Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally, caused by expanded CAG repeats in the ATXN3 gene and consequent pathogenic accumulation of mutant ATXN3 (mATXN3) aggregates. The formation of these aggregates perturbs neuronal functions and leads to progressive neurodegeneration, yet the molecular mechanisms controlling mATXN3 proteostasis remain incompletely understood. Here, we identify RAD23 homolog B (Rad23b), a ubiquitin-binding shuttle factor, as a potential regulator of mATXN3 aggregates and toxicity upon high throughput proteomic analysis. Functional assays reveal that Rad23b overexpression enhances, while Rad23b knockdown or knockout reduces, mATXN3 aggregates and neuronal cell death. Mechanistically, Rad23b directly interacts with mATXN3, promotes its ubiquitination, and facilitates its delivery to the proteasome. Paradoxically, Rad23b disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Immunohistochemical analysis in SCA3 transgenic mice confirms colocalization of Rad23b with mATXN3 aggregates in cerebellar neurons. These findings highlight Rad23b as a crucial modulator of mATXN3 proteostasis, and imply Rad23b as a potential therapeutic target in SCA3.

Lactoferrin (LF)-derived peptides (LDPs) are short cationic and amphipathic fragments generated primarily from the N-terminal lobe of LF through pepsin-mediated proteolytic processes. The best-characterized LDPs include lactoferricin (LFcin), lactoferrampin (LFampin), and LF1-11. In addition to these native peptides, a growing range of engineered LDPs has been developed by modifying the LFcin-derived RRWQWR motif through the incorporation of non-natural amino acids, cyclization, multimerization, and conjugation with chemotherapeutic agents. LDPs have garnered significant interest as potential anticancer peptides due to their ability to preferentially engage with the surfaces of malignant cells and initiate various tumor-suppressive mechanisms. This review article provides an overview of the principal classes of LDPs and elucidates how structural features influence membrane interaction, selectivity, intracellular targeting, apoptotic pathways, and immune modulation. It also discusses current mechanistic insights and examines the major challenges and opportunities for translating innovative LDPs into clinically useful cancer therapeutics.

Microplastics (MP) and particulate matter (PM) are pervasive environmental contaminants that pose significant threats to intestinal homeostasis. This study systematically investigated the individual and combined effects of MP and PM on intestinal injury using complementary in vivo and in vitro models. In mice, co-exposure to MP and PM induced pronounced oxidative stress, intestinal inflammation, disruption of epithelial barrier integrity, mucin accumulation, activation of endoplasmic reticulum (ER) stress, and dysregulation of autophagy. Consistently, in C2BBe1 intestinal epithelial cells, combined exposure significantly reduced cell viability and exacerbated oxidative stress, ER stress, and autophagic imbalance, as evidenced by increased reactive oxygen species (ROS), elevated BiP and ATF6 expression, and accumulation of p62 and LC3B-II. Moreover, co-exposure promoted intestinal inflammation, barrier dysfunction, and mucin accumulation, demonstrated by increased ICAM-1, IL-1β, IL-6, and TNFα levels, reduced ZO-1 expression, and upregulated MUC2 expression. Strikingly, combined exposure-induced mucin accumulation may provide physical protection and compensate for barrier disruption. Notably, pretreatment with kefir peptides (KPs) markedly attenuated these deleterious effects in vivo and in vitro, supporting their protective potential. KPs pretreatment alleviated cytotoxicity by reducing oxidative and ER stress markers and normalizing autophagy-related protein expression. In addition, KPs decreased ICAM-1 levels, restored epithelial barrier integrity, and limited mucin accumulation in intestinal cells. Collectively, these findings demonstrate that concurrent exposure to MP and PM exacerbates intestinal injury through coordinated activation of oxidative stress, ER stress, and dysregulated autophagy pathways, and identify KPs as a promising preventive strategy for mitigating pollutant-induced intestinal damage.

Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.

