Search Results (2,455)

Perinatal mesenchymal stem cells (MSCs) are characterized by high phenotypic plasticity, allowing them to dynamically adapt to microenvironmental stimuli. However, the extent to which maternal pathophysiology and clinical history in vivo permanently alter their biological properties remains poorly understood. The aim of this study is to determine the influence of the maternal in vivo environment—including vascular stress (gestational hypertension), metabolic stress (hypothyroidism), and obstetric history (miscarriages, stillbirths)—on the transcriptomic, proteomic, and epigenetic profiles of growth factors in umbilical cord blood stem cells (UC-MSCs) and human milk stem cells (MM-MSCs). UC-MSCs (n = 51) and MM-MSCs (n = 78) were isolated from eligible donors. Global transcriptomic pathways associated with maternal hypertension were examined in UC-MSCs using Affymetrix expression microarrays. Targeted polymerase chain reaction (qPCR) validation was performed in both cell sources for key growth factors and receptors and for microRNA-155 in MM-MSCs. Paracrine protein concentrations (HGF, IGF-1, VEGF) in whole milk were quantified using ELISA. Microarray screening demonstrated that maternal hypertension is associated with a transcriptomic shift in the UC-MSCs towards a profibrotic signature, marked by an increased expression of the canonical Wnt signaling pathway and structural components of the extracellular matrix, while simultaneously suppressing the expression of genes associated with cell migration networks. qPCR confirmed that maternal hypertension is associated with significantly reduced FGFR1 expression and a downward trend in EGF and HGF in UC-MSCs, while correlating with an asymmetric response in MM-MSCs. Maternal hypothyroidism was linked to a transcriptomic profile suggestive of a rescue response (a trend toward increased IGF1 and EGF expression) in UC-MSCs, in contrast to a potential paracrine translation deficit (trends toward reduced VEGF, HGF, and IGF-1 protein levels) in the milk matrix. Importantly, a history of miscarriage correlated with alterations in the cellular mechanism of MM-MSCs (a trend toward increased IGF1 and EGF mRNA expression), while previous stillbirths were associated with a systemic, threefold increase in free IGF-1 protein concentration in whole milk. This paracrine dynamic strongly correlated with miR-155 expression, suggesting a potential regulatory role in the lactation niche. Our findings suggest that the molecular and epigenetic makeup of perinatal stem cell niches is dynamically and persistently associated with the mother’s somatic health and reproductive history. This tissue-specific plasticity provides robust molecular support for the DOHaD paradigm, indicating that offspring stem cell profiles may directly reflect the maternal inheritance in vivo. Full article

The blood-brain barrier (BBB) is permeable only to small lipophilic molecules, whereas hydrophilic nutrients, such as glucose and amino acids, cross the BBB via carrier-mediated transport systems. In contrast, circulating proteins do not cross the BBB. However, the BBB expresses receptors able to induce receptor-mediated transcytosis (RMT) of selective proteins across the BBB, as in the case of insulin, transferrin, and insulin-like growth factor 1 (IGF1). This led to the hypothesis that the transport of protein-based biologics to the brain may be possible by targeting BBB receptors that induce RMT. Monoclonal antibodies targeting these receptors penetrate the BBB via RMT and are distributed throughout the brain, acting as molecular Trojan horses and/or shuttle systems. A generation of brain-penetrating fusion proteins was produced targeting BBB insulin, transferrin, and IGF1 receptors, respectively, with full antibodies and/or antibody fragments acting as transport domains. These antibody-based fusion proteins were validated in various experimental models, including lysosomal storage disorders (LSDs), stroke, Parkinson’s disease, and Alzheimer’s disease (AD), respectively. Clinical trials with brain-penetrating antibody-based biologicals targeting BBB transferrin and insulin receptors have been completed or are in progress in LSDs and in AD. The aim of this review is to examine the progress made in antibody-based biologicals for CNS disorders from genetic engineering to clinical trials. Full article

