Systemic lupus erythematosus (SLE) and idiopathic pulmonary fibrosis (IPF) share immune-inflammatory features, yet their convergent peripheral-blood transcriptomic signatures remain incompletely defined. We sought to identify shared blood gene programs linking SLE and IPF, prioritize robust cross-disease markers, and evaluate parsimonious diagnostic models with experimental and external assessments. Peripheral-blood transcriptomes were analyzed in GEO discovery cohorts (SLE: GSE49454; IPF: GSE33566). Differential expression (limma) and weighted gene co-expression network analysis (WGCNA) were performed separately per disease, and concordant shared signals were integrated to form a shared candidate pool. Consensus feature selection combined LASSO logistic regression, nested cross-validated SVM-RFE, and random forest to derive parsimonious gene panels for SLE and IPF. Logistic-regression models were trained in discovery cohorts and externally validated in independent cohorts (SLE: GSE65391, GSE72509; IPF: baseline samples from longitudinal GSE93606). Experimental validation was conducted in an independent hospital cohort (60 SLE, 30 healthy controls) using PBMC RT-qPCR and serum GRN ELISA, with correlation and covariate-adjusted association analyses. Fixed models were additionally applied without refitting to non-target inflammatory cohorts (RA: GSE93272; ICU sepsis/non-infectious critical illness: GSE134347). Discovery analyses identified 389 SLE and 248 IPF DEGs and yielded 43 concordantly regulated shared DEGs; WGCNA identified 43 shared module genes, producing a non-redundant shared candidate pool of 78 genes enriched for B-cell and myeloid programs. Consensus selection generated a 6-gene SLE panel (EIF2AK2, GRN, ASGR2, KLRB1, LGALS9, KLF13) and a 4-gene IPF panel (GRN, ARG1, KLRB1, FCMR). The SLE model achieved AUC 0.996 in discovery and validated at AUC 0.888 (GSE65391) and 0.761 (GSE72509); the IPF model achieved AUC 0.906 in discovery and 0.722 in baseline validation. In the hospital cohort, RT-qPCR confirmed dysregulation of the six-gene panel, and serum GRN was markedly elevated in SLE (median [IQR] 43.58 [38.44-54.42] vs. 14.26 [12.79-15.26] ng/mL). Within SLE, serum GRN correlated with SLEDAI and inversely with C3/C4 and WBC; after covariate adjustment, associations with WBC, ESR, C3, and C4 remained significant, whereas associations with hs-CRP and SLEDAI were attenuated. In non-target cohorts, the SLE model showed moderate discrimination for RA (AUC 0.73) but limited discrimination for ICU sepsis (AUC 0.64) and none for non-infectious critical illness (AUC 0.50), while the IPF model showed minimal discrimination for RA (AUC 0.51) but high discrimination for ICU groups (AUC 0.99 and 0.96). GRN and KLRB1 anchor a shared peripheral-blood transcriptomic signature linking SLE and IPF, enabling parsimonious diagnostic models with multi-cohort validation and clinical experimental support. External in silico applications to other inflammatory contexts indicate context-dependent model behavior, underscoring the importance of cohort-appropriate interpretation and validation.

Atractylenolide I alleviates bleomycin-induced idiopathic pulmonary fibrosis via regulating HIF-1α to suppress oxidative stress and endoplasmic reticulum stress.

Unraveling the therapeutic mechanisms of Polygonum cuspidatum in pulmonary fibrosis: Modulation of M2 macrophage polarization and glycolysis pathways.

Unraveling miRNA-mediated TGF-β/hedgehog Signaling in bleomycin-induced pulmonary fibrosis: targeting inflammation-fibrosis crosstalk with candesartan and chlorogenic acid.

Ophiopogon japonicus polysaccharide ameliorates pulmonary fibrosis via gut microbiota-metabolite crosstalk.

The immunodynamics of pulmonary fibrosis.

Shengxian decoction mitigate bleomycin-induced pulmonary fibrosis in mice via MerTK mediated macrophage efferocytosis.

Coumarin derivatives in fibrosis therapy: Mechanistic insights from natural to synthetic scaffolds.