Hemophilia A, an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency, necessitates lifelong factor replacement therapy with high treatment burden. To explore a non-viral alternative, we evaluated minicircle DNA carrying the FVIII-E1984V mutation-engineered for improved stability and activity-as a gene therapy for sustained coagulation correction. Mini-circle DNA constructs (with the bacterial backbone excised) encoding either wild-type FVIII or E1984V-FVIII were delivered via hydrodynamic tail vein injection into FVIII-KO mice, a typical murine model of hemophilia A. Coagulation outcomes (aPTT, FVIII activity, tail-clip assay) and transgene persistence were monitored over 26 weeks. Minicircle DNA delivery demonstrated higher transfection efficiency in vitro and sustained coagulation improvement in vivo for at least 26 weeks, markedly exceeding the short durability of conventional FVIII infusion (days versus weeks). Furthermore, exogenous FVIII DNA and RNA persisted in hepatocytes without evidence of hepatotoxicity. These findings highlight minicircle DNA-based FVIII gene therapy as a promising strategy for hemophilia A. Future studies will focus on optimizing vector design for sustained expression, advancing toward clinical translation.

Aldo-keto reductase family 1 member A1 (AKR1A1) is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme that catalyzes the reduction of aldehydes to alcohols. In this study, we investigated whether AKR1A1 acts as a context-dependent stress-associated factor whose role may differ depending on the degree, duration, and cellular context of injury in kidney allografts and explored its underlying molecular mechanisms. In human kidney transplant specimens, AKR1A1 expression was upregulated in renal tubular epithelial cells (RTECs) exhibiting tubular injury and oxidative stress, particularly during rejection accompanied by acute tubular injury. Although AKR1A1 expression showed an inverse correlation with pyruvate kinase muscle isoenzyme 2 (PKM2), this association was statistically non-significant. Notably, higher AKR1A1 expression was associated with increased oxidative stress yet correlated with a reduced risk of serum creatinine doubling in this cohort. In vitro, hypoxia/reoxygenation (H/R) reduced cell viability and induced AKR1A1 expression alongside the pro-apoptotic marker C/EBP homology protein (CHOP). Pharmacological inhibition of S-nitrosoglutathione reductase using N6022 functionally attenuated AKR1A1 activity without a direct effect on CHOP expression. Genetic modulation further confirmed the role of AKR1A1 in apoptosis, as AKR1A1 knockdown increased CHOP expression, whereas AKR1A1 overexpression attenuated it. Reciprocal activation between AKR1A1 and the silent information regulator 1 (SIRT1)/ peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway was observed both in vitro and in vivo. In addition, N6022 altered LC3B-associated autophagy markers, suggesting the activation of compensatory cytoprotective mechanisms under conditions of AKR1A1 deficiency. Together, these findings indicate that AKR1A1 serves as a marker of tubular stress and contributes to kidney allograft survival by modulating CHOP-mediated apoptosis and the SIRT1/PGC-1α axis. Inhibitory S-nitrosylation and activation of SIRT1/PGC-1α provide compensatory protection against oxidative stress and apoptosis. Targeting these pathways may represent a promising therapeutic strategy to improve kidney allograft outcomes.

KFP-1, a kefir-fermented peptide, promotes osteoblast differentiation and bone formation while inhibiting osteoclast differentiation and bone resorption. We also confirmed the bioaccessibility of KFP-1 in bone tissue and its overall benefits for bone health. Kefir is a dairy beverage rich in bioactive peptides with diverse health benefits. We identified a kefir-fermented peptide, KFP-1 (TEVPAINTIASAEPTVH), which enhances intestinal calcium absorption and may modulate bone remodeling. This study investigated the effects of KFP-1 on osteoblast and osteoclast gene expression and differentiation in BMMSCs, MC3T3-E1, BMMs, and Raw264.7 cells. Using iodine-125 labeling, we tracked KFP-1 distribution in mice following oral and intravenous administration, and evaluated its osteoprotective effects in AKR1A1 knockout (AKR1A1-KO) osteoporotic mice. KFP-1 upregulated osteogenic markers (ALP, Col1a1, OCN, OPG, RUNX2, OSX, BMP-2, β-catenin) and promoted osteoblast differentiation and mineralization, while downregulating osteoclastic markers (CTK, CTR, DC-STAMP, TRAP, c-Fos, c-Src, NFATc1) and inhibiting osteoclast differentiation and resorption via the inhibition of NFATc1, c-Fos, and c-Jun nuclear translocation and attenuation of RANKL-induced p38 MAPK, JNK, ERK, and NF-κB signaling. Biodistribution analysis showed KFP-1 reached femur and tibia at approximately 0.4