Adult growth hormone deficiency (GHD) is characterized by insulin resistance, visceral adiposity, and adverse body composition. Asprosin (ASP), an adipokine involved in glucose homeostasis and energy metabolism, has emerged as a potential biomarker of metabolic dysfunction. This study investigated longitudinal changes in circulating ASP and their relationships with metabolic, body composition, and bone parameters during 24 months of recombinant human growth hormone (rhGH) therapy. Nineteen adults with severe GHD were prospectively evaluated before and during rhGH replacement. Serum ASP, insulin-like growth factor-1 (IGF-1), metabolic and lipid parameters were assessed, while body composition and bone indices were determined by dual-energy X-ray absorptiometry. Associations between ASP and clinical variables were analyzed using Spearman’s rank correlation. RhGH therapy significantly reduced circulating ASP concentrations at 12 and 24 months, while IGF-1 concentrations increased significantly throughout follow-up. Body fat percentage and fat mass decreased, whereas lean mass increased after 24 months of treatment. Significant changes in bone mineral content and lumbar spine Z-score were also observed after 24 months. ASP was consistently inversely correlated with fasting glucose and developed negative associations with IGF-1 and fat mass during follow-up. Time-dependent associations were also observed with visceral adiposity and lipid parameters, whereas no consistent associations between ASP and skeletal parameters were identified. Long-term rhGH replacement was associated with sustained reductions in circulating ASP concentrations and metabolic remodeling. These findings suggest that ASP may represent a candidate marker of metabolic adaptation during rhGH replacement, although validation in larger prospective cohorts is required. Full article

Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its “writers,” “erasers,” and “readers,” yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration. Full article

Background/Objectives: Obesity may alter the prognostic value of biomarkers in childhood asthma. We examined whether transforming growth factor beta 1 (TGF-β1), soluble suppression of tumorigenicity 2 (sST2), C-X-C motif chemokine ligand 8 (CXCL8), and insulin-like growth factor 1 (IGF-1) were associated with sustained treatment escalation and whether associations differed by obesity status. Methods: The development cohort included 292 children: 90 non-atopic controls, 108 with normal-weight asthma, and 94 with obese asthma; longitudinal analyses included 202 with asthma. Biomarkers were modeled continuously in prespecified Cox models with biomarker-by-obesity interactions, internally validated with 1000 bootstrap resamples, and applied without refitting or recalibration to an independent Van cohort of 180 children with asthma. Results: Seventy-five children experienced sustained treatment escalation. TGF-β1 was associated with escalation in obese asthma (hazard ratio [HR] per 500 pg/mL, 2.12; 95% confidence interval [CI], 1.66–2.70; interaction q < 0.001), whereas CXCL8 was associated with escalation in normal-weight asthma (HR per 10 pg/mL, 2.06; 95% CI, 1.67–2.54; interaction q < 0.001). Adding TGF-β1 or CXCL8 increased 12-month time-dependent area under the curve (AUC) from 0.623 to 0.732 and 0.746. In Van, AUCs were 0.751 and 0.744, and interactions remained significant after adjustment (q = 0.036). sST2 showed a weaker obesity-related signal, whereas IGF-1 added little prognostic information. Conclusions: Prognostic biomarker associations differed by obesity status. TGF-β1 was associated with escalation in obese asthma, whereas CXCL8 was associated with escalation in normal-weight asthma. Further validation is needed before clinical use. Full article

