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PubMed2025

C6ORF120 regulates hepatic lipid metabolism through PPAR signaling pathway in metabolic dysfunction-associated steatotic liver disease.

Background Emerging evidence indicates that C6ORF120 is highly expressed in the liver and may modulate immune responses in various hepatic disorders. However, its role in hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease (MASLD) is unexplored. This study aimed to elucidate the effects and potential mechanisms of C6ORF120 on hepatic lipogenesis. Methods C6ORF120 expression in MASLD was assessed using patient serum and the Gene Expression Omnibus (GEO) database. A high-fat diet-induced MASLD model was established in C6orf120-KO rats. Fatty acid-induced lipid accumulation models were generated in primary hepatocytes, HepG2 and Huh7 cells. These models were employed to investigate the effects of C6ORF120 on hepatic lipogenesis and MASLD progression. Results C6ORF120 expression was significantly upregulated in MASLD patients and obese rat models. Genetic deletion of C6ORF120 markedly alleviated high-fat diet-induced steatosis in the liver of rats. In vitro, C6orf120 gene deficiency attenuated lipid accumulation and suppressed key lipogenic genes (such as fatty acid synthase (Fasn), phospho-acetyl coenzyme carboxylase (p-ACC), sterol regulatory element binding protein-1c (Srebp1c)) in primary hepatocytes and HepG2 cells. Conversely, C6ORF120 overexpression increased lipid accumulation in HepG2 cells. RNA sequencing analysis showed that lipid metabolism pathway and peroxisome proliferators activated receptor (PPAR) signaling pathway were significantly altered in the liver of C6orf120-KO rats. We demonstrated that C6ORF120 may regulate lipid metabolism through the hepatic PPARα, which is involved in fatty acid production and lipid oxidation. Further, we found that serum C6ORF120 expression was correlated with clinical indicators in patients with MASLD. Conclusion This study preliminarily revealed a novel function for C6ORF120 in hepatic lipid metabolism via affecting the PPAR pathway. The result identifies C6ORF120 as a novel regulator of hepatic lipid metabolism through PPARα-dependent mechanisms, offering potential therapeutic targets for MASLD.

Lipid Metabolism↗

PubMed2026

Multi-omics integrative analysis provides insight into potential molecular responses to sustained high water flow in common carp (Cyprinus carpio) cultured in recirculating aquaculture.

To investigate the potential molecular responses by which water flow intensity affects the growth of common carp (Cyprinus carpio) in a recirculating aquaculture system (RAS), a control group (CG, actual water velocity 0.3 cm/s) and three sustained flow treatment groups were established, including a low-flow group (LF, 1 body length per second, bl/s), a medium-flow group (MF, 2 bl/s), and a high-flow group (HF, 3 bl/s). After 12 weeks of culture in the RAS, growth performance was compared among groups under different flow intensities. The best-performing group and the control group were then selected for the determination of intestinal digestive enzyme activities, as well as transcriptomic and whole-genome bisulfite sequencing analyses of muscle tissue. The results showed that the specific growth rate and feed intake of the HF group were significantly higher than those of the other groups (P < 0.05), whereas no significant difference in feed conversion ratio was observed among groups. Compared with the CG group, lipase activity was significantly higher in the HF group (P < 0.05), while α-amylase and trypsin activities showed increasing trends without significant differences. RNA-seq identified a total of 273 differentially expressed genes, including 72 upregulated genes and 201 downregulated genes in the HF group relative to the CG group. These genes were mainly enriched in glycolysis, pyruvate metabolism, ATP metabolism, the pentose phosphate pathway, the insulin signaling pathway, the PPAR signaling pathway, and the adipocytokine signaling pathway, indicating that sustained high water flow induced a muscle transcriptional response characterized by remodeling of energy metabolism and substrate utilization. Whole-genome bisulfite sequencing analysis showed that DNA methylation in common carp muscle occurred predominantly in the CpG context. Differentially methylated regions between the HF and CG groups were mainly distributed in transcription-related regulatory regions, including promoters, CpG islands, and CpG island shores. In promoter regions, the number of hypermethylated regions in the HF group relative to the CG group was markedly higher than that of hypomethylated regions. Integrated analysis further identified two candidate genes showing both promoter differential methylation and differential expression, namely LOC109094644 and bcorl1, suggesting that adaptation to high water flow may involve IGF-related growth regulation and remodeling of upstream transcriptional programs. The qPCR results were consistent with the transcriptomic data. Taken together, within the tested range, a sustained water flow of 3 bl/s was more conducive to the growth of common carp in the RAS, which may be associated with enhanced lipid digestion and utilization, remodeling of the muscle energy metabolic network, changes in promoter methylation, and the coordinated regulation of key candidate genes. This study provides a theoretical basis for clarifying the exercise adaptation mechanism of common carp in recirculating aquaculture and for optimizing flow velocity parameters.