BACKGROUND:Vitamin C (VC) plays essential but incompletely defined roles in osteoclast (OC) development. We examined how exogenous VC and AKR1A-dependent endogenous VC regulate OC differentiation, cytoskeletal organization, resorptive activity, and apoptosis. METHODS:Murine bone marrow-derived macrophages (BMDMs) from wild-type and AKR1A-deficient mice, together with RAW264.7 cells, were used to assess the effects of exogenous and endogenous VC on OC differentiation, actin ring formation, resorption, apoptotic signaling, and ERK1/2 activation. RESULTS:AKR1A1 deficiency altered osteoclastogenic kinetics, delaying early differentiation, impairing actin ring formation and early resorption, yet promoting late accumulation of large multinucleated OCs. VC exhibited stage-dependent effects: it was required to initiate osteoclastogenesis but, when supplemented at later stages, suppressed OC maturation and enhanced apoptosis. In both primary cells and RAW264.7 cultures, VC dose-dependently promoted peripheral F-actin ring assembly and increased matrix resorption. Mechanistically, VC enhanced ERK1/2 phosphorylation in mature OCs, selectively increased reactive oxygen species, and activated the DAPK1-caspase-3 axis, including nuclear localization of phospho-DAPK1 and cleaved caspase-3. Pharmacologic ERK inhibition suppressed OC formation and resorptive function. CONCLUSION:VC acts as a stage-dependent modulator of OC fate, linking ERK1/2-associated cytoskeletal maturation and resorptive activity to DAPK1-caspase-3-mediated apoptotic termination during bone remodeling.

BACKGROUND:The global prevalence of pediatric obesity has risen sharply, increasing from 0.7% to 5.6% in girls and from 0.9% to 7.8% in boys between 1975 and 2016. Genetic factors contribute an estimated 50-80% to obesity risk. In 2007, FTO was identified as the first obesity-associated gene through a genome-wide association study (GWAS), but research in Asian pediatric populations remains limited. This study investigated the genetic architecture of pediatric obesity in Taiwanese children. METHODS:Data were obtained from the China Medical University Hospital Biobank. Obese cases were defined as BMI above 95th percentile for age and sex; controls had BMI between the 3rd and 50th percentiles. GWAS was performed on 5854 cases and 12,343 controls aged 2-17 years using the TPMv1 customized single nucleotide polymorphism (SNP) array. Polygenic risk scores (PRS) were constructed with PRSice2. Phenome-wide association studies (PheWAS) evaluated PRS-disease associations, and network analyses were conducted via Ingenuity Pathway Analysis. (IPA). RESULTS:GWAS identified 367 SNPs associated with pediatric obesity at P < 1 × 10-5, with leading SNPs rs79500119 (ASB3, chromosome 2) and rs74617772 (near FTO, chromosome 16). Obesity cases had significantly higher PRS (P < 0.05). PheWAS linked obesity PRS to type 2 diabetes, hypertension, respiratory infections, liver disease, and precocious puberty. Network analysis highlighted the insulin-AKT pathway as potentially central to pathogenesis. CONCLUSIONS:This first GWAS of pediatric obesity in Taiwan revealed novel, population-specific genetic associations. The PRS offers potential for metabolic risk stratification, and the insulin-AKT pathway represents a relevant biological framework for further investigation of pediatric obesity pathogenesis.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated blood glucose levels due to insulin deficiency or resistance. While conventional treatments are effective, integrating nutraceuticals that aid in blood sugar control is crucial for patients with low compliance or prediabetes. This study aimed to assess the efficacy of kefir-derived exopolysaccharides (KEPS) in ameliorating type 2 DM in rats induced by streptozotocin (STZ) and a high-fat diet. Eight-week-old male SD rats were fed a high-fat diet for 4 weeks and subsequently administered STZ (35 mg/kg body weight) via intraperitoneal injection to induce type 2 diabetes. Diabetic rats were randomly assigned to three groups: untreated diabetes (mock), diabetic rats + high-dose KEPS (STZ-KEPSH), and diabetic rats + low-dose KEPS (STZ-KEPSL), and treated for an additional 4 weeks. An age-matched SD rat group without STZ induction was used as a control. Our findings demonstrate that high-dose KEPS administration in diabetic rats enhances hepatic glucose uptake and stabilizes blood glucose levels by upregulating GLUT2 protein expression and PI3k phosphorylation in liver cells. KEPS mitigates lipid production, reduces β cell damage, and preserves islet cell integrity, thereby improving insulin sensitivity and alleviating diabetes symptoms. High-dose KEPS treatment also exhibits less renal enlargement and lower kidney-to-body weight ratio than the diabetic group. Exopolysaccharides derived from kefir show promising potential in managing type 2 diabetes mellitus in rats, suggesting a viable nutraceutical therapy. Further research is needed to validate these findings in human subjects.