Bisphenol A (BPA) is a widespread plasticizer widely used in the food industry worldwide. However, a consensus on the safe level of its daily intake does not currently exist, while there are numerous data pointing to a link between prenatal exposure to BPA and early neuropsychiatric disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The global average human-equivalent dose of BPA is estimated at 30 ng/kg body weight/day. Thus, the research herein was conducted on newborn and juvenile rat offspring of both sexes delivered from rats treated with 30 ng/kg body weight/day orally from day 6 to 21 of pregnancy and for a further 21 days during lactation. Our data indicate that prenatal exposure to 30 ng/kg/day from gestation day 6 to delivery induced sexually dimorphic, region-specific alterations in the neonatal (PD1) rat brains, impacting inflammatory reactions, estrogen receptor signaling, and neural progenitor dynamics. Prenatally BPA-treated males exhibited a pro-inflammatory state characterized by an increased total number of ramified Iba1+ microglia cells in the hippocampus alongside upregulation of Aif1, Nfkb, Tnf, Il1b, and Hif1a. Conversely, prenatally BPA-treated females showed only an increased total number of hippocampal Iba1+ cells and displayed inflammatory resilience, lacking upregulation of these markers. Both sexes exhibited a pro-inflammatory state in the prefrontal cortex via upregulation of Nfkb, Tnf, Il1b, and Hif1a. While both sexes showed decreased Tgfb in the prefrontal cortex, they deployed distinct compensatory responses: males upregulated the neuroprotector Igf1 only in the hippocampus, whereas in females, it was upregulated in both the hippocampus and the prefrontal cortex. Estrogen receptor expression was also highly dimorphic. In the hippocampus, males displayed an imbalance via Esr1 upregulation and Esr2 downregulation, while females showed Esr2 downregulation alone. In the prefrontal cortex, these transcriptional profiles were the opposite. Finally, neural progenitor markers were altered. In the prefrontal cortex, BPA drove the upregulation of Sox2 and Pax6 in males but Sox9 in females; in the hippocampus, only Pax6 was upregulated, and only in males. The PAX6 protein level in the hippocampus was significantly increased in males but decreased in females. In juvenile offspring (PD21), behavioral patterns characterized by hyper-exploration, increased environmental investigation, and heightened emotional reactivity during social exposure were more pronounced in female offspring. These baseline neonatal disparities followed by behavioral changes underscore the necessity of sex-specific approaches when evaluating early-life neurodevelopment and subsequent adult behavioral and biological vulnerabilities. Full article

Oxidative stress contributes to hair follicle degeneration by inducing inflammation and apoptosis in dermal papilla cells. This study investigated whether Saccharomyces cerevisiae fermentation enhances the anti-hair loss potential of Laminaria japonica (kelp) by-products by improving their antioxidant, anti-inflammatory, and cytoprotective activities. Fermentation significantly increased the superoxide dismutase (SOD) activity of kelp. In H₂O₂-stimulated human hair follicle dermal papilla cells, fermented kelp culture (KF) dose-dependently protected against oxidative-stress-induced cytotoxicity, reduced IL-6 and IL-8 secretion, inhibited NFκB phosphorylation, restored insulin-like growth factor-1 (IGF-1) expression, enhanced AKT phosphorylation, reduced Bax expression, and restored total caspase-3 expression. These findings indicate that KF attenuates oxidative-stress-induced inflammation and apoptosis while preserving dermal papilla cell function. A four-week application study further showed that a shampoo containing KF reduced hair loss and improved hair gloss, scalp sebum, and scalp scaling. Together, these findings suggest that S. cerevisiae fermentation enhances the biological activity of kelp by-products and supports the potential of KF as a functional cosmetic ingredient for anti-hair loss applications. Full article