The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation, with prognostic value in interstitial lung disease (ILD). However, the association between baseline NLR and the therapeutic efficacy of nintedanib remains unclear. This study investigates the relationship between baseline NLR values and clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF) and progressive fibrosing-ILD (non-IPF ILD) receiving nintedanib therapy. This retrospective multicenter study included 406 patients-169 with IPF and 237 with non-IPF ILD-who initiated nintedanib treatment between 2019 and 2023 across 15 institutions in Japan. Patients were stratified into low- and high-NLR groups using a cutoff of 2.86. Comparative analysis assessed survival time, forced vital capacity (FVC) changes, and acute exacerbations. The high-NLR group demonstrated shorter median survival time in the overall study population (1,171 vs. 1,386days; p =0.025). In subgroup analyses, higher NLRs were associated with shorter survival time in patients with IPF (778 vs. 1,447days; p =0.006), but not in the non-IPF ILD group. While nintedanib mitigated FVC decline in most subgroups, this effect was attenuated in patients with IPF and high-NLR, with no statistically significant benefit (-8.63% vs. -6.71%). In multivariable analysis, NLR was not found to be an independent predictor of the annual relative FVC decline in any group. The incidence of acute exacerbations did not differ significantly between groups. While baseline NLR did not independently predict the annual relative FVC decline, it was identified as a significant independent predictor of survival time in patients with ILD, particularly those with IPF, following the initiation of nintedanib.

The therapeutic strategy for Idiopathic Pulmonary Fibrosis (IPF) has undergone a fundamental transformation over recent decades. Combination therapy with glucocorticoids and immunosuppressants, particularly the “triple therapy” regimen including corticosteroids, azathioprine, and an antioxidant, has shifted from being the standard of care to being completely abandoned. This article reviews the key evidence-based milestones in this historical shift and, grounded in a modern understanding of the disease’s nature, delves into the pathophysiological basis for the ineffectiveness and even harm of glucocorticoids and immunosuppressants in IPF. The core argument posits that IPF is a disorder of immune microenvironment dysregulation, initiated by persistent alveolar epithelial injury, driven by pro-fibrotic phenotype macrophages, and ultimately resulting in myofibroblast activation and aberrant extracellular matrix deposition. Traditional glucocorticoids and immunosuppressants, whose primary target cells are lymphocytes, are misaligned with the core immune drivers (macrophages) and effector cells (myofibroblasts) of IPF. Consequently, they not only fail to reverse the fibrotic process but may also potentially promote fibrogenesis by enhancing transforming growth factor-beta (TGF-β) signaling pathways, inducing factors like CTGF, and they carry significant safety risks. Current treatment for IPF has fully transitioned into an era centered on antifibrotic therapy.

Idiopathic pulmonary fibrosis (IPF) is characterized by parenchymal scarring reflecting an imbalance between collagen deposition by myofibroblasts (MFs) and its turnover. Although collagen clearance is essential for fibrosis resolution, this process and its potential for therapeutic modulation in IPF are poorly understood. Here we evaluated internalization of degraded collagen and the role of its requisite endocytic receptor mannose receptor C-type 2 (MRC2), in lung tissue and MFs from IPF patients and bleomycin-injured mice. Fibrotic human and murine lung tissue exhibited an accumulation of degraded collagen, highlighting a failure of its clearance. MFs from fibrotic lung demonstrated a reduced capacity to internalize extracellular degraded collagen, with a concomitant reduction in MRC2 expression and endolysosomal activity. Both diminished collagen uptake and MRC2 expression recovered to baseline levels during spontaneous resolution of bleomycin fibrosis. In vitro treatment of IPF or TGF-β-elicited MFs with a variety of mechanistically distinct agents known to effect phenotypic dedifferentiation restored defective collagen internalization. Although enhanced uptake was MRC2-dependent, it involved increased endolysosomal activity rather than increased MRC2 expression. These results implicate defective MRC2-dependent collagen internalization and endolysosomal function in MFs as important factors contributing to fibrosis that may be therapeutically targeted to promote resolution.

An aerosolized dual-action autotaxin inhibitor-PPARγ agonist for the treatment of pulmonary fibrosis.

Gut microbiota modify immunity. Dysregulated immunity plays a key role in the pathogenesis of IPF. However, the role of gut microbiota in IPF pathogenesis is unknown. Determine associations between gut microbiota, disease severity and lung transplant-free survival in IPF. Gut microbiota from patients enrolled in the CleanUP-IPF trial were characterized using fecal swab samples (n = 411). CleanUP-IPF investigated the clinical efficacy of long-term anti-microbials in IPF. 16S rRNA gene amplicon sequencing and shotgun metagenomic sequencing were performed to comprehensively profile gut microbial communities. Associations between baseline microbiota with disease severity, transplant-free survival, and treatment heterogeneity were analyzed using principal component analysis, multivariate generalized linear models, additive models and Cox regression models. Gut microbiota composition varied significantly with sex, age, and proton pump inhibitor use. Gut microbial diversity and community composition were significantly associated with impaired gas exchange (percent predicted (pp) DLCO). Several genera including the Lachnospiraceae unclassified genus were associated with improved transplant-free survival (HR 0.34 95% CI 0.14-0.87, P = .02) in patients not assigned to anti-microbial treatment. Patients with a higher abundance of the Lachnospiraceae unclassified genus exposed to long term co-trimoxazole had worse survival (HR 6.09 95% CI 1.36-27.27, P = .02). Survival in pirfenidone treated patients was significantly associated with a higher abundance of the gut Lachnospiraceae unclassified genus. In exploratory post-hoc analysis, gut microbiota correlated with disease severity, associated with treatment heterogeneity and transplant-free survival in patients with IPF.

