BioFactors最新文献

{"title":"Gut Microbial Metabolite Crosstalk in Crohn's Disease: Network Pharmacology Unveils Dual-Axis Pathogenesis and Therapeutic Targets","authors":"Shiting Chen,&nbsp;Yang Li,&nbsp;Jiaxin Liu,&nbsp;Junmei Wu,&nbsp;Huange Zhao,&nbsp;Rong Cao,&nbsp;Songlin Zhou","doi":"10.1002/biof.70038","DOIUrl":"10.1002/biof.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Crohn's disease (CD), a chronic inflammatory bowel disorder, is driven by dysregulated interactions between gut microbiota and host metabolism. Here, we developed a computational framework integrating multiomics profiling, network pharmacology, and molecular dynamics simulations to systematically map microbiota-metabolite-target-signaling (M-M-T-S) networks and identify therapeutic candidates. By analyzing gut microbial metabolomics and CD-associated targets (via SwissTargetPrediction [STP]/SEA), we constructed a protein–protein interaction (PPI) network enriched for 50 intestinal hub targets (IL6, AKT1, PPARG; degree centrality [CD] &gt; 19.4), which orchestrate inflammatory (TNF/IL-17/TLR, FDR = 3.8 × 10⁻¹²) and metabolic (PPAR, FDR = 1.5 × 10⁻¹⁰) pathways. Structure-based screening (AutoDock Vina/AMBER20) revealed 3-indolepropionic acid (IPA) as a high-affinity AKT1 binder (Δ<i>G</i> = −67.4 kJ/mol), while Genipin exhibited robust binding to PTGS2, both validated by 100-ns dynamics simulations (RMSD &lt; 3.8 Å). Mechanistic network analysis uncovered a dual-axis regulatory paradigm: a pro-inflammatory axis (<i>Clostridium</i>spp.-derived LPS aggravates Th17 polarization via TLR4/IL-17 signaling) and a reparative axis (<i>Faecalibacterium prausnitzii</i>-produced butyrate enhances barrier integrity through PPARγ-mediated NF-κB suppression). Phylogenetic analysis linked microbial functional traits (e.g., LPS/SCFA synthesis) to evolutionary conservation, highlighting clade-specific roles in CD progression. Drug-likeness evaluation (SwissADME/ADMETlab 2.0) prioritized IPA as a lead candidate due to its superior solubility (7.65 mg/mL), nonhepatotoxic profile, and AhR agonism, outperforming Genipin. This study establishes IL6/AKT1/PPARG as central therapeutic hubs and positions IPA for clinical translation. Our framework bridges multiomics integration with precision medicine, offering a scalable strategy to decode microbiome-driven pathologies and accelerate metabolite-based therapeutics.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of High Hydrostatic Pressure (HHP) on the Enzymatic Hydrolysis of Fish Gelatin","authors":"Ilhami Okur,&nbsp;Mecit Halil Oztop,&nbsp;Hami Alpas","doi":"10.1002/biof.70042","DOIUrl":"10.1002/biof.70042","url":null,"abstract":"<p>Fish gelatin offers an alternative source for gelatin production; however, it possesses weaker functional properties, such as a low melting temperature and gel strength. Protein hydrolysates, produced through the hydrolysis of food proteins, demonstrate a wide range of biological activities, including antihypertensive, hypocholesterolemic, antimicrobial, and antioxidant properties. High hydrostatic pressure (HHP) is a non-thermal technology that can modify protein structures by inducing unfolding, thereby enhancing enzymatic accessibility and hydrolysis efficiency. Therefore, this study aimed to investigate the effects of different HHP parameters (400 and 500 MPa for 5, 15, and 30 min) and different Alcalase concentrations (2 and 4% wt/vol) on the production of fish protein hydrolysate. The results showed that HHP-assisted enzymatic hydrolysis increased the degree of hydrolysis and antioxidant capacity. However, when the pressure increased from 400 to 500 MPa, the degree of hydrolysis and antioxidant capacity decreased. FTIR spectroscopy was used to characterize the secondary structural changes of gelatin during HHP-assisted hydrolysis. The spectra revealed that more visible peaks of fish gelatin hydrolysate samples between 1000 and 1100 cm⁻¹ attributed to the asymmetric stretching of phosphate group (PO₄³⁻) were observed. Protein unfolding is an important factor in increasing HHP-assisted hydrolysis. In conclusion, HHP combined with enzymatic hydrolysis is a promising alternative to produce protein hydrolysates with improved properties.