Aggregation of misfolded mutant Huntingtin (mHTT) is a pathological characteristic in Huntington’s disease (HD), implying clearance of mHTT is a therapeutical direction for this neurodegenerative disorder. Based on previous studies, Insulin-like growth factor 2 (IGF2) enhances microfilament polymerization in HD models; however, the role of IGF2 against mHTT aggregates is still unclear. Here, we demonstrate that IGF2 expression is significantly lower in symptomatic HD patients compared to presymptomatic individuals, and IGF2 activation mechanistically enhances phosphorylation of Protein Kinase B(AKT; serine/threonine kinase), which subsequently reduces mHTT aggregates in vitro. Furthermore, IGF2 stimulates Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, promoting the secretion of mHTT within extracellular vesicles, thereby aiding cellular clearance. In vivo studies in R6/2 HD transgenic mice reveal that IGF2 administration improves motor functions and decreases mHTT levels. Collectively, our findings elucidate the multifaceted role of IGF2 in HD, highlighting its therapeutic potential through modulation of AKT and NF-κB signaling pathways.

The increased global incidence of hemophilia, along with its concomitant consequences arising from prolonged hemorrhage after an injury and a heightened vulnerability to internal bleeding in joints or the brain, brings to the forefront the development of innovative therapeutic strategies to alleviate this hereditary genetic disorder. Current treatments for hemophilia primarily depend on plasma concentrates; however, their widespread use is constrained by the reliance on blood donations and the associated risk of infections. Alternative protein-based therapeutics, such as recombinant coagulation factors, bypassing agents, and non-factor-based drugs, have been approved and utilized for the prophylaxis and treatment of hemophilia with promising outcomes; yet, their shortcomings consist of the necessity for repeated administration and the likelihood of inhibitor formation. With the emergence of the cutting-edge gene editing (CRISPR/Cas9) and gene delivery (viral and non-viral vectors) techniques, the recent progression in gene therapy, stem cell transplantation, and prenatal interventions via in utero stem cell therapy inspires optimism for individuals afflicted with hemophilia and their families, even though these innovative techniques remain in the preclinical stage with a lot of technical and ethical issues needing to be resolved. This review article provides a comprehensive overview of hemophilia management, from traditional therapies to advanced prenatal stem cell treatments, highlighting the evolution and future directions in addressing this genetic bleeding disorder.

