, lysosomal dysfunction, DNA-damage responses, and stress-responsive pathways involving p53, NRF2, ATF4, STAT3, and FOXO1. Direct SALI evidence is currently strongest for ferroptosis-induced senescence-associated remodeling in pulmonary endothelial cells, whereas senescence-associated ferroptosis resistance is supported mainly by non-pulmonary models. Likewise, SASP-mediated paracrine ferroptosis in neighboring pulmonary cells remains insufficiently validated. We therefore propose an evidence-informed, temporally and cell-type-dependent ferroptosis–senescence framework in SALI, in which acute senescence-associated responses may coexist with ferroptotic injury, whereas persistent senescence-associated remodeling may contribute to defective repair and microenvironmental injury amplification. Targeting this axis through ferroptosis inhibition, restoration of endogenous antioxidant defenses, senotherapeutic modulation, and regenerative strategies may offer stage-informed therapeutic opportunities. Further time-resolved and cell-specific studies are required to define causal relationships and clinically actionable therapeutic windows.

Elevated lactate levels in lung tissue are a distinct hallmark of acute lung injury (ALI), but the biological functions of glycolytic reprogramming and lactate-derived protein modification in damaged alveolar epithelial cells remain poorly elucidated. In the present study, we validated markedly increased lactate abundance in peripheral samples and lung tissues of multiple ARDS patients and multiple ALI mouse models. Administration of glycolysis inhibitor 2-DG to deplete endogenous lactate effectively mitigated lung injury and alveolar epithelial barrier dysfunction, whereas exogenous lactate supplementation significantly worsened these pathological manifestations. Genetic silencing of pulmonary LDHA via intratracheal injection of AAV9-shLdha successfully reproduced the protective phenotypes conferred by 2-DG treatment. Mechanistically, accumulated lactate facilitated Tip60-dependent lactylation modification of YY1 at lysine 183. Biochemical assays confirmed that YY1 K183 lactylation inhibited the expression of PGC-1α at transcriptional level, further causing mitochondrial homeostasis disorder and destruction of alveolar epithelial barrier. In vivo rescue experiments using lactylation-deficient YY1-K183R mutant verified the essential pathogenic role of this site-specific lactylation in LPS-triggered ALI progression. Additionally, we established two feasible translational therapeutic strategies, including K183-targeted cell-penetrating peptide and glycyrrhizin screened from compound libraries. Both candidates efficiently suppressed YY1 K183 lactylation, restored PGC-1α expression and mitochondrial function, and relieved pulmonary edema, inflammatory infiltration and cell apoptosis. In summary, lactate-driven YY1 K183 lactylation disrupts PGC-1α-mediated mitochondrial quality control and epithelial barrier stability. Intervening this lactate-YY1 lactylation axis provides a reliable and promising therapeutic direction for clinical treatment of ALI and ARDS.

Idiopathic pulmonary fibrosis (IPF) and Crohn’s disease (CD) share overlapping immune and fibrotic processes, yet their convergent molecular mechanisms remain poorly defined. Here, we performed an integrative transcriptomic analysis of nine public datasets to identify shared transcriptional signatures across IPF and CD. The main discovery and validation analyses were based on bulk transcriptomic datasets and combined differential expression profiling, weighted gene co-expression network analysis, and machine-learning–based feature prioritization. We identified 28 shared disease-associated module genes, from which three core genes—ZNF395, EEF2K, and BAHD1—were prioritized based on reproducibility and biological consistency. Functional enrichment analysis revealed their involvement in immune regulation, protein homeostasis, and stress-response pathways. Immune deconvolution and supportive single-cell RNA-sequencing further suggested associations between these genes and T-cell and myeloid cell populations, suggesting coordinated immune-fibrotic regulation. Experimental validation in a repetitive bleomycin challenge model and TGF-β1-stimulated fibroblasts showed consistent downregulation of these genes during fibrotic remodeling, supporting their association with fibrosis-related transcriptional states. Collectively, our study identifies conserved immune–fibrotic transcriptional programs shared across intestinal inflammation and pulmonary fibrosis, providing a hypothesis-generating molecular framework for understanding extraintestinal pulmonary involvement in Crohn’s disease and prioritizing candidate genes for future mechanistic investigation.