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Cellular Energetics via Ferroptosis Mediated Cell Death in Resistant Colorectal Cancer Stem Cells","authors":"Tanika Biswas,&nbsp;Sumit Mallick,&nbsp;Utsav Sen,&nbsp;Debajit Chaudhury,&nbsp;Sudheer Shenoy P,&nbsp;Bipasha Bose","doi":"10.1002/biof.70024","DOIUrl":"10.1002/biof.70024","url":null,"abstract":"<div>\u0000 \u0000 <p>Ferroptosis, a newly discovered non-apoptotic form of cell death triggered by iron-dependent toxic membrane lipid peroxidation, establishes a link between redox biology, metabolism, and human health. By inducing ferroptosis, it is possible to selectively eliminate cancer cells and cancer stem cells (CSCs) that are resistant to traditional therapies. Recent research has shown that inducing ferroptosis can effectively kill colorectal cancer stem cells (CRC CSCs) that are resistant to other forms of cell death and treatment modalities, positioning it as a potentially innovative strategy for developing treatments for colorectal cancer. This review delves into the intricate molecular mechanisms underlying ferroptosis in colorectal CSCs, focusing on the specific pathways and signaling networks that regulate ferroptotic cell death in these cells, including the roles of iron metabolism, lipid peroxidation, amino acid metabolism, and antioxidant systems. Additionally, we explored the application of ferroptosis-associated genes for the early diagnosis and prognosis of CRC and also discuss ferroptosis inducers as anticancer agents, highlighting their potential to effectively target therapy-resistant CSCs by disrupting their redox balance and triggering lipid peroxidation. Last, we discuss potential challenges and directions for future research in this developing area, offering insights into future studies pertaining to ferroptosis in CRC treatment.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteins and Carbon Dioxide Struggle Against Peroxynitrite","authors":"Giovanna De Simone,&nbsp;Alessandra di Masi,&nbsp;Grazia R. Tundo,&nbsp;Andresa Messias,&nbsp;Dario A. Estrin,&nbsp;Massimo Coletta,&nbsp;Paolo Ascenzi","doi":"10.1002/biof.70030","DOIUrl":"10.1002/biof.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Nitrosative stress plays a key role in the etiology of several human diseases, such as atherosclerosis, inflammation, cancer, and neurological diseases. Peroxynitrite is one of the most potent biological nitrosative agents, being produced at extremely rapid rates when nitric oxide (^●NO) and superoxide (^●O₂⁻) are combined. Peroxynitrite undergoes self-degradation at a slow rate, yielding ~70% nitrate (NO₃⁻) and H⁺, and ~30% nitrite (NO₂⁻) and dioxygen (O₂). Peroxynitrite degradation can be speeded up by the interaction with either (<i>i</i>) carbon dioxide (CO₂), through the transient formation of 1-carboxylato-2-nitrosodioxidane adduct (ONOOC(O)O⁻), which eventually decays to CO₂ and NO₃⁻ via the intermediate strong oxidants trioxocarbonate (CO₃^●−) and (nitrogen dioxide) ^●NO₂⁻, and/or (<i>ii</i>) proteins, such as thiol peroxidases and heme-proteins by different mechanisms. Under physiological conditions, peroxynitrite detoxification, which brings about different effects on the cellular metabolism, depends on the relative concentration of CO₂ and proteins. In this review, we analyze the intrinsic parameters of processes involved in peroxynitrite scavenging, which are crucial in poorly oxygenated tissues (such as the retina), exploring conditions that alternatively favor one process or the other.