Tissue-resident immune cells play a crucial role in chronic lung diseases, yet a comprehensive profile of these cells in human lungs is lacking. Here, we explore alterations of resident immune cells in idiopathic pulmonary fibrosis (IPF), a fatal lung disease characterized by tissue inflammation and progressive scarring. Utilizing ex-vivo human lung perfusion with single-cell RNA-sequencing, we successfully segregate the resident immune cells. By analyzing approximately 100,000 resident immune cells from seven patients with IPF and five healthy control lungs, we identify 13 distinct cell types. Previously unrecognized aberrant lymphocyte phenotypes are uncovered. Specifically, among T lymphocytes, we observe an enrichment of GZMK+ CD8+ T cells in IPF lungs, possessing a potential pro-fibrotic function. The fraction of pro-inflammatory HSPhi CD4+ conventional T cells increases in IPF lungs, while the quiescent subset decreases. Despite an increased presence of Tregs in IPF lungs, these cells show reduced expression of genes associated with immune suppression. Moreover, significant B cell expansion and activation occur, with continuous differentiation into IgG-producing plasma cells. Stromal niche interaction analysis shows that IPF fibroblasts, especially the CTHRC1hi subset, exert stronger effects on lymphocytes. These findings provide evidence of dysregulated immune cell populations in IPF, advancing our understanding of its immunopathology.

Two phase 3, randomized trials of inhaled treprostinil for idiopathic pulmonary fibrosis (IPF) were conducted on the basis of preclinical and clinical evidence of an antifibrotic mechanism. TETON-2 was completed first, and results were published; the results of TETON-1 and of both trials combined are reported here. In the double-blind TETON-1 trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily). The primary end point was the change in forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening (the first occurrence of death from any cause, hospitalization for a respiratory cause, or a relative decline of ≥10% in the percentage of predicted FVC) and acute exacerbation of IPF (each assessed in a time-to-event analysis), survival, change in percentage of predicted FVC, quality of life, and change in diffusion capacity of the lungs for carbon monoxide at week 52. A total of 598 patients underwent randomization and received at least one dose of treprostinil (299 patients) or placebo (299 patients). Of these, 434 completed the assessments through week 52 (218 in the treprostinil group and 216 in the placebo group). The mean age of the patients was 73.0 years, 77.3% were men, and 77.6% were receiving background antifibrotic therapy; the percentage of predicted FVC at baseline was 74.6%. The median change in FVC at week 52 was -43.3 ml (95% confidence interval [CI], -92.1 to -9.1) with treprostinil and -196.2 ml (95% CI, -227.1 to -155.6) with placebo (difference, 130.1 ml; 95% CI, 82.2 to 178.1; P<0.001). Clinical worsening occurred in 95 patients (31.8%) with treprostinil and in 133 patients (44.5%) with placebo (hazard ratio, 0.67; 95% CI, 0.52 to 0.88; P = 0.003). No significant difference was observed in the time to an IPF exacerbation, and no further inferences regarding secondary end points were made. The most frequent adverse event was cough (reported in 54.8% of the patients in the treprostinil group and 33.1% patients in the placebo group). Discontinuation of treprostinil or placebo occurred in 40.5% and 32.8% of the patients, respectively, with adverse event being the primary reason (20.7% and 14.7%). Efficacy and safety outcomes were similar in analyses of the combined trial data. In patients with IPF, treatment with inhaled treprostinil led to a smaller decline in FVC and fewer clinical-worsening events than placebo over the course of 52 weeks. (Funded by United Therapeutics; TETON-1 ClinicalTrials.gov number, NCT04708782.).

To describe nerandomilast, a preferential phosphodiesterase 4B inhibitor indicated for the treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. A PubMed search was conducted from origin to mid-April 2026 using the terms nerandomilast, Jascyd, BI 1015550, idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis, and interstitial lung disease. Phase 2 and 3 clinical trials, prescribing information, pooled analyses, and relevant guideline documents were included. Two phase 3 randomized controlled trials evaluating nerandomilast in IPF and progressive pulmonary fibrosis were reviewed, along with regulatory prescribing information. In the FIBRONEER-ILD and FIBRONEER-IPF trials, nerandomilast reduced forced vital capacity decline at 52 weeks compared with placebo. Treatment effects were observed in patients receiving background antifibrotic therapy and those treated with nerandomilast alone. Secondary time-to-event outcomes were not statistically significant. Diarrhea was the most common adverse event and occurred more frequently with nerandomilast, while serious adverse events were similar across treatment groups.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:Nerandomilast targets inflammatory and profibrotic pathways distinct from currently available antifibrotic therapies and may be used as monotherapy or in combination with existing agents. Its role is best understood as disease stabilization rather than reversal of established fibrosis. Nerandomilast represents an additional therapeutic option for patients with IPF and progressive pulmonary fibrosis. Ongoing long-term and real-world data will further clarify its place in clinical practice.