The mechanisms underlying sepsis remain poorly understood and specific therapeutic options remain lacking. Accumulating evidence suggests that butyrate metabolism and oxidative stress (OS) are involved in the pathogenesis of sepsis. This study aims to elucidate molecular characteristics of butyrate metabolism and OS-related genes in sepsis and find potential therapeutic targets. Using sepsis-related datasets, 876 differential expression genes (DEGs) were screened and intersected with butyrate metabolism and OS-related genes to yield 8 differentially expressed butyrate metabolism and OS-related genes (DEBORGs). Machine learning algorithms finally identified 3 feature genes (ALDH1A1, CYP1B1, and GADD45A) with favourable diagnostic values for sepsis. CIBERSORT immune infiltration analysis demonstrated strong associations between feature genes and the infiltration proportions of various immune cell types, such as monocyte, macrophage, and neutrophil. Cellular experiment and prospectively collected clinical samples were utilized to validate the expression levels and diagnostic efficacy of feature genes. The scRNA-seq analysis indicated that monocyte plays a crucial role in mediating the effect of feature genes on sepsis. This study elucidates that ALDH1A1, CYP1B1, and GADD45A are feature genes linked to butyrate metabolism and OS in sepsis, with monocytes being the primary cells involved, providing novel insights into the sepsis pathogenesis and potential therapeutic targets.

Background: Acute respiratory distress syndrome (ARDS) is a major complication in hospitalized patients with coronavirus disease 2019 (COVID-19). Early identification of patients at increased risk of ARDS progression and invasive ventilation remains clinically important. This study aimed to investigate whether plasma hyaluronic acid (HA), alone or in combination with established clinical severity scores, could help identify ARDS, stratify severe disease, and assess the risk of endotracheal intubation in patients with COVID-19. Methods: This retrospective single-center cohort study included 502 adult patients with COVID-19 admitted between September 2022 and February 2023. Plasma HA levels were measured within 24 hours after admission. Demographic characteristics, comorbidities, laboratory findings, clinical severity scores, and outcome data were collected. Receiver operating characteristic analysis, multivariable logistic regression, and nomogram construction were used to evaluate the association of HA with ARDS diagnosis, severe ARDS stratification, and intubation risk. Results: This retrospective cohort analysis of 502 COVID-19 patients (361 in the non-ARDS group and 141 in the ARDS group) identified plasma hyaluronic acid (HA) as a potential biomarker for early ARDS diagnosis, severity stratification, and intubation risk assessment. HA levels were positively correlated with disease severity, with concentrations significantly increasing alongside ARDS severity, and showed good discrimination for ARDS (AUC = 0.904; sensitivity 81.6%, specificity 87.5% at a cut-off of 103 μg/L). HA also demonstrated excellent discrimination for severe ARDS, with an AUC of 0.953, comparable to that of the APACHE II and SOFA scores. It also showed good discrimination for endotracheal intubation risk in the overall cohort. The AUC for predicting intubation requirement reached 0.890 (sensitivity 76.6%, specificity 90.8%, NPV = 95.5% at a cut-off value of 140.1 μg/L). Integrating HA with clinical scores further improved model performance; incorporating age, lymphocyte count, CRP, CK, APACHE II, and SOFA into the baseline model increased the AUC for predicting severe ARDS from 0.960 to 0.973 (ΔAUC = 0.013). Furthermore, multivariable regression analysis showed that HA was independently associated with ARDS diagnosis (OR = 1.04, P = 0.007), severe ARDS (OR = 1.00, P < 0.001), and intubation risk (OR = 1.00, P = 0.011). Conclusion: Plasma HA was positively associated with ARDS severity and intubation risk in patients with COVID-19. HA may serve as a complementary biomarker for early risk stratification, particularly when used in combination with established clinical severity scores.

Sepsis remains a major cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions characterized by high mortality and limited therapeutic options. Among the diverse inflammatory pathways implicated in their pathogenesis, the CXCL12/CXCR4 chemokine axis has gained increasing attention for its dual capacity to drive acute inflammation while also supporting tissue repair. Although numerous studies have investigated this signaling pathway, an integrated framework that reconciles its context-dependent functions, upstream regulatory mechanisms, and translational relevance has been lacking. In this review, we synthesize current evidence on the multifaceted roles of the CXCL12/CXCR4 axis in sepsis-induced ALI, highlighting its cell-type-specific effects in neutrophils, macrophages, alveolar epithelial cells, and endothelial cells through downstream pathways such as NF-κB, MAPK, and PI3K/Akt. We further evaluate emerging therapeutic approaches, including small-molecule antagonists (e.g., AMD3100), natural products, and epigenetic modulators. Newly added sections summarize the upstream regulation of CXCL12 by hypoxia, cytokines, and epigenetic factors, discuss the regulatory influence of the alternative receptor CXCR7/ACKR3, and differentiate preclinical insights from human clinical observations. Finally, we outline key obstacles to clinical translation and propose future directions to develop precision medicine strategies that more effectively target this axis. Collectively, our analysis suggests that although the CXCL12/CXCR4 pathway represents a promising target for ALI/ARDS therapy, its context-dependent and cell-specific actions demand carefully tailored modulation rather than uniform inhibition.