Animals↗

PubMed2026

Liver transcriptome analysis revealed multiple immune processes and lipid metabolism pathways involved in the defense response of the turbot (Scophthalmus maximus) against Aeromonas salmonicida.

Aeromonas salmonicida is a significant pathogen causing notable economic losses in Scophthalmus maximus aquaculture. This study utilized Illumina sequencing technology to examine the transcriptional response characteristics of S. maximus liver at 24 h following A. salmonicida infection. A total of 2363 differentially expressed genes (DEGs) were identified when compared to the negative control group. The immunity-related Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, as well as metabolism-related PPAR signaling pathway and insulin signaling pathway, were notably enriched. Significant differences exist in the expression of key genes within the PPAR pathway, particularly cd36, acsl4a, pparαa, and plin2, all of which mediate the interaction between lipid metabolism and the immune response. These results offer valuable insights into the immunometabolic regulatory mechanism of S. maximus response to A. salmonicida infection.

Animals↗

PubMed2026

Antibacterial and preventive effects of Terminalia chebula Retz. aqueous extract and methyl gallate in American shad Alosa sapidissima (Wilson, 1981) against Aeromonas hydrophila YML1.

American shad, Alosa sapidissima (Wilson, 1981), is an economically important emerging species in recirculating aquaculture systems and photovoltaic aquaculture. However, Aeromonas hydrophila poses a threat to the healthy development of its aquaculture industry. This study investigated the effects of 95.5 mg·L-1 aqueous extract from Terminalia chebula Retz. and 318.3 mg·L-1 methyl gallate (Experiment I) and methyl gallate at 31.8-127.3 mg·L-1 (Experiment II) together with A. hydrophila YML1 challage groups (1.0 × 107 and 1.58 × 105 CFU·mL-1 in Experiments I and II) on liver morphology, hepatic enzyme profiles, and transcriptional responses in American shad. Results for Experiment I showed after high-dose pathogen infection, vacuolar degeneration and inflammatory cell infiltration were observed. In addition, caspase-3, tumor necrosis factor α (TNF-α), and malondialdehyde (MDA) contents increased significantly, and the steroid biosynthesis pathway was significantly enriched via the transcriptional analysis. However, inflammation and apoptosis remained evident after high-dose A. hydrophila YML1 infection. After treatment with 95.5 mg·L-1 T. chebula Retz. extract, triphosphopyridine nucleotide (NADPH), Fructose-1,6-bisphosphatase (FBP), and phospho fructo kinase 1 (PFK) levels decreased significantly. After treatment with 318.3 mg·L-1 methyl gallate, nicotinamide adenine dinucleotide (NADH), NADPH, PFK, caspase-3, TNF-α, and MDA contents decreased significantly. For Experiment II, caspase-3 and TNF-α also decreased in the 31.8 mg·L-1 group at 24-96 h and in the 127.3 mg·L-1 group at 96 h. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and fatty acid metabolism were also significantly enriched after methyl gallate treatment.Different expression genes (DEGs) in the cytokine-cytokine receptor interaction pathway showed a time- and dose-dependent pattern. At 48 h, the MAPK signaling pathway and apoptosis were enriched in the 95.5 mg·L-1 group, whereas at 96 h the PPAR-MAPK (mitogen-activated protein kinase) signaling pathway was enriched, with downregulation of fabp7b, soat2, cpt1ab2, and pparg. These changes were associated with inflammatory cell infiltration and increased MDA contents. Enhanced fatty acid degradation, possibly via cpt2, together with reduced fatty acid transporter transcription, may have alleviated liver injury in shad.