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Bioactive Peptides in Preterm Human Milk: Impact of Maternal Characteristics and Their Association to Neonatal Outcomes”","authors":"","doi":"10.1002/biof.70033","DOIUrl":"10.1002/biof.70033","url":null,"abstract":"<p>C. Balcells-Esponera, C. Borràs-Novell, M. López-Abad, et al. “Bioactive Peptides in Preterm Human Milk: Impact of Maternal Characteristics and Their Association to Neonatal Outcomes,” <i>BioFactors</i> 50, no. 1 (2024): 135–144, https://doi.org/10.1002/biof.1997.</p><p>In the originally published article, the project code PI20/00294 was omitted from the funding information. The correct text is included below. This has been updated in the online version of this article.</p><p>This manuscript is part of Health Research Projects from Instituto Nacional Carlos III (Ministry of Science and Innovation, Government of Spain) granted to Isabel Iglesias-Platas, with financial support from the National R+D+I Plan (PI17/00107, PI20/00294) of the Subdirección General de Evaluación y Fomento de la Investigación Sanitaria (ISCIII), which was co-founded by the European Union Regional Development Fund (FEDER). Funding was also received from the Spanish Association of Pediatrics (Asociación Española de Pediatría; 1a Beca de Nutrición Dinosaurus-Artiach).</p><p>We apologize for this error.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to EVs Biodistribution and Antifibrotic Impact in Aged Lung Fibrosis Model","authors":"","doi":"10.1002/biof.70034","DOIUrl":"10.1002/biof.70034","url":null,"abstract":"<p>I. Amtil-Ouahdi, F. Vergara, C. Rio, C. González-Martínez, A. Jahn, M. A. Forteza-Genestra, A. Gayá, J. Calvo, E. Sala-Llinas, B. A. Navarrete, A. D. Romero-Ortiz, M. Monjo, J. M. Ramis, and F. G. Ortega, “EVs Biodistribution and Antifibrotic Impact in Aged Lung Fibrosis Model,” <i>BioFactors</i> 51 (2025): e70021, https://doi.org/10.1002/biof.70021.</p><p>In the originally published article, author Joana M. Ramis' name was mistakenly published as Johana M. Ramis. We have corrected this in the online version of the article.</p><p>We apologize for this error.</p>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/biof.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fucosterol Promotes Browning in Mouse 3T3-L1 Adipocytes Through HO-1/Nrf2 and AMPK Pathways","authors":"Indyaswan T. Suryaningtyas,&nbsp;Won-Kyo Jung,&nbsp;Jae-Young Je","doi":"10.1002/biof.70035","DOIUrl":"10.1002/biof.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Browning of white adipose tissue offers a promising strategy to manage obesity by enhancing thermogenesis and lipid oxidation. Although fucosterol, a phytosterol found in brown seaweeds, has been recognized for its antioxidant and metabolic benefits, its ability to trigger browning has not been previously reported. In this study, we demonstrate for the first time that fucosterol induces adipocyte browning in 3T3-L1 cells. Treatment with fucosterol (10–50 μM) during adipogenic differentiation suppressed lipid accumulation and downregulated adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1), while enhancing lipolysis via increased phosphorylation of HSL and AMPK. Critically, browning markers PRDM16, PGC1α, and UCP1 were robustly upregulated in a dose-dependent manner. Fucosterol also activated the Nrf2/HO-1 antioxidant pathway, as evidenced by increased HO-1 expression and Nrf2 nuclear translocation. Pharmacological inhibition of HO-1 or AMPK reversed these effects, confirming their essential role in fucosterol-induced thermogenic remodeling. Interestingly, despite activation of p38 and ERK MAPKs—often linked to stress signaling—fucosterol reduced pro-inflammatory cytokine levels (IL-6, IL-1β, TNF-α) and elevated antioxidant enzymes (SOD, GPx, CAT), suggesting a non-inflammatory metabolic adaptation. These findings reveal a previously uncharacterized function of fucosterol in promoting adipocyte browning, driven by HO-1/Nrf2 and AMPK pathways, with potential relevance for therapeutic strategies targeting obesity.