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.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, with unknown pathogenesis and no effective treatment. Identifying the key molecular of IPF in underlying mechanisms is critical for developing targeted therapies. Differentially expressed genes (DEGs) were identified based on GSE53845 data from the Gene Expression Omnibus (GEO) database and the Limma R package, followed by gene set enrichment analysis (GSEA). The key module genes selected by Weighted Gene Co-expression Network Analysis (WGCNA) were integrated with the DEGs. The hub genes were screened using three machine-learning algorithms, with further performance validated through Receiver Operating Characteristic (ROC) curves and nomogram models. In addition, validation was performed using external validation sets, in vitro experiments and human lung tissues. Enrichment analyses were conducted using GeneMANIA and GSEA. Branched chain amino acid transferase 2 (BCAT2) was identified as a central hub gene in IPF by intersecting key module genes with DEGs through WGCNA and machine learning methods. Experimental validation confirmed the significantly downregulation of BCAT2 in the lung tissues of IPF patients and in TGF-β1-treated alveolar epithelial cells (AECs). Moreover, upregulation of BCAT2 attenuated the expression of fibrosis markers in AECs exposed to TGF-β1. Ultimately, Co-expression analysis and GSEA indicated that BCAT2 is closely involved in several key signaling pathways. Collectively, our findings suggest that BCAT2 is a critical protective molecule in the pathogenesis of IPF and represents a potential therapeutic target for modulating the progression of pulmonary fibrosis.

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.

Patients with pre-existing interstitial lung disease (ILD) are highly vulnerable to SARS-CoV-2 infection, yet the long-term radiologic and clinical consequences remain poorly defined. This study evaluated 24-month outcomes, radiologic trajectories, and the impact of corticosteroid strategies in hospitalized COVID-19 patients with ILD. We conducted a retrospective longitudinal cohort study including 82 hospitalized COVID-19 patients with pre-existing ILD (December 2022–April 2023). Clinical variables, treatments, and serial high-resolution CT (HRCT) scans at baseline, 6, 12, and 24 months were analyzed. HRCT data were quantified using AI-assisted automated whole-lung segmentation, and radiologic trajectory phenotypes were identified using latent class growth mixture modeling (LCGMM). Cox regression, ROC analysis, and LOESS models assessed the associations between corticosteroid exposure, tapering duration, radiologic progression, and mortality. Three distinct 24-month CT trajectories were identified: Improved (n = 22, 43.1