American shad↗

PubMed2026

Impaired leptin A signaling disrupts hepatic lipid metabolism and growth in female medaka (Oryzias latipes).

Leptin is a central regulator of appetite and energy metabolism in vertebrates, and its deficiency in mammals typically results in hyperphagia and severe obesity. In fish, however, the physiological roles of leptin remain less clearly defined, partly due to the whole genome duplication (WGD) and divergent expression patterns. In this study, we generated a leptin A (lepa) loss-of-function mutant in medaka (Oryzias latipes) using CRISPR/Cas9 to investigate the function of leptin signaling. Phenotypic analysis revealed that female homozygous mutants exhibited significantly reduced body length and body weight compared with wild-type females, indicating growth impairment. Unexpectedly, despite their lean phenotype, the female mutants developed pronounced hepatic steatosis accompanied by the formation of spongiosis hepatis structures, while no obvious fibrosis was detected. To explore the molecular mechanisms underlying these abnormalities, transcriptomic profiling of mutant livers was performed. Differentially expressed genes were significantly enriched in pathways related to lipid metabolism, including Fatty acid metabolism and PPAR signaling pathway, suggesting a potential reduction in hepatic fatty acid β-oxidation capacity. In addition, genes involved in endoplasmic reticulum stress, autophagy, and apoptosis were altered, indicating transcriptional changes in cellular stress-response pathways under leptin A deficiency. Together, these findings suggest that leptin A may play an important role in coordinating growth and hepatic lipid metabolism in medaka and highlight potential differences in leptin-mediated metabolic regulation between fish and mammals.

Animals↗

PubMed2026

Integrated Multi-omics Profiling of 2,4-dinitrochlorobenzene (DNCB)-induced Atopic Dermatitis in Mice Reveals a Coordinated Network of Barrier Dysfunction, Immune Activation, and Metabolic Reprogramming.

Atopic dermatitis (AD) is caused by a combination of epidermal barrier defect and immune imbalance. However, the molecular networks between these structural abnormalities and metabolic variations are unclear. This study aim of this research was to examine the concurrent molecular alterations in skin barrier damage and metabolic disorders in an AD-like mouse model by a multi-omics strategy. A 2,4-dinitrochlorobenzene (DNCB)-induced AD-like mouse model was established and the skin tissues were examined through the combination of transcriptomic, quantitative proteomic, and metabolomic analyses. Cross-omics correlation and network analyses were performed to identify consistently abnormal molecular pathways and crucial regulatory molecules. DNCB treatment caused severe epidermal hyperplasia, and prominent infiltration of CD3⁺ T cells, F4/80⁺ macrophages, and mast cells. Transcriptomic and proteomic analysis indicated significant disruption in keratinocyte differentiation, extracellular matrix organization, and cornified envelope formation pathways. Combined analysis detected 171 molecules which were simultaneously altered at both mRNA and protein levels, and network analysis identified FLG2 and KRT6B as central barrier-related molecules. Pathway enrichment analysis consistently showed the participation of AMPK and PPAR signaling pathways. Metabolomic analysis also revealed coordinated changes in lipid and amino acid metabolism which were closely associated with cornified envelope-associated genes and collagen-modifying enzymes. These findings indicate a close relationship between barrier, immune and metabolic regulation in DNCB-induced dermatitis and provide a multi-omics resource for future mechanistic studies of atopic skin inflammation.

Animals↗

PubMed2026

Functional characterization of lncIMF_17214 in regulating intramuscular fat deposition of yellow-feathered broilers.