Air pollution, particularly particulate matter (PM), poses a significant health risk worldwide, with rhinitis emerging as a prevalent respiratory condition. This review explores the association between air pollution and rhinitis, focusing on PM-induced inflammation and the potential preventive role of nutritional supplements. A comprehensive literature search was conducted using the PubMed and Scopus databases, covering studies from inception to 2024 that investigated air pollution, rhinitis, and nutritional interventions. This review synthesizes evidence linking PM exposure to increased prevalence and exacerbation of rhinitis through various inflammatory mechanisms. We further examine the potential of nutritional supplements, including kefir peptides, lactoferrin, vitamin D, polyunsaturated fatty acids, and probiotics, in mitigating PM-induced inflammation and rhinitis symptoms. However, the evidence regarding the role of these supplements in modulating immune responses and reducing inflammation related to PM-induced rhinitis is limited. This review highlights the potential efficacy of nutritional interventions in preventing and managing air pollution-associated rhinitis, offering a complementary approach to environmental regulations in addressing this public health challenge.

Osteoporosis is a prevalent skeletal disorder in postmenopausal women and older adults. Kefir has gained attention for its potent antioxidative, anti-inflammatory, and immunomodulatory properties. This review consolidates findings on kefir-derived peptides' interventions in osteoporosis models and evaluates the therapeutic potential of kefir components in preventing osteoporosis, thereby enhancing its application in clinical nutrition strategies for osteoporosis management. Kefir-derived peptides exhibit osteoprotective potential in various animal models of osteoporosis, in which several antioxidative and ACE-inhibitory peptides have been shown to promote osteoblast differentiation and mineralization. In addition, emerging evidence supports the role of kefir-derived probiotics and exopolysaccharides (kefiran) in mitigating bone loss. Kefir holds significant promise in the management of osteoporosis due to its unique composition of bioactive components promoting bone health. While research is still in its early stages, evidence suggests kefir's potential as a natural approach to osteoporosis prevention and management.

Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF) as a neurotrophic agent, systematically evaluating its effects on neuronal differentiation, morphology, and mitochondrial regulation in PC12 cells. We demonstrated that bLF (50 μg/mL) induces neurite outgrowth comparable to nerve growth factor (NGF) while maintaining >90 % cell viability. Mechanistically, bLF activated TrkA by phosphorylation at Ser490, followed by ERK phosphorylation at Thr202/Tyr204 within 60 min, mirroring canonical NGF signaling. bLF also upregulates p35 (CDK5 activator) and phosphorylates Synapsin-I, driving presynaptic maturation. Structurally predicted to bind TrkA's ligand-binding interface, bLF synergizes with NGF to amplify differentiation outcomes. Furthermore, TMRE staining and AMPK phosphorylation assays revealed that bLF enhances axonal mitochondrial activity, surpassing NGF's effects. These results establish bLF as a multifunctional neurotrophic agent that coordinates TrkA-ERK-p35/CDK5 signaling, synaptic protein activation, and AMPK-driven mitochondrial regulation. Given its safety profile and synergy with endogenous neurotrophic pathways, bLF emerges as a promising candidate for neuroregenerative therapies targeting nerve injury or neurodegeneration.

Bone-derived mesenchymal stem cells (BMSCs) are multipotent stem cells capable of differentiating into adipocytes and osteoblasts. Dysfunctional differentiation, characterized by a shift from osteoblastogenesis to adipogenesis, is closely associated with metabolic and senile osteoporosis. The Aldo-keto reductase family 1 member A1 (Akr1A1) enzyme, which utilizes NADPH to reduce aldehyde groups to alcohols, has emerged as a potential regulator. This study investigates the role of reactive oxygen species (ROS) in modulating Akr1A1 expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes. Our findings demonstrate that increased ROS levels enhance the expression of C/EBP homology protein (CHOP) and Akr1A1 during adipogenic differentiation. Conversely, reduced ROS levels suppress CHOP and Akr1A1 expression in osteogenically committed cells. Functional studies involving Akr1A1 silencing and overexpression revealed that Akr1A1 expression levels dictate MSC lineage commitment without altering ROS production or CHOP expression. Knockdown of Akr1A1 suppressed adipogenesis while promoting osteoblastogenesis, accompanied by upregulation of SIRT1, PGC-1α, TAZ, and other osteogenic transcription factors. In contrast, overexpression of Akr1A1 reduced SIRT1, PGC-1α, and TAZ levels, thereby enhancing adipogenesis and inhibiting osteogenesis. These findings position Akr1A1 as a downstream target of the ROS/CHOP signaling pathway. Using an oxidative stress cell model induced by D-galactose in BMSCs, we confirmed that elevated ROS levels upregulate CHOP and Akr1A1 expression, preferentially driving differentiation into adipocytes over osteoblasts. Our results reveal that intracellular ROS modulate CHOP and Akr1A1 expression, which regulate commitment to adipogenic and osteogenic lineages. This regulation appears to occur through inhibiting SIRT1-dependent pathways, shedding light on potential therapeutic targets for metabolic and age-related osteoporosis.

