There is growing scientific interest in uncovering the mechanisms of lung regeneration, aiming to inform the development of innovative therapies for irreversible lung damage associated with chronic diseases. Cellular metabolism and its associated metabolites are increasingly recognised as active regulators of stem cell behaviour and tissue repair in other organs, yet little is known about how metabolic programmes and metabolite-mediated processes influence lung progenitor cell fate decisions. This Review explores current knowledge of how cellular metabolism directs the stem cell functions of alveolar type 2 (AT2) cells, the main epithelial progenitor cells of the distal lungs. Recent studies suggest that AT2 cell regenerative functions are linked to shifts in glycolytic and oxidative metabolism and require tight regulation of mitochondrial function and lipid metabolism for effective repair. Dysregulation of AT2 cell metabolism, as observed in chronic lung diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease, is emerging as a mechanism of regenerative failure and associated with respiratory disease progression. Improving our understanding of how AT2 cell metabolism 'fails to fuel' and starts 'fuelling to fail' lung repair is paramount for the development of innovative therapies that may slow or reverse the progression of chronic lung diseases.

Invasive pulmonary aspergillosis (IPA) presents life-threatening complication mostly seen in patients with severe neutropenia or in patients with solid organ cancers after applied anticancer therapy. The aim of this manuscript is to identify clinical manifestations of IPA in lung cancer patient. A 65-year-old male with a history of severe chronic obstructive lung disease and prior laryngeal carcinoma was admitted to hospital due to fever. Five months before he was operated because of early-stage squamous cell lung carcinoma. Postoperative course was complicated with subcutaneous emphysema and recurrent pneumothorax. The appearance of new excavated lesions in the contralateral lobes on repeated chest computed tomography (CT) raised concern for tumor recurrence. Subsequent bronchoscopy with bronchoaspirate culture yielded Aspergillus niger. Molecular tests also showed positive findings for Aspergillus presence. First-line treatment with voriconazole resulted in significant clinical and radiological improvement. Positron emission tomography (PET-CT) done 6 months after voriconazole treatment showed only mild fluorodeoxyglucose (FDG) uptake in the right lower lobe, with no other areas of involvement This case highlights the importance of a multidisciplinary approach in lung cancer patients, where post-operative radiologic changes can represent tumor recurrence, bacterial infection or fungal disease.

Saw palmetto (SP) is a widely used herbal supplement for benign prostatic hyperplasia (BPH) and is generally considered safe. However, rare cases of SP-associated drug-induced liver injury (DILI) have been reported. We describe a case of cholestatic hepatitis attributed to SP, highlighting the diagnostic challenges associated with herbal supplement use and polypharmacy. A 70-year-old male with a history of BPH, hypertension, chronic obstructive pulmonary disease, atrial fibrillation, and cholecystectomy presented with one month of jaundice, pruritus, and pale stools. Physical examination demonstrated scleral icterus without abdominal tenderness. Laboratory evaluation revealed an alkaline phosphatase level of 215 U/L, total bilirubin of 7.3 mg/dL (direct bilirubin = 5.0 mg/dL), alanine aminotransferase of 305 U/L, aspartate aminotransferase of 133 U/L, and an international normalized ratio of 3.8 while receiving warfarin therapy for atrial fibrillation. Viral hepatitis serologies were negative. Right upper quadrant ultrasonography demonstrated mild biliary ductal prominence, and magnetic resonance cholangiopancreatography excluded biliary obstruction. Liver injury was initially attributed to congestive hepatopathy because of newly reduced left ventricular ejection fraction (34%-40%). However, the patient remained clinically euvolemic, liver biochemistries failed to improve, and progressive hyperbilirubinemia prompted further evaluation. A detailed medication history revealed over-the-counter SP use for approximately four months, discontinued two months before presentation, and a recent one-week course of trimethoprim-sulfamethoxazole for a urinary tract infection. Transjugular liver biopsy with measurement of the hepatic venous pressure gradient (6 mmHg) demonstrated cholestatic hepatitis with portal and lobular inflammation, eosinophilic infiltration, and bile duct proliferation, consistent with DILI. Right and left heart catheterization demonstrated normal filling pressures and the absence of obstructive coronary artery disease, making congestive hepatopathy unlikely. Warfarin was reversed with vitamin K and transitioned to apixaban because of concern for potential hepatotoxicity. The patient was treated with ursodiol and cholestyramine, resulting in gradual improvement in liver enzymes and bilirubin, and was discharged with close hepatology and cardiology follow-up. This case highlights SP as a rare but important suspected cause of cholestatic DILI. Although causality cannot be definitively established because of concomitant exposure to other drugs, SP was considered the most likely implicated agent based on the temporal relationship with exposure, exclusion of alternative etiologies, compatible histopathologic findings, and clinical improvement after its discontinuation. Clinicians should routinely inquire about over-the-counter and herbal supplement use when evaluating unexplained liver injury. Increased awareness, comprehensive medication reconciliation, and improved regulation of dietary supplements may facilitate earlier recognition and reduce preventable hepatotoxicity.