Intramuscular fat (IMF) content and lipid composition are key determinants of both the nutritional value and sensory attributes of poultry meat, yet the underlying regulatory mechanisms remain insufficiently elucidated. In this study, triglyceride (TG) content was employed as a quantitative phenotypic proxy to dissect the molecular basis of IMF deposition in yellow-feathered broilers. By integrating TG phenotypic data from 315 individuals with transcriptomic profiles and whole-genome resequencing datasets, a TG-associated long noncoding RNA (lncRNA), lncIMF_17214, was identified. Functional characterization revealed that lncIMF_17214 functions as a negative regulator of lipid deposition. Specifically, its knockdown led to significant increases in TG and total cholesterol concentrations, promoted lipid droplet accumulation, and decreased shear force in breast muscle, whereas its overexpression elicited the opposite effects. Mechanistically, lncIMF_17214 interacts with the RNA-binding protein CNBP, forming a regulatory complex that inhibits lipid accumulation. Furthermore, liver-directed overexpression increased the abundance of lncIMF_17214 in plasma exosomes, while liver-directed manipulation was associated with changes in hepatic and breast-muscle lipid deposition; direct exosome-mediated transfer to intramuscular adipocytes remains to be established. Transcriptomic profiling coupled with pathway enrichment analyses demonstrated that lncIMF_17214 predominantly influences steroid biosynthesis, unsaturated fatty acid metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. This suggests that it may be involved in the regulation of these pathways, although the underlying molecular mechanisms remain to be further elucidated. Collectively, these findings define a lncIMF_17214-centered regulatory axis linking intracellular and systemic lipid metabolism and provide a robust molecular framework for the targeted improvement of meat quality traits in yellow-feathered broilers.

Breast muscle↗

PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed2026

Inheritance of the epigenetic signature and reduced intermuscular bone phenotype acquired via DNA methylation editing of the runx2 b promoter in zebrafish.

The presence of intermuscular bones (IBs) can directly affect the economic value of aquaculture fish. Although genome editing can create IB-free fish by knocking out key IB-related genes, such as runx2b, the associated DNA sequence alterations raise food safety and health concerns, limiting its breeding applications. In this study, we used CRISPR/dCas9-mediated epigenome-editing technology targeting the runx2 b promoter in zebrafish to alter DNA methylation patterns without changing the DNA sequence. Our results showed that higher runx2 b promoter methylation patterns significantly inhibited eGFP mRNA expression levels in the recombinant plasmid. Using the CRISPR/dCas9-Dnmt7 system to enhance methylation of the zebrafish runx2b promoter, we observed a significant decrease in runx2 b mRNA expression levels in the F0 generation. The IBs in the 11 th-16 th muscle segments of the adult F0 fish were significantly shorter compared with the controls. Inbreeding of fish was used to produce F1 and F2 offspring that retained these high promoter methylation levels, along with persistent runx2b expression suppression and IB development inhibition. Transcriptome sequencing analysis suggested that increasing runx2 b promoter methylation levels may synergistically induce additional epigenetic modifications, potentially affecting the PPAR signaling pathway and FoxO transcription factor regulation, which appears to inhibit osteoblast proliferation and differentiation. Overall, this study demonstrates an innovative application of epigenetic editing technology for aquaculture breeding. By precisely regulating the expression patterns of key genes for economically important traits while preserving genomic DNA integrity, this approach provides a theoretical foundation and technical support for improving fish economic traits.

Animals↗

PubMed2026

[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].

This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.

Animals↗

PubMed2026

Muscular fiber properties and multi-omics investigation of larval and adult locomotor muscle in Microhyla fissipes.

