Proc SPIE Int Soc Opt Eng. 2024 Feb;12933:1293319. Epub 2024 Apr 3.

ABSTRACT

Segmentation of microvascular structures, such as arterioles, venules, and capillaries, from human kidney whole slide images (WSI) has become a focal point in renal pathology. Current manual segmentation techniques are time-consuming and not feasible for large-scale digital pathology images. While deep learning-based methods offer a solution for automatic segmentation, most suffer from a limitation: they are designed for and restricted to training on single-site, single-scale data. In this paper, we present Omni-Seg, a novel single dynamic network method that capitalizes on multi-site, multi-scale training data. Unique to our approach, we utilize partially labeled images, where only one tissue type is labeled per training image, to segment microvascular structures. We train a singular deep network using images from two datasets, HuBMAP and NEPTUNE, across different magnifications (40×, 20×, 10×, and 5×). Experimental results indicate that Omni-Seg outperforms in terms of both the Dice Similarity Coefficient (DSC) and Intersection over Union (IoU). Our proposed method provides renal pathologists with a powerful computational tool for the quantitative analysis of renal microvascular structures.

PMID:40375952 | PMC:PMC12080525

J Respir Biol Transl Med. 2025 Mar;2(1):10002. doi: 10.70322/jrbtm.2025.10002. Epub 2025 Mar 24.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. A previous genome-wide association study (GWAS) with Affymetrix microarray analysis data exhibited elevated histidine triad nucleotide-binding protein 3 (HINT3) in the lung samples of PAH compared to control subjects (failed donors, FD) and the positive correlations of HINT3 with deubiquitinase USP11 and B-cell lymphoma 2 (BCL2). In this study, we aim to investigate the roles and interplay of USP11 and HINT3 in the apoptosis resistance of PAH. The levels of USP11 and HINT3 were increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice. USP11 and HINT3 interacted physically, as shown by co-immunoprecipitation (co-IP) assay in human pulmonary arterial endothelial cells (HPAECs). HINT3 was degraded by polyubiquitination, which was reversed by USP11. Furthermore, HINT3 interacted with the anti-apoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, the knockdown of HINT3 function led to a depletion of BCL2. Thus, we conclude that USP11 stabilizes HINT3 activation, which contributes to endothelial apoptosis-resistance of pulmonary arterial endothelial cells in PAH. This can potentially be a novel therapeutic target for ubiquitination modulators for PAH.

PMID:40376595 | PMC:PMC12080269 | DOI:10.70322/jrbtm.2025.10002

Biophys Rev. 2025 Mar 4;17(2):667-685. doi: 10.1007/s12551-025-01290-1. eCollection 2025 Apr.

ABSTRACT

Bacterial communication is essential for survival, adaptation, and collective behavior. While chemical signaling, such as quorum sensing, has been extensively studied, physical cues play a significant role in bacterial interactions. This review explores the diverse range of physical stimuli, including mechanical forces, electromagnetic fields, temperature, acoustic vibrations, and light that bacteria may experience with their environment and within a community. By integrating these diverse communication pathways, bacteria can coordinate their activities and adapt to changing environmental conditions. Furthermore, we discuss how these physical stimuli modulate bacterial growth, lifestyle, motility, and biofilm formation. By understanding the underlying mechanisms, we can develop innovative strategies to combat bacterial infections and optimize industrial processes.

PMID:40376406 | PMC:PMC12075086 | DOI:10.1007/s12551-025-01290-1

Plant Biol (Stuttg). 2025 May 16. doi: 10.1111/plb.70035. Online ahead of print.

