Renwei Luo

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.

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.

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.