Preeclampsia (PE) is one of the major problems for global healthy burden. It affects 2 to 8% of all pregnancies and causes both maternal and infant morbidity and mortality. Kefir peptides are products from many kinds of prebiotic fermentation in whole milk by kefir grain. In this study, we used the N(ω)-nitro-L-arginine methyl ester (L-NAME) in drinking water to mimic the preeclampsia in spontaneous hypertension rat stroke-prone (SHRSP) pregnant rats, the rats were assigned to five treatment groups: the normal group, untreated group, L-NAME group, L-NAME+KPs (LD and HD dose diets) for 20-day experiment. Data showed that rats only gave the L-NAME group induced severe high blood pressure, urine protein, placenta damage, and embryo reabsorption. After KPs pre-administration significantly reduced urine protein production and generalized vessel endothelial dysfunction, anti-oxidative, and anti-inflammation levels in SHRSP rats placenta. In conclusion, kefir peptides is a multipurpose peptide that can suppress oxidative stress, HIF-1a, anti-TNF-α and IL-6 inflammation levels, reducing urine protein production and generalized vessel endothelial dysfunction and balance the sFlt-1:PlGF ratio through blocking eNOS/NO. KPs might be a promising protective nutraceutical agent for early pregnancies. The Higher Education Sprout Project by the Ministry of Education (MOE-112-S-0023) in Taiwan. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening lung disease with high mortality rates. The limited availability of effective drugs for IPF treatment, coupled with concerns regarding adverse effects and restricted responsiveness, underscores the need for alternative approaches. Kefir peptides (KPs) have demonstrated antioxidative, anti-inflammatory, and antifibrotic properties, along with the capability to modulate gut microbiota. This study aims to investigate the impact of KPs on bleomycin-induced pulmonary fibrosis.MethodsMice were treated with KPs for four days, followed by intratracheal injection of bleomycin for 21 days. Comprehensive assessments included pulmonary functional tests, micro-computed tomography (µ-CT), in vivo image analysis using MMPsense750, evaluation of inflammation- and fibrosis-related gene expression in lung tissue, and histopathological examinations. Furthermore, a detailed investigation of the gut microbiota community was performed using full-length 16 S rRNA sequencing in control mice, bleomycin-induced fibrotic mice, and KPs-pretreated fibrotic mice.ResultsIn KPs-pretreated bleomycin-induced lung fibrotic mice, notable outcomes included the absence of significant bodyweight loss, enhanced pulmonary functions, restored lung tissue architecture, and diminished thickening of inter-alveolar septa, as elucidated by morphological and histopathological analyses. Concurrently, a reduction in the expression levels of oxidative biomarkers, inflammatory factors, and fibrotic indicators was observed. Moreover, 16 S rRNA sequencing demonstrated that KPs pretreatment induced alterations in the relative abundances of gut microbiota, notably affecting Barnesiella_intestinihominis, Kineothrix_alysoides, and Clostridium_viride.ConclusionsKefir peptides exerted preventive effects, protecting mice against bleomycin-induced lung oxidative stress, inflammation, and fibrosis. These effects are likely linked to modifications in the gut microbiota community. The findings highlight the therapeutic potential of KPs in mitigating pulmonary fibrosis and advocate for additional exploration in clinical settings.