Cough is a prominent and often persistent manifestation of chronic bronchitis (CB) that is frequently difficult to resolve. While Qi Feng Gu Biao Granules (QFGBG) is a traditional Chinese medicine commonly used to treat CB, its pharmacological basis for CB-related cough remains unclear.This study characterized the chemical profile of QFGBG by UPLC-Q-TOF/MS, evaluated its antitussive and anti-inflammatory effects in a rat model induced by lipopolysaccharide instillation combined with cigarette smoke exposure, and integrated network pharmacology, molecular docking, Western blotting, and plasma metabolomics to explore the underlying mechanism.QFGBG reduced cough frequency, prolonged cough latency, improved body-weight gain, and decreased the lung index and wet-to-dry ratio. Histological analyses showed attenuation of lung and tracheal inflammatory injury and mucus hypersecretion. QFGBG also decreased the expression of inflammatory and cough-related factors. Network pharmacology identified 215 overlapping QFGBG-CB targets, with enrichment in inflammatory and metabolic pathways, including the AGEs/RAGE signaling pathway. Molecular docking suggested favorable binding of core components, including Formononetin, Acacetin, and Vanillin, to key targets. Western blotting confirmed that QFGBG downregulated AGEs, RAGE, p-STAT1/STAT1、p-STAT3/STAT3. Metabolomics indicated regulation of glycerophospholipid and arachidonic acid metabolism. These findings suggest that the active components of QFGBG may alleviate CB-related cough by inhibiting the AGEs/RAGE signaling pathway and regulating arachidonic acid and glycerophospholipid metabolism, thereby reducing pulmonary and neurogenic inflammation and the release of cough-related mediators.

Chronic obstructive pulmonary disease (COPD) remains under-recognized as a severe condition despite its global burden. This review revisits the concept of "difficult-to-treat" disease, widely applied in asthma, and explores its relevance to COPD. Through a comparative approach, we highlight key pathophysiological overlaps and differences between asthma and COPD, particularly the distinct inflammatory profiles and lack of robust biomarkers in COPD that hinder individualized treatment. A subset of COPD patients remains highly symptomatic and vulnerable to frequent exacerbations and hospitalizations despite optimal therapy-posing a clinical challenge beyond the emerging definition of "uncontrolled COPD" and reflecting a significant unmet need within the current therapeutic arsenal. Building on lessons from severe asthma, this review proposes a multidimensional framework for defining and managing difficult-to-treat COPD, incorporating biological phenotyping, treatable traits, comorbidities, environmental exposure, and social determinants of health. We discuss the importance of confirming diagnosis, addressing modifiable factors (e.g., inhaler misuse, poor adherence), and exploring refractory symptoms such as persistent dyspnea or hypoxemia, including the role of pulmonary hypertension and extrapulmonary contributors. The review also evaluates therapeutic strategies for this population, from pharmacological and non-pharmacological interventions to advanced options such as biologics, lung volume reduction, and transplantation. Finally, we advocate for earlier integration of palliative care and broader inclusion in clinical trials. By refining the definition of difficult-to-treat COPD, we aim to promote more personalized, biomarker-guided care strategies that address unmet needs and improve outcomes in this high-risk population.

This review consolidates and evaluates current evidence on the epigenetic interaction between microRNA-144 [miR-144] and DNA methyltransferase 3A (DNMT3A) and its collective role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The available literature was narratively synthesized to provide a comprehensive overview of the current evidence regarding the mechanistic, epigenetic, and clinical implications of miR-144 and DNMT3A in COPD. Across the included studies, miR-144 was consistently reported to be upregulated in smokers and individuals with COPD, with parallel findings demonstrating a reduction in DNMT3A expression and associated hypomethylation of key inflammatory gene promoters. Functional assays and mechanistic analyses further substantiated that miR-144 directly targets and suppresses DNMT3A, leading to impaired methyltransferase activity, dysregulated DNA methylation patterns, heightened oxidative stress, and enhanced secretion of pro-inflammatory cytokines. These molecular alterations collectively contribute to a self-sustaining cycle of chronic inflammation, epithelial injury, and airway remodeling, which are potential features of COPD progression. The literature that is now available indicates that DNMT3A-mediated epigenetic regulation and miR-144 dysregulation both contribute to important molecular processes implicated in the pathophysiology of COPD, such as oxidative stress, inflammation, and aberrant gene regulation. There is currently little direct mechanistic evidence connecting the miR-144-DNMT3A axis in COPD, despite the literature supporting the individual roles of these molecules. Therefore, rather than being a completely developed pathway, this regulatory interaction should be viewed as an evolving mechanistic framework. To fully understand its diagnostic, prognostic, and therapeutic potential in COPD, more experimental research, extensive clinical validation, and phenotype-specific studies are needed.