ABSTRACT

Sulphur (S) deficiency is known to hinder iron (Fe) uptake and distribution in wheat, mainly by reducing phytosiderophores (PS) synthesis and release. This study investigated the impact of S supply on Fe accumulation in four tetraploid wheat genotypes with different genetic backgrounds: a modern genotype, Svevo (Triticum turgidum subsp. durum), two ancient Khorasan wheats, Turanicum_21 and Etrusco (T. turgidum subsp. turanicum) and an ancient Polish wheat, Polonicum_2 (T. turgidum subsp. polonicum). Plants were grown hydroponically for 20 days under adequate (S = 1.2 mM) or limiting (L = 0.06 mM) sulfate levels, while receiving sufficient Fe (80 μM). Most genotypes exhibited reduced Fe accumulation under low S conditions, as expected. However, Polonicum_2 showed a unique response, accumulating significantly more Fe in both shoots and roots. This increased Fe accumulation was associated with a higher rate of PS release and upregulation of both TdYSL15 and TdIRO2 in roots of Polonicum_2, suggesting altered regulation of Fe deficiency responses. However, the expression pattern of TdIDEF1 was not correlated with TdYSL15 expression in this plant, suggesting the involvement of additional regulatory pathways beyond Fe supply. Finally, there was a strong correlation between O-acetylserine(thiol)lyase activity in shoot tissues and PS release rate across all genotypes. There is increased interest in Khorasan and Polish wheats as alternative crops for marginal areas, hence, these findings are noteworthy from a biofortification perspective and could potentially lead to innovations in agriculture that benefit food security.

PMID:40375730 | DOI:10.1111/plb.70035

Scand J Med Sci Sports. 2025 May;35(5):e70074. doi: 10.1111/sms.70074.

ABSTRACT

Scarce evidence exists on the demands needed to attain the highest positions during Grand Tours (Giro d'Italia, Tour de France, Vuelta a España). Using power output (PO) and heart rate (HR) data, we aimed to compare the racing demands of successful (at least top-5) and less successful (at least top-15) cyclists during Grand Tours. We identified Grand Tours in which we could compare cyclists who had attained a top-5 position (Top) with riders who also competed for the General Classification in the same race but attained a worse position (Non-Top, at least top 15). Different race-derived measures of physical demands (e.g., PO, kJ spent, training stress score, durability and repeatability measures, time in different PO/HR zones) were analyzed. Data from 9 Grand Tours, including 9 Top (average position 3rd, range 1st-5th) and 9 Non-Top cyclists (average position 9th, range 4th-12th) were available. Despite significant between-group differences in finishing time (86.2 ± 6.3 vs. 86.3 ± 6.3 h, p < 0.001), no differences were found for any of the analyzed outcomes, except for a slightly higher proportion of time spent at low PO levels (zone 1 (≤ 55% of functional threshold power)) in Top compared to Non-Top cyclists (60.9% ± 1.8% vs. 58.4% ± 2.5%, respectively, p = 0.011). In summary, achieving a top position during a Grand Tour does not necessarily imply overall higher physical demands compared to those cases in which cyclists attain a slightly lower position, which suggests that other factors (e.g., individual or team tactics) or metrics might have a greater influence.

PMID:40375449 | DOI:10.1111/sms.70074

Comput Biol Med. 2025 May 14;192(Pt B):110296. doi: 10.1016/j.compbiomed.2025.110296. Online ahead of print.

ABSTRACT

We present an easy-to-use, nonlinear filter for effective background identification in fluorescence microscopy images with dense and low-contrast foreground. The pixel-wise filtering is based on comparison of the pixel intensity with the mean intensity of pixels in its local neighborhood. The pixel is given a background or foreground label depending on whether its intensity is less than or greater than the mean respectively. Multiple labels are generated for the same pixel by computing mean expression values by varying neighborhood size. These labels are accumulated to decide the final pixel label. We demonstrate that the performance of our filter favorably compares with state-of-the-art image processing, machine learning, and deep learning methods. We present three use cases that demonstrate its effectiveness, and also show how it can be used in multiplexed fluorescence imaging contexts and as a pre-processing step in image segmentation. A fast implementation of the filter is available in Python 3 on GitHub.

PMID:40375425 | DOI:10.1016/j.compbiomed.2025.110296

Front Cardiovasc Med. 2025 May 1;12:1498700. doi: 10.3389/fcvm.2025.1498700. eCollection 2025.

ABSTRACT

OBJECTIVE: Utilizing the FDA Adverse Event Reporting System (FAERS) database, this study conducts signal detection for drugs associated with cardiac arrest (CA), aiming to optimize clinical decision-making and ensure safer drug usage.

METHODS: Adverse event reports related to CA from the first quarter of 2004 to the second quarter of 2024 were extracted from the FAERS database. Signal detection was conducted using the reporting odds ratio (ROR) and proportional reporting ratio (PRR) to identify drugs associated with an increased risk of CA.