The etiology and underlying mechanisms of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) remain poorly understood. Although several animal models have been developed to study AE-IPF, a systematic evaluation and comparison of these models has not yet been reported. In the present study, PF was induced in mice by a single intratracheal administration of bleomycin (BLM). On day 14 after the initial BLM challenge, AE-PF in mice was induced by intratracheal re-challenge with replication-deficient adenoviral vectors (ADV), lipopolysaccharide (LPS) or a second dose of BLM. Micro-chest computed tomography (CT) was performed on day 20, and blood, bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected after sacrifice on day 21. Compared with mice receiving a single dose of BLM alone, all three AE-PF groups exhibited significant body weight loss and increased mortality (with the highest mortality in the LPS group), as well as more extensive lung injury on CT. Histopathological scores for inflammation and fibrosis, hydroxyproline content and expression levels of fibrotic markers (fibronectin, collagen I, α-smooth muscle actin and MMP7) were significantly elevated in the AE-PF groups. Inflammatory cytokines (IL-6, IL-1β and TNF-α) were markedly increased in both serum and BALF. Furthermore, the AE-PF models showed downregulation of alveolar epithelial cell markers (E-cadherin and pro-surfactant protein C) and a significant increase in apoptotic activity. Notably, fibrosis progression was more severe in the ADV and two-dose BLM groups than in the LPS group. Taken together, these findings indicate that all three triggers can induce AE-PF through enhanced apoptosis, inflammation and fibrosis. These results support the use of day 14 re-challenge as a standardized model for AE-PF. Among the three models, the ADV-induced AE-PF model may serve as a particularly suitable platform for investigating the pathogenesis of acute exacerbations in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease without any effective treatment. Berberine (BBR), a botanical alkaloid, possesses extensive biological activities and has significant therapeutic value in various diseases. However, the effect and potential mechanisms of BBR on pulmonary fibrosis remain elusive. In vivo, BBR was administered by gavage following intratracheal instillation of bleomycin (BLM) in a mouse model from Day 1 to Day 20. In vitro, Human Lung Fibroblast (HLF) and A549 cell lines were used to explore the effects of BBR on transforming growth factor β1 (TGF-β1) treated cells. Both cell lines were transfected with a lentivirus carrying TGF-β receptor 2 (TGFBR2) knockdown genes, and the autophagy inhibitor chloroquine (CQ) and PI3K inhibitor LY294002 were employed to investigate the underlying effects of BBR on TGF-β signaling and autophagy in pulmonary fibrosis. BBR administration attenuates pulmonary inflammation and fibrosis of BLM-induced mice in vivo. Analogously, BBR treatment significantly alleviates matrix collagen deposition and reduces the expression of fibrotic markers in TGF-β1-treated human lung fibroblasts (HLF) and alveolar epithelial cell (A549) in vitro. Mechanistically, we found that BBR downregulates the expression of TGFBR2 and suppresses TGF-β/Smad2/3 signaling in vivo and in vitro. Furthermore, BBR inhibits the activation of the PI3K/AKT/mTOR pathway and autophagy, then downregulates the expression of pro-fibrotic genes. The effect of BBR on pulmonary fibrosis was further verified using both TGF-β1-treated HLF and A549 cells with the addition of the inhibitors of PI3K, LY294002, and autophagy, CQ in vitro, respectively. Our study suggests that BBR can inhibit pulmonary fibrosis by down-regulating the expression of TGFBR2, attenuating TGF-β/Smad2/3 signal, and activating autophagy through phosphorylation of PI3K/AKT/mTOR.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) poses a significant clinical challenge due to its high morbidity and mortality, coupled with a lack of effective targeted therapies. Here, utilizing single-cell transcriptomic analysis and validation in AE-IPF patient samples, we identified integrin and CD44 as markedly upregulated in injured alveolar type II cells and myofibroblasts, highlighting their potential as pathological delivery targets in AE-IPF. Based on these findings, we developed a dual-targeted liposomal nanoplatform (ND-RHL) co-encapsulating nintedanib and dexamethasone, specifically engineered to exploit integrin/CD44 overexpression for pulmonary precise drug delivery and synergistic anti-fibrotic and anti-inflammatory effects. ND-RHL exhibited favorable physicochemical characteristics, efficient dual-drug loading, and selective accumulation in integrin/CD44-high cells both in vitro and in vivo. In a murine model of AE-IPF, intratracheal administration of ND-RHL markedly improved survival, mitigated lung inflammation and fibrosis, and preserved pulmonary architecture, with minimal systemic toxicity. Mechanistically, transcriptomic profiling and immune phenotyping demonstrated that ND-RHL reversed AE-induced gene expression patterns and inhibited pivotal signaling pathways, including PI3K-AKT-mTOR, Wnt/β-catenin, and NF-κB-PPARγ, thereby orchestrating the remodeling of both immune and extracellular matrix microenvironments. This study presents ND-RHL as a mechanistically informed, cell-targeted nanotherapeutic with robust therapeutic potential and translational promise for the treatment of AE-IPF and related fibrotic lung diseases.

Emphysema is common in fibrotic interstitial lung diseases, and its combination with pulmonary fibrosis is known as "Combined Pulmonary Fibrosis and Emphysema (CPFE) syndrome". The diagnosis of CPFE significantly impacts treatment strategies and prognosis. In this article, we report the clinical, imaging, and especially the pathological features of two CPFE patients. Case 1: A 51-year-old male patient with a history of smoking. CT scans revealed interstitial lung disease combined with pulmonary bullae. Pathology showed extensive deposition of mononuclear cells in the alveolar spaces, with some cells phagocytosing pigment. Mild fibrous tissue hyperplasia was present in the lung interstitium, along with chronic inflammation and lymphoid nodule formation. The histological findings were consistent with desquamative interstitial pneumonia (DIP), and the clinical, imaging, and pathological correlation confirmed a diagnosis of CPFE. Case 2: A 58-year-old male, a driver with a history of dust exposure and smoking, was admitted due to chest tightness and a cough for 2 years. Chest CT revealed interstitial changes, emphysema, and bullae in both lungs. Histopathology showed fibrous widening of alveolar septa, mild chronic inflammation, and dust cell deposition, along with emphysematous changes and bulla formation, consistent with CPFE. The purpose of this report is to increase pathologists' awareness of this complex disease and emphasize the importance of multidisciplinary cooperation in the diagnosis and treatment of CPFE. Furthermore, this article encourages further research into CPFE.

