Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive scarring interstitial lung disease with an unknown cause. Some patients may experience acute exacerbations (AE), which result in severe lung damage visible on imaging or through examination of tissue samples, often leading to high mortality rates. However, the etiology and pathogenesis of AE-IPF remain unclear. AE-IPF patients exhibit diffuse lung damage, apoptosis of type II alveolar epithelial cells, and an excessive inflammatory response. Establishing a reliable animal model of AE is critical for investigating the pathogenesis. Recent studies have reported a variety of animal models for AE-IPF, each with its own advantages and disadvantages. These models are usually established in mice with bleomycin-induced pulmonary fibrosis, using viruses, bacteria, small peptides, or specific drugs. In this review, we present an overview of different AE models, hoping to provide a useful resource for exploring the mechanisms and targeted therapies for AE-IPF.

Introduction: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear.Methods: RNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-β1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA.Results: GO enrichment highlighted significant enrichment of DEGs in TGF-β cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-β1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-β1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization.Conclusions: CALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Identifying novel therapeutic targets is urgent for idiopathic pulmonary fibrosis (IPF), a fatal disease with limited treatment options. N-acetyltransferase 10 (NAT10), the sole enzyme responsible for RNA N4-acetylcytidine (ac4C) modification, is implicated in diverse pathological processes. This study aimed to validate NAT10 as a potential therapeutic target for pulmonary fibrosis by utilizing the established small-molecule inhibitor, Remodelin, to functionally interrogate its role. We observed that NAT10 was significantly upregulated in lung tissues from IPF patients and bleomycin (BLM)-treated mice. Pharmacological blockade of NAT10 activity using Remodelin significantly attenuated lung structural destruction and collagen deposition in vivo. In vitro, inhibiting NAT10 function suppressed fibroblast activation and extracellular matrix production. Mechanistically, rather than directly modifying effector molecules, NAT10 stabilized the mRNA of transcription factor C/EBPβ via ac4C modification. This stabilization led to the transcriptional upregulation of Integrin α11 (ITGA11), thereby promoting fibroblast activation. Rescue experiments confirmed that the pro-fibrotic effects of NAT10 are dependent on this C/EBPβ-ITGA11 axis via its acetyltransferase activity. Collectively, our findings characterize NAT10 as a key pathogenic driver and demonstrate that inhibition of this epigenetic regulator offers a promising therapeutic strategy for ameliorating pulmonary fibrosis.

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Pulmonary alveolar proteinosis (PAP) is a rare pulmonary syndrome characterized by impaired surfactant clearance, driven by dysfunctional cholesterol efflux in alveolar macrophages (AMs). However, the molecular determinants governing AM cholesterol homeostasis remain incompletely defined. Here, through a genome-wide CRISPR screen in foamy macrophages and bulk RNA sequencing of AMs from PAP patients, we identify DTX4 as a pivotal regulator of cholesterol efflux in AMs. In mice, AAV-mediated silencing of DTX4 led to excessive AM lipid accumulation, exacerbated proteinosis, increased lung opacities, and deteriorated pulmonary function. Similarly, DTX4 depletion in primary AMs impaired cholesterol efflux and promoted intracellular lipid deposition. Conversely, AM-specific overexpression of DTX4 in the Csf2ra ^–/– PAP model markedly alleviated lipid accumulation, mitigated alveolar proteinosis, restored lung densities, and rescued pulmonary function. Mechanistically, DTX4 stabilizes the GM-CSF receptor via an E3-independent interaction to sustain JAK2/STAT5 signaling, which reciprocally maintains DTX4 transcription. This positive-feedback loop drives PPARγ expression, and its disruption in PAP impairs cholesterol efflux, a defect partially reversible by ectopic PPARγ expression. Collectively, our findings identify DTX4 as a central orchestrator of AM cholesterol efflux and surfactant homeostasis, positioning it as a promising therapeutic target for PAP.