RESULTS: A total of 66,431 reports were analyzed, comprising 34,508 males (51.9%) and 31,923 females (48.1%). The majority of cases (71.8%) were reported by healthcare professionals, with adults (≥18 years old) representing the predominant group. Clinical outcomes showed that 67.2% of cases resulted in death. Out of 82 drugs with over 100 CA-related reports, 43 displayed positive signals. The top five drugs identified by ROR were: carisoprodol [ROR (95% CI): 34.13 (29.62-39.32)], sugammadex [ROR (95% CI): 26.93 (22.56-32.16)], regadenoson [ROR (95% CI): 20.00 (17.69-22.60)], alprazolam [ROR (95% CI): 12.82 (12.19-13.48)], and propofol [ROR (95% CI): 11.93 (10.61-13.41)]. In the system drug signal detection, musculo-skeletal system drugs ranked highest [ROR (95% CI): 30.99 (27.74-34.62)], followed by alimentary tract and metabolism drugs [ROR (95% CI): 4.75 (4.59-4.92)], nervous system drugs [ROR (95% CI): 4.51 (4.4-4.61)], anti-infective drugs [ROR (95% CI): 4.13 (3.74-4.57)], cardiovascular drugs [ROR (95% CI): 3.89 (3.78-4.01)], and antineoplastic and immunomodulating agents [ROR (95% CI): 2.16 (2.13-2.2)].

CONCLUSION: This study identifies over 40 drugs potentially associated with an elevated risk of CA based on FAERS data. Healthcare professionals should be particularly vigilant when prescribing these drugs, especially to patients with a history of heart disease, and ensure rigorous monitoring of their cardiac health.

PMID:40376150 | PMC:PMC12078221 | DOI:10.3389/fcvm.2025.1498700

N Engl J Med. 2025 Jun 12;392(22):2235-2243. doi: 10.1056/NEJMoa2504747. Epub 2025 May 15.

ABSTRACT

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).

PMID:40373211 | DOI:10.1056/NEJMoa2504747

Trends Cancer. 2025 May 15:S2405-8033(25)00106-2. doi: 10.1016/j.trecan.2025.04.010. Online ahead of print.

ABSTRACT

The acknowledged relationship between metabolism and cancer retains important potential as a novel target in therapy. Reallocating glucose-lowering drugs (GLDs) in cancer treatment offers valuable perspectives for the ability of these molecules to regulate metabolism at cellular and systemic level. This comprehensive review addresses the therapeutic potential of the main antidiabetic classes of glucose-lowering drugs with emerging anticancer effects, such as metformin, rosiglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium/glucose cotransporter-2 inhibitors. The multifaceted actions of these drugs are explored, from in vitro evidence to clinical evidence as monotherapy or as a sparing agent with chemotherapy and immunotherapy. For each molecule, unconventional mechanisms, benefits, and limitations are dissected and possible concerns addressed, supporting evidence for the potential use of the drug in cancer.

PMID:40374399 | DOI:10.1016/j.trecan.2025.04.010

J Mol Graph Model. 2025 May 10;139:109076. doi: 10.1016/j.jmgm.2025.109076. Online ahead of print.

ABSTRACT

The hallmark of Alzheimer's disease (AD), a progressive neurodegenerative condition, is the buildup of amyloid-beta (Aβ) plaque, which is mainly caused by β-secretase 1 (BACE-1) activity. BACE-1 inhibition is a potentially effective treatment strategy to lower the progression of AD. In order to find possible BACE-1 inhibitors using a drug repurposing technique, this study uses an integrated computational approach that includes pharmacophore modelling, virtual screening, molecular docking, MM-GBSA, molecular dynamics (MD) simulations, in-silico ADMET profiling, and PBPK modelling. A pharmacophore model, was created with known BACE-1 inhibitors to enable virtual screening of both novel and FDA-approved chemical libraries. Top candidates with good free energy scores and strong binding affinities were found using molecular docking and MM-GBSA calculations. The stability of shortlisted Hits inside the BACE-1 active site was further validated using MD simulations, which showed that some of the important interactions were maintained across a period of 50ns. ADMET and PBPK studies predicted favorable pharmacokinetic and safety profiles for the shortlisted hits, particularly for B2 and B9. These findings identify potential candidates for future experimental validation, offering an inexpensive approach for identification of compounds as potential BACE-1 inhibitors.