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Intake of Oleic Acid-Rich Palm Oil Induces Obesity Without Impairing Hypothalamic Insulin Sensitivity and Redox Activity in Male Wistar Rats","authors":"Aleksandra Ruzicic,&nbsp;Tamara Dakic,&nbsp;Tijana Srdic,&nbsp;Iva Lakic,&nbsp;Sanja Stankovic,&nbsp;Milos Mojovic,&nbsp;Djura Nakarada,&nbsp;Damir Kracun,&nbsp;Jelena Djordjevic","doi":"10.1002/biof.70036","DOIUrl":"10.1002/biof.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>The debate over the impact of extensive palm oil consumption on human health, driven by its economic affordability, persists due to its high saturated fat content and potential health risks. Conversely, its diverse bioactive compounds offer antioxidant and anti-inflammatory properties. This study seeks to investigate the effects of prolonged palm oil consumption on hypothalamic insulin signaling, inflammation, and oxidative stress markers. Rats were fed either standard chow or a palm oil-enriched diet (POD) for 21 weeks, with the latter diet prepared by soaking standard briquette food in commercially available palm oil. The palm oil used in our study contained slightly more oleic acid than palmitic acid (44.3% and 39.5%, respectively). Prolonged consumption of a diet enriched with 20% of palm oil resulted in obesity in rats, accompanied by concurrent changes in blood lipid content. Additionally, palm oil consumption induced hyperinsulinemia and hyperglycemia, indicating the presence of peripheral insulin resistance. Despite these findings, our study did not reveal differences in hypothalamic insulin resistance between obese and control rats. In the cerebrospinal fluid, insulin concentration remained consistent after palm oil consumption, while glucose levels increased. Hypothalamic gene expression analysis did not show significant changes in the levels of NF-κB, IL-6, IL-1β, and Nrf2 mRNA. Moreover, the activation of insulin receptor and its substrate IRS1, as well as the expression of glucose transporters GLUT1-4 in the rat hypothalamus, remained unaltered. Ex vivo EPR spectroscopy of the obese rat hypothalamus indicated no variations in the total redox status compared to control rats. In summary, our results suggest that long-term consumption of palm oil rich in oleic acid induces obesity but does not significantly impact hypothalamic insulin expression and response, inflammation, or oxidative stress, which at least in part may be attributed to the specific fatty acid composition of the palm oil used. However, the potential contribution of other phytochemicals and bioactive compounds, such as vitamin E, must not be overlooked when interpreting the overall metabolic response to the prolonged palm oil intake.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Effects of SELFormer-Selected β-Citronellol and β-Caryophyllene in Vagotomized Ischemic Stroke Model Through Direct Brain Protection and Gut Microbiota Modulation","authors":"Yu Yue,&nbsp;Chen Li,&nbsp;Ting Zhang,&nbsp;Sunmin Park","doi":"10.1002/biof.70031","DOIUrl":"10.1002/biof.70031","url":null,"abstract":"<div>\u0000 \u0000 <p>Natural compounds identified via the SELFormer pipeline for cognitive enhancement may exert neuroprotective effects in ischemic stroke (IS) through both direct actions on the central nervous system and potential modulation of the gut microbiota. However, it remains unclear whether such benefits persist under conditions in which gut-brain neural communication is compromised. We aimed to evaluate the neuroprotective potential of β-citronellol (BCT), β-caryophyllene (BCP), and citronellyl acetate (CTA) in an IS model with compromised vagal signaling. Mongolian gerbils received daily oral treatment with dextrin (Control), BCT (100 mg/kg), BCP (20 mg/kg), or CTA (100 mg/kg) for 2 weeks before undergoing subdiaphragmatic vagotomy followed by bilateral common carotid artery occlusion; sham-operated