Diabetes mellitus (T2DM) represents a major health problem with several potentially life-threatening complications including cardiovascular disease and osteopathy. Bone marrow mesenchymal stem cells (BM-MSCs) are a promising candidate for bone regeneration, and the insulin-like growth factor (IGF) axis plays a fundamental role in both bone regeneration and stem cell biology. Still, its expression profile is yet to be assessed in diabetic BM-MSCs. This study investigated IGF axis gene and protein expression in BM-MSCs isolated from the knee joints of diabetic and non-diabetic donors. BM-MSCs were cultured under basal and osteogenic conditions for 1, 2 and 3 weeks. Relative expression levels of the IGF axis genes were assessed using qPCR while protein concentrations of IGFBP-2, -3 and -4 were assessed using ELISA. Diabetic BM-MSCs showed lower mRNA levels of IGF binding proteins (IGFBP)-2, -3 and -4 but both cell populations displayed comparable protein levels. Moreover, the osteogenic cultures of diabetic and non-diabetic BM-MSCs equally demonstrated a trend of IGFBP-2 upregulation along with IGF-1 and IGFBP-5 downregulation. Non-diabetic BM-MSCs showed significant time-dependent increases in IGFBP-3 and -4 concentrations in basal and osteogenic cultures respectively. These molecules could be addressed to improve the regenerative potentials of BM-MSCs particularly under diabetic conditions, and further research is warranted into the possible roles of IGFBPs proteinases and their inhibitors in bone biology. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory condition that is marked by the growth of lesions outside the uterus, along with angiogenesis, fibrosis, immune dysregulation, and pain sensitization. There is now growing evidence that receptor tyrosine kinase (RTK) signaling networks are central to these processes, integrating proliferative, angiogenic, inflammatory, endocrine, and microenvironmental signals. This review summarizes the roles of six major RTK axes in endometriosis and evaluates their receptor-specific mechanisms, therapeutic relevance, and modulation by representative phytochemicals. An English-language literature search of PubMed was conducted with no publication date restrictions using combinations and variations of the following keywords: phytochemicals, endometriosis, EGFR, VEGFR, IGF1R, PDGFR, FGFR, MET, curcumin, resveratrol, epigallocatechin gallate (EGCG), quercetin, naringenin, berberine, apigenin, luteolin, genistein, and baicalein. Additional search terms related to receptor signaling mechanisms, downstream pathways, cellular phenotypes, and therapeutic relevance were also incorporated to ensure comprehensive coverage of the literature. The RTK signaling pathways control stromal activation, lesion survival, angiogenic support, extracellular matrix remodeling, neuroimmune sensitization, and malignant progression. Of the six RTK axes examined, EGFR, VEGFR, and IGF1R have the strongest mechanistic and pharmacological support, whereas PDGFR, FGFR, and MET remain biologically plausible targets. Even though phytochemicals do not consistently act as receptor-selective RTK inhibitors, evidence shows they reduce RTK-centred signaling networks by targeting common downstream hubs. As a result of their effects at the network level, the phytochemicals may help to suppress lesion proliferation, angiogenesis, invasion, fibrosis, inflammation, oxidative stress, and pain sensitization. Endometriosis should be viewed as an RTK-centered network disease rather than a single-pathway disorder. In this context, phytochemicals act as modulators that attenuate signaling hubs, offering a mechanistically aligned strategy for a disease driven by redundancy and microenvironmental crosstalk. Full article

Although robust observational data have long associated physical activity with improved colon cancer survival, the lack of randomized evidence has perpetuated a “causality gap,” confining exercise to supportive lifestyle advice and creating a clinical dilemma for surgeons. This paradigm has been fundamentally reshaped by the landmark phase III CHALLENGE trial. This review synthesizes the clinical, epidemiological, and translational evidence establishing exercise as a validated, disease-modifying intervention. In the CHALLENGE trial, a 3-year structured physical activity program significantly improved both disease-free survival (HR 0.72) and overall survival (HR 0.63) in patients with resected stage III or high-risk stage II colon cancer post-adjuvant chemotherapy, demonstrating a clinically meaningful additive benefit following completion of standard adjuvant chemotherapy. Mechanistically, exercise drives a multi-layered host–tumor reprogramming. Each acute exercise bout triggers transient surges of muscle-derived myokines (e.g., IL-6, SPARC) and immune-cell mobilization, enhancing natural killer and CD8⁺ T cell tumor infiltration. Cumulatively, these repeated acute pulses drive chronic adaptations, including downregulation of the pro-proliferative insulin/IGF-1 axis, attenuation of pro-tumor systemic inflammation, and microenvironmental remodeling at metastatic sites. To bridge the implementation gap, exercise oncology must transition from vague recommendations to structured, biomarker-driven clinical prescriptions defining type, dose, and duration. Mirroring the institutional success of Enhanced Recovery After Surgery (ERAS) protocols, physical activity should be systematically embedded into multidisciplinary, post-adjuvant oncologic care pathways. As the primary coordinators of colorectal cancer care, gastrointestinal surgeons must lead the transformation of exercise from optional supportive care into a validated, disease-modifying standard of care. Full article