Background/Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic disease. Amphiregulin (AREG) is both required and sufficient to drive fibrosis in preclinical models. High levels of serum AREG correlate significantly with profound deteriorations in lung function of IPF patients. PMG1015, a first-in-class anti-AREG antibody, is currently under development for IPF treatment. Results from a Phase Ib multiple ascending dose study evaluating the safety, tolerability, pharmacokinetics, and target engagement of PMG1015 in IPF patients are expected in early 2025. Here, we report the results of two Phase Ia clinical studies (NCT05022771 and CTR20221571) to assess the safety, tolerability, pharmacokinetics, and immunogenicity of PMG1015 in healthy volunteers. Methods: The first-in-human (FIH) study in Australia (NCT05022771) was a randomized, double blind, placebo-controlled, single ascending dose (SAD) study to assess the safety, tolerability, pharmacokinetics, and immunogenicity of PMG1015 in healthy adult subjects. The study enrolled 54 healthy volunteers in 7 cohorts to receive IV doses of PMG1015 of 0.5, 1.5, 4.5, 10, 20, 30, and 40 mg/kg. Study CTR20221571 was a randomized, double blind, placebo-controlled study conducted in healthy volunteers in China. The study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of single doses of PMG1015 (10, 30, and 40 mg/kg IV). The study enrolled 30 participants. Results: PMG1015 exhibited a consistently favorable safety profile across both Phase Ia studies, demonstrating that it is well-tolerated in healthy subjects. No SAE related to the study treatment were reported in either study. The majority of the TEAEs were mild in severity. The incidence of TEAEs did not increase with increasing PMG1015 dose and was comparable between the PMG1015 and placebo groups. Pharmacokinetic profiles from both studies were consistent, showing a dose-dependent proportional increase in Cmax and AUC0-last. Conclusions: PMG1015 is safe and well-tolerated with favorable pharmacokinetic characteristics in healthy volunteers. These results support the progression of PMG1015 to further studies in patients with IPF.

Background and ObjectiveAcute exacerbation (AE) is often the fatal complication of idiopathic pulmonary fibrosis (IPF). Emerging evidence indicates that metabolic reprogramming and dysregulation of lipid metabolism are distinctive characteristics of IPF. However, the lipid metabolic mechanisms that underlie the pathophysiology of AE-IPF remain elusive.MethodsSerum samples for pilot study were collected from 34 Controls, 37 stable IPF (S-IPF) cases and 41 AE-IPF patients. UHPLC-MS/MS was utilized to investigate metabolic variations and identify lipid biomarkers in serum. ELISA, quantitative PCR and western blot were employed to validate the identified biomarkers.ResultsThere were 32 lipid metabolites and 5 lipid metabolism pathways enriched in all IPF patients compared to Controls. In AE-IPF versus S-IPF, 19 lipid metabolites and 12 pathways were identified, with 5-hydroxyeicosatetraenoic Acid (5-HETE) significantly elevated in AE-IPF. Both in internal and external validation cohorts, the serum levels of 5-HETE were significantly elevated in AE-IPF patients compared to S-IPF subjects. Consequently, the indicators related to 5-HETE in lipid metabolic pathway were significantly changed in AE-IPF patients compared with S-IPF cases in the lung tissues. The serum level of 5-HETE was significantly correlated with the disease severity (CT score and PaO2/FiO2 ratio) and survival time. Importantly, the receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Multivariate Cox regression analysis demonstrated that 5-HETE represents a promising lipid biomarker for the diagnosis and prognosis of AE-IPF.ConclusionOur study highlights lipid reprogramming as a novel therapeutic approach for IPF, and 5-HETE may be a potential biomarker of AE-IPF patients.

Objectives Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD.Methods This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis.Results Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model.Conclusions We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Purpose Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the primary cause of death in patients with IPF, characterised by diffuse, bilateral ground-glass opacification on high-resolution CT (HRCT). This study proposes a three-dimensional (3D)-based deep learning algorithm for classifying AE-IPF using HRCT images.Materials and methods A novel 3D-based deep learning algorithm, SlowFast, was developed by applying a database of 306 HRCT scans obtained from two centres. The scans were divided into four separate subsets (training set, n=105; internal validation set, n=26; temporal test set 1, n=79; and geographical test set 2, n=96). The final training data set consisted of 1050 samples with 33 600 images for algorithm training. Algorithm performance was evaluated using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and weighted κ coefficient.Results The accuracy of the algorithm in classifying AE-IPF on the test sets 1 and 2 was 93.9% and 86.5%, respectively. Interobserver agreements between the algorithm and the majority opinion of the radiologists were good (κw=0.90 for test set 1 and κw=0.73 for test set 2, respectively). The ROC accuracy of the algorithm for classifying AE-IPF on the test sets 1 and 2 was 0.96 and 0.92, respectively. The algorithm performance was superior to visual analysis in accurately diagnosing radiological findings. Furthermore, the algorithm’s categorisation was a significant predictor of IPF progression.Conclusions The deep learning algorithm provides high auxiliary diagnostic efficiency in patients with AE-IPF and may serve as a useful clinical aid for diagnosis.