Combined small cell lung cancer (CSCLC) is a cancer that mixes small cell lung cancer (SCLC) with non-small cell lung cancer (NSCLC) components according to the World Health Organization's 2015 New Pathologic Classification of Lung Cancer. Composed of a mixture of SCLC and NSCLC components, CSCLC is classified as a subtype of SCLC in neuroendocrine tumors. Currently, research on SCLC mainly focuses on single-component pure SCLC, with relatively few studies on CSCLC, which is clinically rare and has no standardized treatment protocols and lacks a unified perception of the clinicopathological features and prognostic predictive indexes of CSCLC. Further observation of efficacy and prognosis is needed. We report the treatment course of a case of CSCLC and provide a literature review of the current status of research on CSCLC. .

Glaucoma is a leading cause of irreversible blindness worldwide, with its pathogenesis incompletely understood. Inflammation, as an important aspect of glaucoma, has attracted increasing attention. In this study, we performed a Mendelian randomization (MR) analysis to investigate the association between 91 circulating inflammatory proteins and glaucoma. First, a bidirectional MR was employed to screen for inflammatory proteins that potentially influence glaucoma risk, with the findings further confirmed by a replication sample MR. Then, a mediation analysis was employed to assess the mediating effects of glaucoma endophenotypes on glaucoma. Finally, we performed a subgroup MR to investigate the association between circulating proteins and glaucoma subtypes, including primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). The bidirectional MR suggested 7 out of the 91 proteins were possibly related with glaucoma risk, with T-cell surface glycoprotein CD5 (CD5) (odds ratio (OR) = 0.87; 95% confidence interval (CI): 0.81–0.94; P = 2.46 × 10⁻⁴) passing false discovery rate correction. This result was verified by the replication sample MR. The mediation analysis revealed that intraocular pressure (IOP) (β=-0.05; 95% CI: −0.02-−0.09; P = 1.56 × 10⁻³) was a mediator of CD5’s protective effect on glaucoma. The subgroup MR indicated that CD5 conferred a protective causal effect specifically on POAG, not PACG. Moreover, IOP served as a mediator in the association between CD5 and POAG, explaining a proportion of 38.29% of CD5’s protective effect against POAG. Our findings suggest a negative causal association between circulating CD5 and POAG risk, which is partially mediated by IOP. This indicates that targeted CD5 therapy may be beneficial to POAG eyes.

Lung ischemia–reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R. First, we identified O-GlcNAc transferase 1 (Ogt1) as a differentially expressed gene in lung epithelial cells of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, and Gene Ontology analysis (GO analysis) revealed the enrichment of the ferroptosis process. We found a time-dependent dynamic alteration in lung O-GlcNAcylation during I/R injury. Proteomics analysis identified the differentially expressed proteins enriched in ferroptosis and multiple redox-related pathways based on KEGG annotation. Thus, we generated Ogt1-conditional knockout mice and found that Ogt1 deficiency aggravated ferroptosis, as evidenced by lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, as well as alterations in critical protein expression glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Consistently, we found that elevated O-GlcNAcylation inhibited ferroptosis sensitivity in hypoxia/reoxygenation (H/R) injury-induced TC-1 cells via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both the chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter assay indicated that Nrf2 could bind with translation start site (TSS) of glucose-6-phosphate dehydrogenase (G6PDH) and promote its transcriptional activity. As an important rate-limiting enzyme in the pentose phosphate pathway (PPP), elevated G6PDH provided a mass of nicotinamide adenine dinucleotide phosphate (NADPH) to improve the redox state of glutathione (GSH) and eventually led to ferroptosis resistance. Rescue experiments proved that Nrf2 knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished the protective effect of ferroptosis resistance. In summary, we revealed that O-GlcNAcylation could protect against I/R lung injury by reducing ferroptosis sensitivity via the Nrf2/G6PDH pathway. Our work will provide a new basis for clinical therapeutic strategies for pulmonary ischemia–reperfusion-induced acute lung injury.

While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.