Physiological metabolic reprogramming is a cells strategy to resist/counteract stress to preserve homeostasis. Hypoxia is an important stress stimulus that can promote tissue remodeling and fibrosis, in which alterations in sphingolipid metabolism may contribute to fibroblast responses. Here, we investigated the potential role of acid ceramidase (ASAH1), a key enzyme of the sphingolipid salvage pathway, in fibroblast adaptation to hypoxic stress.

Spontaneous pneumomediastinum and subcutaneous emphysema are uncommon complications of idiopathic pulmonary fibrosis (IPF). We report the case of a 74-year-old man with advanced IPF and long-term oxygen dependence who was hospitalised because of acute exacerbation of IPF. During hospitalisation, he developed acute chest discomfort, cervical swelling, and facial swelling. Physical examination revealed subcutaneous crepitus, and high-resolution computed tomography (HRCT) confirmed pneumomediastinum and extensive subcutaneous emphysema without pneumothorax or CT findings suggestive of oesophageal perforation. The patient remained haemodynamically stable and was managed conservatively with supplemental oxygen, analgesia, and close clinical monitoring. Positive-pressure ventilation was not clinically required and was avoided because of its potential to aggravate the existing air leak. Follow-up computed tomography demonstrated marked regression of pneumomediastinum and complete resolution of subcutaneous emphysema after two weeks. This case highlights that clinically significant pneumomediastinum may complicate acute exacerbation of IPF even in the absence of trauma, invasive procedures, or positive-pressure ventilation. Early recognition, HRCT confirmation, exclusion of secondary causes, and individualised management may result in favourable outcomes in selected patients.

Nerandomilast is a novel PDE4 inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). This case series reports 5 patients with an acute exacerbation of IPF or PPF within 2 weeks of administration of nerandomilast. One patient was on background nintedanib and none were on pirfenidone at the time of the exacerbation. All exacerbations were confirmed by a change in dyspnea and/or cough, worsening oxygen requirement, and new ground glass infiltrates on CT. All required hospitalization. A suggested mechanism for exacerbations on nerandomilast includes upregulation of cAMP by nerandomilast, which can drive IL-17 production. IL-17 has a known association with IPF exacerbations. The results of this case series need to be evaluated prospectively and ongoing pharmacovigilance is required.

Thrombocytopenia is not a monolithic disease but a common final pathway of disrupted platelet homeostasis spanning production, clearance, and distribution. The traditional count-centric paradigm, relying on empirical transfusion or steroid administration, frequently obscures underlying mechanistic drivers. This review advances a framework progressing from physiological homeostasis imbalance through pathological mechanisms to precision diagnosis and therapy. Recognizing that immune-targeted therapies are only appropriate when cytopenia is genuinely immune-mediated, we systematically deconstruct both immune and non-immune mechanisms to enable accurate etiological anchoring and avoid inappropriate immunomodulation. We systematically deconstruct the multidimensional pathogenesis along five axes: impaired production, immune-mediated destruction, distributional abnormality, consumptive loss, and pseudothrombocytopenia. Key molecular insights include megakaryocyte transcriptional governance (GATA-1, FLI-1, RUNX1), the platelet desialylation-Ashwell-Morell receptor clearance axis, complement cascade activation, and FcRn-mediated IgG homeostasis. Building on this mechanistic foundation, we propose a three-stage diagnostic algorithm: artifact exclusion, mechanistic localization via non-invasive biomarkers (IPF, TPO, autoantibodies), and etiological anchoring. In the therapeutic landscape, Thrombopoietin receptor agonists (TPO-RAs), FcRn antagonists (efgartigimod and rozanolixizumab), BTK inhibitors (rilzabrutinib), and Syk inhibitors have reshaped ITP management, while complement pathway inhibition (eculizumab, ravulizumab, narsoplimab) has transformed thrombotic microangiopathy outcomes.We posit that thrombocytopenia management has entered the precision medicine era; nevertheless, dynamic biomarker development for refractory cases, artificial intelligence-assisted decision-making, and interdisciplinary integration remain pressing frontiers.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that advances over time and is ultimately life-threatening. Despite advances in antifibrotic therapies, disease progression remains largely unavoidable, highlighting the necessity for advancing mechanistic research and identifying new therapeutic options. Bone morphogenetic protein receptor 2 (BMPR2) is a key receptor for BMP signaling and exerts potent antifibrotic role in lung fibrosis; however, the molecular mechanisms regulating BMPR2 protein stability in fibrotic lungs remain poorly understood. In this study, we identify that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4-like (Nedd4L) as a critical regulator of BMPR2 stability in lung fibroblasts. BMPR2 levels are markedly reduced in lung fibroblasts derived from patients with IPF and in lung tissues from experimental lung fibrosis models. Mechanically, elevated lipid peroxidation in fibrotic lungs induces K48-linked ubiquitination of BMPR2, leading to its degradation and attenuation of BMPs-induced Smad1/5 phosphorylation. Notably, Nedd4L overexpression counteracts lipid peroxidation-induced BMPR2 degradation and promotes BMPs/BMPR2 signaling by shifting BMPR2 ubiquitination toward a stabilizing K63-linked polyubiquitination in lung fibroblasts. We further show that Nedd4L is regulated through threonine phosphorylated by Raf1 kinase in response to increased lipid peroxidation. In vivo, fibroblast-Nedd4L-deficient mice exacerbates experimental lung fibrosis, which is significantly alleviated by BMPR2 overexpression. Collectively, our findings reveal a previously unrecoganized regulatory mechanism of BMPR2 degradation in fibrotic lungs and indicate that stabilizing BMPR2 in lung fibroblasts may represent a promising approach for the treatment of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive extracellular matrix deposition and irreversible distortion of lung architecture. We hypothesized that aberrant kinase-dependent splicing may contribute to IPF pathogenesis and offer an avenue for therapeutic intervention. We therefore analyzed multiple independent transcriptomic cohorts and found that SRPK1, compared with other SRPK family members, was most consistently elevated in fibrotic lung tissue. Higher SRPK1 expression was linked to poorer lung function and was associated with mortality after adjustment for age and sex (HR = 2.11, 95% CI: 1.10-4.04). Co-expression analysis, validation across independent cohorts, and single-cell profiling pointed to SRSF1 as a splicing factor closely associated with SRPK1 in fibrotic lungs. In lung fibroblasts, SRSF1 overexpression induced broad changes in alternative splicing. Integration of these events with human pulmonary fibrosis datasets highlighted AKT1 and KRT8 as candidate SRSF1-responsive splicing targets. We then tested the SRPK-targeting compound SPHINX31 in bleomycin-induced pulmonary fibrosis. SPHINX31 reduced hydroxyproline content, collagen deposition, myofibroblast activation, and histological fibrosis. These changes were accompanied by lower SRPK1 and SRSF1 protein levels in lung tissue. Our results link SRPK1 to disease severity and SRSF1-associated splicing changes in pulmonary fibrosis, and support further evaluation of SRPK inhibition as an antifibrotic strategy.