PMID:40373679 | DOI:10.1016/j.jmgm.2025.109076

Orphanet J Rare Dis. 2025 May 15;20(1):231. doi: 10.1186/s13023-025-03692-6.

ABSTRACT

BACKGROUND: Genomic newborn screening (gNBS) offers the potential to detect genetic conditions early, enhancing outcomes through timely treatment. It can serve as an additional tool to identify conditions that are not detectable via metabolic screening. The Screen4Care project seeks to develop a systematic approach for selecting treatable rare diseases (RDs) for inclusion in gNBS through the creation of the TREAT-panel.

METHODS: A set of six selection criteria containing treatability, clinical validity, age of onset, disease severity, penetrance, and genetic feasibility was applied to a comprehensive list of gene-disease pairs. Genes meeting a defined threshold score were included in the TREAT-panel. This automated scoring process was complemented by expert review from clinicians and patient representatives to ensure clinical relevance and adherence to current medical guidelines.

RESULTS: The initial gene list, derived from multiple data sources, included 484 gene-disease pairs. After applying the scoring system and two rounds of expert curation, a final list of 245 genes was selected. These genes predominantly represent disorders in metabolic, neurological, and immunological categories, with treatability and early disease onset as key inclusion factors.

CONCLUSION: The Screen4Care TREAT-panel provides a curated, scientifically robust gene set for gNBS, focusing on treatable RDs with early onset and clinical actionability. The panel will be tested in a European pilot project involving approximately 20,000 newborns, contributing to the growing body of evidence for the implementation of next-generation sequencing (NGS) in newborn screening programs.

PMID:40375093 | DOI:10.1186/s13023-025-03692-6

Orphanet J Rare Dis. 2025 May 15;20(1):230. doi: 10.1186/s13023-025-03674-8.

ABSTRACT

The traditional process of intercultural adaptation, while suitable for one or a few target languages, is not optimal for developing instruments for rare connective tissue diseases (CTDs) in multiple languages simultaneously. The European Reference Network ReCONNET presents the protocol for a novel methodology for cross-cultural adaptation of instruments for research and care in the context of rare CTDs (ReCONNET-CROSSADAPT). It is initiated by the identification of 'key-terms' that are crucial for maintaining the original meaning of the source document. Each language group, led by a senior member and two collaborators, independently assesses the existence and equivalence of these key terms in target languages. Reconciliation meetings are held to establish agreed-upon terms for consistent usage across translations when difficulties arise with key-terms. Subsequently, each language group translates the source document, followed by a reconciliation meeting involving one CTD patient in each group. The purpose of this meeting is to address potential discrepancies among translations, ensuring a comprehensive assessment from a linguistic, cultural and patient perspective. Collective feedback and consensus-based decision-making guide the resolution process. This methodology eliminates the need for backward translation, optimizing time and cost utilization. This new ReCONNET-CROSSADAPT methodology ensures linguistic accuracy, cultural relevance, and contextual appropriateness for the cross-cultural adaptation of instruments for research and care in the context of rare CTDs.

PMID:40375068 | DOI:10.1186/s13023-025-03674-8

Eur J Hum Genet. 2025 May 15. doi: 10.1038/s41431-025-01863-4. Online ahead of print.

ABSTRACT

WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.

PMID:40374945 | DOI:10.1038/s41431-025-01863-4

Nat Chem Biol. 2025 May 15. doi: 10.1038/s41589-025-01896-2. Online ahead of print.

ABSTRACT

Allosteric modulation of receptor responses to endogenous agonists has therapeutic value, maintaining ligand profiles, reducing side effects and restoring mutant responses. Adhesion G-protein-coupled receptors (aGPCRs), with large N termini, are ideal for allosteric modulator development. We designed a nanobody strategy targeting ADGRG2 N-terminal fragments and got a specific nanobody Nb23-bi, which promoted dehydroepiandrosterone (DHEA)-induced ADGRG2 activation and reversed mutant-induced dysfunctions. By combining structural characterization, crosslinking mass spectrometry, mutational analysis and molecular dynamics simulations, we clarified the allosteric mechanism of how the Nb23-bi modulates conformational changes in the DHEA-binding pocket. Animal studies showed that Nb23-bi promoted the response of DHEA in alleviating testicular inflammation and reversing mutant defects. In summary, we developed an allosteric nanobody of ADGRG2 and gained insights into its functions in reversing disease-associated dysfunctions. Our study may serve as a template for developing allosteric modulators of other aGPCRs for biological and therapeutic purposes.