During metamorphosis, Microhyla fissipes undergoes a critical transition from an aquatic to a terrestrial lifestyle, accompanied by significant remodeling of skeletal muscle. Notably, larval tail muscle degenerates, while adult hindlimb muscle develops. However, the molecular mechanisms that orchestrate these muscle type-specific adaptations to the changing environment remain unclear. In this study, histological observation, transcriptomics, and metabolomics were integrated to compare locomotor muscles from two stages: larval muscle from tail versus adult muscle from hindlimb. Our results revealed that adult muscle fibers exhibited reduced diameter and shorter sarcomere length compared to those of tadpoles. Transcriptomic analysis identified 4103 differentially expressed genes (DEGs), including 2182 up-regulated and 1921 down-regulated genes. Up-regulated genes were mainly involved in energy metabolism and cellular homeostasis pathways, including PPAR signaling and oxidative phosphorylation, whereas down-regulated genes were associated with carbohydrate metabolism and cell proliferation pathways, such as glycolysis/gluconeogenesis and PI3K-Akt signaling. Metabolic profiling indicated a metabolic shift from anaerobic to aerobic energy production, with 57 differential metabolites identified, mainly involved in protein metabolism and insulin-related pathways. Integrated multi-omics analysis further highlighted the AMPK and FoxO signaling pathways play key roles in this process. In conclusion, our findings demonstrate that the metabolic and structural differences between larval and adult skeletal muscles are mediated by AMPK- and FoxO-dependent signaling pathways, providing novel insights into the molecular mechanisms underlying adaptive development and locomotor transition in anuran amphibians.

Animals↗

PubMed2026

Identifying the regulatory network of the key lipid metabolism transcription factor peroxisome proliferator-activated receptor in oysters.

Rising seawater temperatures driven by global warming have led to summer mass mortality events that pose significant challenges for the oyster industry. Peroxisome proliferator-activated receptor (PPAR) serves as a key transcriptional regulator of lipid metabolism and plays an essential role in thermal adaptation. However, the upstream regulatory mechanisms of PPAR remain poorly understood in marine organisms. In this study, we identified two PPAR subtypes (PPARα and PPARβ/δ) in oysters and compared transcriptomic data in different tissues and under various environmental stressors, with PPARα exhibiting higher expression levels and responsiveness to environmental stresses. We observed significantly higher PPARα gene expression levels and promoter activity in the relatively cold-tolerant Crassostrea gigas compared to C. angulata. The low expression of the inhibitory transcription factor CTNNB1 in C. gigas may contribute to higher gene expression of PPARα. Additionally, the expression genome-wide association study (eGWAS) identified 9 significant SNPs and 124 candidate regulatory genes associated with PPARα expression, including ubiquitination, phosphorylation, signaling pathways, lipid metabolism, and glucose metabolism. We provided the first experimental validation of the PPARα ubiquitination-degradation pathway in marine organisms via Co-IP, which was mediated by the E3 ligase RFWD3. The protein kinase SNF1 and signaling-related proteins PIKA and KCNK2 indirectly modulated PPARα downstream pathway activation to varying degrees. This study presents the first systematic investigation of PPARα expression regulation in marine organisms. It identifies key molecular regulators and provides novel insights into lipid metabolic regulation and molecular targets for genetic improvement of heat tolerance in oysters under global warming.

Animals↗

PubMed2026

Multi-omics integration uncovers adaptive responses of stomach and pyloric ceca to artificial feed in mandarin fish (Siniperca chuatsi).