IntroductionIdiopathic 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.MethodsRNA 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.ResultsGO 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.ConclusionsCALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Respiratory diseases pose a major public health challenge globally, necessitating collaborative efforts between basic researchers and clinicians for effective solutions. China, which is heavily impacted by a broad spectrum of respiratory disorders, has made notable strides in both research and clinical management of these diseases. The International Respiratory Medicine (IRM) meeting was organized with the primary goal of facilitating the exchange of recent research developments and promoting collaboration between Chinese and American scientists in both basic and clinical research fields. This article summarizes key insights from IRM2024, held in Shanghai, where a wide range of topics were discussed, including lung tissue development, disease mechanisms, and innovative therapeutic strategies. By integrating perspectives from basic, translational, and clinical research, IRM2024 highlighted recent advancements, addressed persistent challenges, and explored future directions in respiratory science and clinical practice. The insights gained from IRM2024 are poised to be pivotal in shaping future research and therapeutic approaches, further reinforcing the global commitment to enhancing respiratory health and improving patient outcomes.

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.

目的 为临床医师诊治肺诺卡菌病提供参考,并探讨宏基因组二代测序技术(mNGS)对肺诺卡菌病的临床诊断价值.方法 对 2017 年 1 月至 2022 年 10 月南京大学医学院附属鼓楼医院通过mNGS检测诊断的 13 例肺诺卡菌患者进行回顾性分析,并进行相关文献复习.结果 13 例患者中,男 9 例,女 4 例,年龄 35～79 岁,平均(57±10)岁;10 例伴有基础疾病,4 例使用激素或免疫抑制剂.临床表现主要为咳嗽、咳痰、发热、气喘、咯血、消瘦等.胸部CT表现为结节、肺实变、胸膜增厚、空洞、肿块、胸腔积液、支气管扩张、纵隔及腋窝淋巴结肿大、磨玻璃影.通过经支气管镜肺泡灌洗液行mNGS检测确诊9 例,经支气管镜肺活检组织行mNGS检测确诊 1 例,经皮肺穿刺活检组织行mNGS检测确诊 3 例,标本均未培养出诺卡菌.入院至确诊中位时间为 8 d(3.50～15.00 d).治疗药物以复方磺胺甲噁唑为主,分别联合利奈唑胺、阿米卡星、亚胺培南、美罗培南、莫西沙星等抗菌药物.11 例随访病情好转,1 例随访无好转,3 个月后确诊为肺癌,1 例自动出院,未继续治疗.结论 肺诺卡菌病的临床表现及影像学无明显特异性,容易漏诊、误诊.肺诺卡菌感染可能合并其他潜在病因,需密切随访以免漏诊.相较于传统细菌培养法,mNGS对于肺诺卡菌病是一种敏感高效的诊断方法,有很好的应用前景.

Interstitial lung disease (ILD) is a common extramuscular manifestation of the anti-synthetase syndrome (ASS). Patients with ASS-ILD are at risk in developing a progressive fibrosing phenotype despite appropriate treatments. This study investigated the risk factors and the predictive value of multiple risk factors for progressive pulmonary fibrosis (PPF) in patients with ASS-ILD. Ninety patients with a diagnosis of ASS and evidence of ILD on high-resolution computed tomography (HRCT) were recruited. Among them, 72 participants completed follow-up for more than 12 months. These patients were further divided into a PPF-ASS group (n = 18) and a non-PPF-ASS group (n = 54). Logistic regression analysis was performed to investigate the risk factors for PPF. The predictive value of the combined risk factors for predicting PPF were analyzed by a ROC curve. The PPF-ASS group had a higher rate of positive non-Jo-1 antibodies, a significantly higher neutrophil-to-lymphocyte ratio (NLR) and serum lactate dehydrogenase (LDH), and a significantly lower PaO2/FiO2 ratio and diffusing capacity for carbon monoxide (DLCO

AbstractElevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the mAb RP215, which specifically recognizes the Asn162 sialylation–related epitope on SIA-cIgG, effectively blocked the SIA-cIgG–driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.Significance:Sialylated cancer IgG activates c-Met-SOX2 signaling to promote stemness properties in cancer cells and can be targeted to suppress tumor growth.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.