Background: The diagnosis of adult growth hormone (GH) deficiency (GHD) relies on demonstrating a reduced GH response to stimulation tests. Excess body weight, an increasingly prevalent condition, is associated with a blunted GH response to all types of stimulation tests. Therefore, establishing body mass index (BMI)-dependent cut-offs is essential for accurate interpretation. This study aimed to identify BMI-specific diagnostic thresholds for the insulin tolerance test (ITT), using residual pituitary function as the clinical gold standard. Methods: We retrospectively analyzed 105 patients with hypothalamic-pituitary disorders who underwent ITT. GHD was defined by the presence of at least three pituitary hormone deficiencies, while preserved somatotropic function was defined by the absence of other pituitary deficits and an insulin-like growth factor-I (IGF-I) standard deviation score ≥ 0. Receiver operating characteristic (ROC) curve analysis was used to determine optimal BMI-stratified cut-offs, defined as those maximizing sensitivity (SE) and specificity (SP). Results: The optimal GH cut-off was 2.8 μg/L for patients with normal weight (SE 84.6%, SP 97.4%) and those with overweight (SE 100%, SP 92.3%), and 2.1 μg/L for patients with obesity (SE 88.2%, SP 87.5%). The area under the ROC curve was 0.968, 0.957, and 0.897 for patients with normal weight, overweight, and obesity, respectively. Conclusions: This is the first study to define GH diagnostic thresholds for the ITT according to BMI, using a clinical definition of GHD as reference. More restrictive cut-offs in patients with obesity are needed to avoid GHD overdiagnosis and potential overtreatment. These findings should be considered hypothesis-generating and require prospective external validation before routine clinical implementation. Full article

Background: Fetal growth restriction (FGR) is associated with placental dysfunction and adverse perinatal outcomes. Although insulin-like growth factor-1 (IGF-1) signaling is important for placental and fetal development, the mRNA expression, immunopositivity and potential biological significance of specific IGF-1 isoforms in FGR remain incompletely characterized. This study investigated placental IGF-1Eb mRNA expression and immunopositivity in FGR pregnancies compared with appropriate-for-gestational-age (AGA) pregnancies. Methods: A total of 62 third-trimester human placentas were analyzed, including 47 from pregnancies complicated by FGR and 15 from pregnancies with AGA fetal growth. The mRNA expression of the IGF-1Eb isoform was assessed by reverse-transcription quantitative PCR in a subset of 28 fresh placental samples. IGF-1Eb protein immunoreactivity was assessed in paraffin-embedded tissue sections. Histopathological lesions were classified according to the Amsterdam criteria, and associations with clinical, demographic, and pathological parameters were evaluated using appropriate statistical analyses. Results: IGF-1Eb mRNA expression did not differ significantly between the FGR and AGA groups. In contrast, significant differences in IGF-1Eb immunoreactivity were observed in selected placental compartments. Moderate immunoreactivity in the perivillous syncytiotrophoblast was more frequent in FGR placentas and was associated with histological features of maternal vascular malperfusion, as well as with gestational age, neonatal birth weight, placental weight, maternal body mass index, and fetal sex. Increased IGF-1Eb immunopositivity was also observed in the endothelium of maternal decidual and fetal villous vessels in FGR placentas. No significant differences were observed in IGF-1Eb immunoreactivity in the extravillous trophoblast. Conclusions: In this observational study, placental IGF-1Eb protein immunoreactivity, but not mRNA expression, differed between FGR and AGA pregnancies in selected placental compartments. These findings indicate compartment-specific differences in IGF-1Eb protein immunoreactivity, associated with FGR and placental pathological features. However, the observational and cross-sectional design does not establish causality or a functional role for IGF-1Eb in placental dysfunction. Larger prospective studies incorporating functional validation are required to clarify the biological significance of these findings. Full article