PMID:40374856 | DOI:10.1038/s41589-025-01896-2

Int J Biol Macromol. 2025 May 13:144190. doi: 10.1016/j.ijbiomac.2025.144190. Online ahead of print.

ABSTRACT

Platycodon grandiflorum (PG) is a traditional medicinal herb with a history of >2000 years, exhibiting various biological activities. However, its anti-lung cancer potential remains largely unexplored. This study aimed to extract Platycodon grandiflorum polysaccharides (PGP) using an environmentally friendly natural deep eutectic solvent (NADES) system and evaluate their anti-lung cancer activity. An NADES system composed of choline chloride and oxalic acid (1:3 M ratio) was selected based on carbohydrate yield. The extraction conditions were optimized using Box-Behnken design (BBD). The structural characterization of PGP was performed using ultraviolet spectroscopy, fourier transform infrared (FT-IR) spectroscopy, and high-performance liquid chromatography (HPLC), revealing that PGP are glucans with a molecular weight of 7.036 kDa and a glucose content of 92.8 %. Biological assays demonstrated that PGP promoted ferroptosis in H1299 cells through mitochondrial dysfunction, lipid peroxidation (LPO), and overproduction of reactive oxygen species (ROS). Also, PGP inhibited cell migration by modulating epithelial-mesenchymal transition(EMT)-related protein expression. These findings provide novel insights into the pharmacological basis of PG and support its potential application in lung cancer therapy.

PMID:40373906 | DOI:10.1016/j.ijbiomac.2025.144190

Nat Nanotechnol. 2025 May 15. doi: 10.1038/s41565-025-01903-6. Online ahead of print.

ABSTRACT

Liver macrophages capture circulating nanoparticles and reduce their delivery to target organs. Serum proteins adsorb to the nanoparticle surface after administration. However, the adsorbed serum proteins and their cognate cell receptors for removing nanoparticles from the bloodstream have not been linked. Here we use a multi-omics strategy to identify the adsorbed serum proteins binding to specific liver macrophage receptors. We discovered six absorbed serum proteins that bind to two liver macrophage receptors. Nanoparticle physicochemical properties can affect the degree of the six serum proteins adsorbing to the surface, the probability of binding to cell receptors and whether the liver removes the nanoparticle from circulation. Identifying the six adsorbed proteins allowed us to engineer decoy nanoparticles that prime the liver to take up fewer therapeutic nanoparticles, enabling more nanoparticles for targeting extrahepatic tissues. Elucidating the molecular interactions governing the nanoparticle journey in vivo will enable us to control nanoparticle delivery to diseased tissues.

PMID:40374797 | DOI:10.1038/s41565-025-01903-6

An Pediatr (Engl Ed). 2025 May 14:503857. doi: 10.1016/j.anpede.2025.503857. Online ahead of print.

ABSTRACT

Cystic fibrosis is a severe genetic disease caused by variants in the CFTR gene. Although it is a multisystem disease, respiratory involvement is the main cause of morbidity and mortality. Cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies have advanced the treatment of this disease by improving function of this protein. Ivacaftor, the first CFTRm, has been found to significantly improve lung function and quality of life in patients with certain gating variants. However, only a small percentage of patients in Spain are eligible for this treatment. Combinations of correctors and potentiators, such as lumacaftor-ivacaftor or tezacaftor-ivacaftor, have been developed for treatment of patients with the most frequent variant (F508del), although with limited benefits. Triple therapy with elexacaftor-tezacaftor-ivacaftor has been found to significantly improve respiratory, gastrointestinal and nutritional outcomes as well as quality of life, thus changing the management of CF in eligible patients. The impact of triple therapy is also reflected in an increase in life expectancy and a decrease in mortality and lung transplantation. As regards hepatic and pancreatic involvement, while CFTR modulators have exhibited promising effects, further research is required. The use of CFTR modulators has also shifted nutritional status trends in patients with CF, reducing the risk of undernutrition but increasing the risk of obesity. The use of these drugs for treatment of less frequent variants and for potential antenatal treatment is currently being investigated. Despite these advances, there is still a subset of patients who are ineligible for treatment with modulators or highly effective therapy.