To compare outcomes of single(SLT) versus bilateral(BLT) lung transplantation among dually listed recipients hypothetically eligible for either treatment. Considerable debate remains regarding the added benefit of BLT versus SLT. Prior analyses were confounded by significant selection bias or limited in generalizability to the contemporary era; a randomized trial remains unlikely due to ethical concerns. Within the Organ Procurement and Transplantation Network, we considered all adults who were dually listed for SLT and BLT and underwent first-time lung allograft transplantation for idiopathic pulmonary fibrosis(IPF) or chronic obstructive pulmonary disease(COPD) in the US between 2017-2024. We applied target trial emulation and clone-censor weight methodology to emulate a prospective randomized trial comparing SLT versus BLT. We tabulated 3,274 dually listed lung allograft recipients, of whom 1,026 were transplanted for COPD and 2,248 for IPF. Median follow-up was 24.5 months. COPD patient survival at five years was superior following BLT (61%[55-66%]) versus SLT (52%[46-58%, P=0.009). Meanwhile, among IPF patients, five year survival was 59%[54-63%] following BLT versus 56%[51-61%], P=0.009) after SLT. In a target trial emulation, among COPD patients, BLT remained associated with reduced mortality hazard (HR 0.67, CI 0.50-0.88). However, stratifying by age, SLT and BLT yielded comparable outcomes among patients ≥70years (HR 0.75, Credible Interval 0.38-1.37). Evaluating IPF recipients, after adjustment, BLT remained associated with comparable mortality hazard (HR 1.04, CI 0.85-1.26). No age-related effect was noted. Our findings suggest SLT could yield acceptable post-transplantation survival in select patients, while expanding access to this invaluable resource.

As part of a therapeutic approach to idiopathic pulmonary fibrosis (IPF) using inhaled ALK5 inhibitors, which enable targeted lung delivery while minimizing systemic side effects, this work describes the optimization process of a previously reported series featuring a 4,6-disubstituted pyridazine core. The medicinal chemistry exploration, aimed at increasing cellular potency while keeping physicochemical and ADME properties favorable for inhalation, was directed to the functionalization of the 3-position in the pyridazine core. An efficient SAR exploration, supported by a late-stage functionalization (LSF) approach, led to the identification of a small set of compounds worthy of in vivo characterization. Compound 20 showed a persistent and lung-restricted target engagement in a pharmacodynamic model, which well-correlated with its in vitro solubility measured in simulated lung fluid (SLF). When tested in a mouse model of lung fibrosis, 20 showed remarkable efficacy, thus representing an advanced lead candidate for the development of topical antifibrotic therapeutics.

Study on mannose-modified panax notoginseng polysaccharide self-assembled micelles to reduce idiopathic pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by an abnormal epithelial‒mesenchymal transition (EMT) and fibroblast activation, although the molecular mechanisms driving these processes remain unclear. Here, we report that the expression of CCAAT enhancer binding protein γ (C/EBPγ), a transcription factor, is significantly upregulated in lung tissues from patients with IPF and the lungs of mice with bleomycin-induced fibrosis. In A549 epithelial cells, C/EBPγ overexpression promoted the EMT, as indicated by decreased E-cadherin expression and increased N-cadherin and vimentin expression. In MRC-5 fibroblasts, C/EBPγ overexpression increased cell migration and upregulated the expression of fibrotic markers, including collagen I, fibronectin, and α-SMA. Mechanistically, C/EBPγ activated the β-catenin pathway by stabilizing β-catenin through the transcriptional repression of AXIN1, a key component of the degradation complex. This repression occurred via an interaction with C/EBPα, antagonizing its promotion of AXIN1 expression, as confirmed by ChIP‒qPCR, luciferase assays, coimmunoprecipitation, immunofluorescence staining, and rescue experiments. In vivo, adeno-associated virus-mediated C/EBPγ overexpression aggravated bleomycin-induced pulmonary fibrosis in mice, increasing collagen deposition, inflammation, and β-catenin expression, whereas C/EBPγ knockdown alleviated these changes. Collectively, these findings suggest that the downregulation of C/EBPγ expression attenuates fibrosis progression through the C/EBPα-AXIN1-β-catenin axis, underscoring its involvement in β-catenin pathway regulation and advancing the understanding of IPF pathogenesis.