The Min pig, a Chinese indigenous breed, is valued for its excellent meat quality and stress tolerance. Nevertheless, its growth rate falls considerably short of commercial pig breeds, a pattern typical of most unselected indigenous populations, and marked individual variation further undermines its economic viability. To explore the genetic basis of this variation, we evaluated a series of nonlinear fixed-effects and mixed-effects models based on the Gompertz, Logistic, and von Bertalanffy functions using body weight records from 92 Min pigs. Model selection was based on AIC, BIC, and leave-one-out cross-validation. The best-fitting model was a Logistic nonlinear mixed-effects model with individual-level random effects on all three growth parameters (Asymptotic weight, timing parameter, and be parameter), which clearly outperformed models with simpler random-effect structures and fixed-effects models. From this model, we identified three characteristic growth transition points: the early transition point (Growth Rate Index, GRI) at 94.83 days (22.32 kg), the single inflection point (Maximum Growth Rate, MGR) at 166.06 days (52.80 kg), and the late transition point (Late Growth Rate Index, LGRI) at 237.29 days (83.29 kg), with a maximum absolute growth rate of 488.2 g/day. These points partitioned growth into initial acceleration, rapid growth, deceleration, and Asymptotic growth phases. Using individual fitted growth curves, we selected five fast-growing and five slow-growing pigs that reached approximately 90 kg during the plateau phase, defined as a predicted body weight of at least 95% of the individual Asymptotic weight. The fast-growing group reached 90 kg at 240.5 ± 20.42 days, whereas the slow-growing group reached the same weight at 286.67 ± 19.20 days. At the 90 kg slaughter weight, we collected longissimus dorsi muscle samples from these pigs during the plateau phase and performed RNA-seq. Transcriptome analysis revealed 864 differentially expressed genes between the two groups, with 540 upregulated and 324 downregulated in the fast-growing group. Pathway enrichment implicated the PI3K-Akt and TGF-β signaling pathways in muscle development, and differential expression of IGFN1, DCN, COL3A1, MYOC, COL1A2, COL1A1, and IGF2 may explain the growth variation between the groups. In summary, the Logistic mixed-effects model with individual-level random effects on all growth parameters effectively captures the growth pattern of Min pigs, and the PI3K-Akt and TGF-β pathways likely mediate growth differences in this breed. Full article

Background and Clinical Significance: Cutaneous angiosarcoma frequently metastasizes to the lungs, where it may rarely present as diffuse cystic lung disease with recurrent pneumothorax, resulting in substantial diagnostic difficulty. We report a case of pulmonary metastatic cutaneous angiosarcoma in which paired whole-genome sequencing (WGS) of the primary and metastatic lesions was performed to clarify clonal origin and characterize metastatic evolution. Case Presentation: A 65-year-old man with recurrent right-sided pneumothorax and progressive bilateral cystic lung lesions underwent skin and lung biopsies. Histopathological examination and immunohistochemistry established the diagnosis of cutaneous angiosarcoma with pulmonary metastases. Paired WGS was performed on matched scalp and lung tumor specimens to evaluate shared and lesion-specific genomic alterations, pathway enrichment, and copy-number changes. Histopathology confirmed metastatic angiosarcoma involving the lungs. WGS identified 128 shared somatic alterations, supporting a common clonal origin, together with lung-specific and skin-specific mutations indicative of continued genomic divergence. Recurrent alterations involving POT1 and FLT4 were preserved in both lesions, whereas additional POT1 and TP53 alterations were detected only in the pulmonary metastasis. Pathway analysis demonstrated preferential enrichment of IGF1–mTOR, RAS, and WNT/LRP6 signaling in the metastatic lesion, while Gene Ontology analysis suggested functional divergence associated with metastatic progression. Conclusions: Pulmonary metastatic angiosarcoma should be considered in patients presenting with unexplained diffuse cystic lung disease and recurrent pneumothorax, particularly when pathological findings are inconclusive. Paired WGS complemented conventional histopathology by confirming the metastatic origin and providing insights into clonal evolution and lesion-specific molecular alterations, highlighting its potential value in the investigation of rare metastatic malignancies. Full article

Weaning stress and antinutritional components in conventional soybean meal may impair intestinal homeostasis and growth in nursery piglets. This study compared five soybean protein sources: conventional soybean meal (SBM), rapidly expanded soybean meal (RSB), fermented soybean meal (FSBM), hydrolyzed soybean protein (HP), and extruded full-fat soybean (ESB). Two concurrent 28-day trials used 120 newly weaned piglets, with 60 piglets per trial allocated to five treatments (six pens per treatment and two piglets per pen): a single-diet trial and a dual-choice feed-preference trial. Growth, feed preference, crude protein digestibility, serum biomarkers, and colonic microbiota were evaluated. HP showed the highest in vitro and apparent crude protein digestibility and increased final body weight and average daily gain relative to SBM and RSB (p < 0.05). Compared with SBM, HP increased serum IgA, IL-2, GH, and IGF-1 and decreased TNF-α (p < 0.05). Serum antioxidant indices and microbial alpha diversity did not differ among treatments (p > 0.05). Descriptive genus-level analyses indicated a higher relative abundance of Lactobacillus in the HP and FSBM groups. Overall, HP produced the most consistent improvements in protein digestibility and selected growth and serum outcomes under the conditions of this study. Full article