PMID:40374426 | DOI:10.1016/j.anpede.2025.503857

Respir Res. 2025 May 15;26(1):185. doi: 10.1186/s12931-025-03227-4.

NO ABSTRACT

PMID:40375119 | DOI:10.1186/s12931-025-03227-4

Sci Rep. 2025 May 15;15(1):16969. doi: 10.1038/s41598-025-01459-4.

ABSTRACT

Objective Idiopathic pulmonary fibrosis (IPF), which radiologically/pathologically manifests mainly as usual interstitial pneumonia (UIP), is easily confused with chronic hypersensitivity pneumonitis (CHP) and collagenous vascular disease in clinical settings, affecting the physician's diagnosis and treatment. Accurate identification of IPF from various diseases presenting as UIP is essential for effective diagnosis and therapy. Methods Gene expression data of CHP, IPF, and rheumatoid arthritis-UIP samples were downloaded from the GEO database, and specific biomarkers were identified to differentiate idiopathic UIP/IPF from secondary UIP. We compared gene expression of specific biomarkers between control, secondary UIP, and IPF groups. The mechanism of specific biomarkers in PF was explored by immunohistochemistry, quantitative polymerase chain reaction, immunofluorescence, and flow cytometry. Results We identified integrin alpha V (ITGAV) as a specific biomarker for distinguishing IPF from secondary UIP. We observed a gradual increase in ITGAV expression across the control, secondary UIP, and IPF groups. Animal studies indicated that the elevated expression of ITGAV in various immune cells, particularly in monocyte-derived macrophages, contributed to the development of PF. Conclusion ITGAV is a specific biomarker linked to the pathogenesis of IPF. The identification of ITGAV provides new perspectives for clinical diagnosis, mechanistic studies and new drug development in IPF.

PMID:40374686 | DOI:10.1038/s41598-025-01459-4

Cell Signal. 2025 May 13:111868. doi: 10.1016/j.cellsig.2025.111868. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder marked by deteriorating dyspnea and declining pulmonary function. Despite its rising prevalence and incidence, therapeutic options remain limited. PTEN-induced kinase 1 (PINK1), known for its role in PINK1/Parkin-dependent mitophagy, contributes to the pathogenesis of various lung diseases. In this study, we elucidate a previously unrecognized mechanism of PINK1, beyond its canonical mitophagy function, during pulmonary fibrosis. We established a bleomycin (BLM)-induced pulmonary fibrosis model in Pink1 knockout (Pink1-/-) mice and treated BEAS-2B cells with transforming growth factor-beta 1 (TGF-β1) to simulate the microenvironment of pulmonary fibrosis. A significant elevation in PINK1 expression was observed in vivo and in vitro systems. While PINK1/Parkin-dependent mitophagy was activated, mitophagy mediated by BCL2-interacting protein 3 (BNIP3) and FUN14 domain-containing 1 (FUNDC1) was suppressed. Further experiments in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated PINK1 knockout (KO) HEK293 cells and YFP-Parkin-expressing HeLa cells demonstrated that PINK1 deficiency enhanced BNIP3- and FUNDC1-mediated mitophagy, whereas PINK1 overexpression inhibited it. Moreover, dual BNIP3/FUNDC1 knockdown significantly reversed the anti-apoptotic effect of PINK1 KO. We conclude that PINK1 deficiency promotes the clearance of damaged mitochondria via BNIP3/FUNDC1 upregulation, preserving mitochondrial homeostasis, mitigating alveolar epithelial injury, and attenuating fibrosis. Thus, PINK1 may inhibit BNIP3- and FUNDC1-mediated mitophagy besides driving PINK1-dependent mitophagy during pulmonary fibrosis.

PMID:40373838 | DOI:10.1016/j.cellsig.2025.111868