animals treated with dextrin served as Normal-C. During an additional 4 weeks of treatment, we assessed neuronal survival, cognitive function, metabolism, neuroinflammation, and gut microbiota composition and metabolism. BCT demonstrated superior neuroprotection, followed by BCP, with CTA showing modest efficacy compared to the control. BCT and BCP increased hippocampal CA1 neurons and improved memory function. Treatments reduced hippocampal acetylcholinesterase activity, lipid peroxidation, and inflammatory markers (TNF-α and IL-1β) while enhancing cerebral blood flow, glucose metabolism, and lipid profiles. Gut microbiota analysis revealed increased α-diversity and restoration of beneficial bacteria, including <i>Akkermansia</i> and <i>Faecalibacterium</i>, particularly with BCT treatment. BCT and BCP increased butyrate-producing bacteria. These improvements occurred despite vagal nerve disruption, indicating alternative neuroprotective mechanisms through enhanced intestinal barrier integrity and microbiota-derived metabolites. In conclusion, these compounds, especially BCT, protect against neuronal death and cognitive impairment in IS conditions through integrated effects on neuroinflammation, oxidative stress, and non-vagal gut-brain communication pathways. Therefore, BCT and BCP were potential for IS prevention and treatment strategies.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-Targeting SIRT3 Activator Effectively Controls Bleomycin-Induced Pulmonary Fibrosis","authors":"Geetanjali Devabattula,&nbsp;Bulti Bakchi,&nbsp;Anamika Sharma,&nbsp;Nagamalli Naga Sidhartha,&nbsp;Amol G. Dikundwar,&nbsp;Venkata Madhavi Yeddanapudi,&nbsp;Chandraiah Godugu","doi":"10.1002/biof.70032","DOIUrl":"10.1002/biof.70032","url":null,"abstract":"<div>\u0000 \u0000 <p>Pulmonary fibrosis is a debilitating condition characterized by excessive collagen deposition and scar formation. Divergent factors often contribute to mitochondrial dysfunction. Oxidative stress is one of the major triggers for the development of pulmonary fibrosis through downregulation of SIRT3. This study aims to enhance the SIRT3 activity at the organelle level by a targeted drug delivery approach. C12 is a known molecule as a SIRT3 activator and is protective in pulmonary fibrosis in our previous studies. We have designed a mitochondrial-targeted delivery approach by introducing a triphenylphosphonium cation (TPP⁺) into the C12 molecule to enhance its mitochondrial specificity and efficacy. The newly designed MitoC12 attenuated the BLM-induced acute lung injury and pulmonary fibrosis more effectively than C12 primarily through activation of SIRT3. The cellular uptake studies revealed that MitoC12 concentrated more in mitochondria than the cytosolic fraction. MitoC12 reduced BLM-induced oxidative stress in BEAS-2B cells and inhibited TGF-β-induced pulmonary fibrosis in MRC-5 cells. MitoC12 inhibited the EMT by decreasing the expression of vimentin and N-cadherin and increasing the expression of E-cadherin. Further, the in vivo studies of MitoC12 exhibited a protective effect in BLM-induced pulmonary fibrosis by improving lung function, decreasing inflammation, and restoring lung architecture. MitoC12 reduced the collagen deposition and expression of fibrotic markers such as TGF-β, collagen 1A and 3A, α-SMA, fibronectin, and vimentin. Mechanistically, MitoC12 showed an anti-fibrotic effect through activation of SIRT3 thereby preventing mitochondrial dyshomeostasis through regulating MnSOD and OGG1 functioning. Overall, this study suggests that MitoC12 could be a potential therapeutic option for pulmonary fibrosis emphasizing TPP⁺-conjugated molecules in treating mitochondrial dysfunction-related diseases.</p>\u0000 </div>","PeriodicalId":8923,"journal":{"name":"BioFactors","volume":"51 4","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144503108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}