The mandarin fish, as an obligate piscivore, is highly dependent on live bait, which restricts its intensive aquaculture. Although domestication has enabled it to partially accept formulated diets, the tissue-specific molecular adaptation mechanisms of its digestive tract to artificial feed remain unclear. In this study, we conducted an integrated analysis of mandarin fish fed with live bait or artificial diet for three weeks, combining growth performance evaluation, gastric histology, and paired transcriptomic and metabolomic analyses of the stomach and pyloric ceca. AD feeding significantly improved growth performance, while histological examination revealed marked hyperplasia of the gastric mucosa and disorganized fold structures. Transcriptomic analysis identified 5065 and 3381 differentially expressed genes in the stomach and pyloric ceca, respectively. In the stomach, the artificial diet induced a glutathione-dependent antioxidant response, accompanied by glycolytic reprogramming and coordinated upregulation of genes in the extracellular matrix (ECM)-receptor interaction signaling pathway, including those encoding collagen, laminin, and integrin. In the pyloric ceca, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation were broadly suppressed, whereas glycosaminoglycan degradation and lysosomal pathways were activated. Metabolomic analysis showed that gastric metabolites were enriched in vascular and inflammatory mediator pathways, while metabolites in the pyloric ceca were enriched in peroxisome proliferator-activated receptor (PPAR) signaling, sphingolipid signaling, and steroid hormone biosynthesis pathways. Following artificial diet feeding, integrated multi-omics analysis of the stomach revealed significant enrichment of pathways such as phospholipase D signaling, sphingolipid signaling, and arachidonic acid metabolism, accompanied by the accumulation of key metabolites including sphingosine-1-phosphate, 20-hydroxyeicosatetraenoic acid, and cellobiose. Integrated analysis of the pyloric ceca identified significantly altered pathways, including sphingolipid metabolism, alpha-linolenic acid metabolism, and glutathione metabolism, along with elevated levels of sphingosine-1-phosphate, sphingosine galactoside, and 9-hydroxy-12-oxo-10,15-octadecadienoic acid, as well as decreased glutathionylspermidine. These findings systematically unveil the tissue-specific molecular adaptation characteristics of the mandarin fish digestive tract in response to artificial feed, providing an important basis for understanding the molecular mechanisms of dietary adaptation in carnivorous fish and for optimizing artificial feed formulations.

Animals↗

PubMed2026

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD. METHODS: Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression. RESULTS: MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.

Humans↗

PubMed2026

Integrative machine learning and transcriptomic analysis reveals molecular mechanisms underlying low survival rate in larval Chinese Bahaba (Bahaba taipingensis).

Chinese Bahaba (Bahaba taipingensis) is a Class I protected marine fish endemic to China. Low larvae survival during artificial breeding severely hinder population recovery. To investigate the molecular mechanism of high mortality in larval fish, this study performed RNA-seq on liver from naturally deceased (ND) and mass-dead (MD) individuals, combined with least absolute shrinkage and selection operator (LASSO) regression and random forest (RF) algorithms to screen for core signature genes. A total of 873 differentially expressed genes (DEGs) were identified, including 112 upregulated and 761 downregulated genes. GO and KEGG enrichment analyses revealed significant enrichment in amino acid metabolism disorders, one‑carbon folate pool impairment, PPAR signaling abnormalities, ECM-receptor interaction, focal adhesion pathway, indicating widespread metabolic suppression accompanied by extracellular matrix remodeling and signaling disturbances in the livers of MD fish. MAD pre-filtering combined with dual machine learning algorithms yielded 18 robust core signature genes, among which SLC38A4, MMP1, FADD, FKBP5, and APOB were consistently identified as high-frequency core genes by both algorithms. SLC38A4 exhibited the highest importance score in the RF model and was significantly downregulated, making it the primary molecule distinguishing ND from MD phenotypes. ROC curve analysis showed that both models achieved an AUC of 1.000 (95% CI lower bound: 0.610), confirming the precise discriminatory ability of the core genes. GSEA further demonstrated significant enrichment of this core gene set in ND samples. This study provides the first systematic elucidation of the molecular mechanisms underlying liver dysfunction in low survival rate B. taipingensis, characterized by amino acid transport impairment, metabolic reprogramming, and structural remodeling, offering theoretical foundations for health assessment, early mortality risk warning, and artificial breeding conservation of this species.

Animals↗

PubMed2026

EWAS in a polyphenol dense, DNA methylation-targeted, controlled diet and lifestyle study.

BACKGROUND: Dietary and lifestyle factors can influence DNA methylation patterns. We previously reported epigenetic age attenuation following a controlled study using an 8-week polyphenol-dense, DNA methylation-targeted diet and lifestyle intervention in healthy males (Methylation Diet and Lifestyle Study), with phytonutrient/polyphenol-rich foods (green tea, oolong tea, curcumin, garlic, and berries) being most predictive of this effect. METHODS: Here we conducted an epigenome-wide association study (EWAS) in 38 participants from the Methylation Diet and Lifestyle Study. The intervention included a dietary pattern intentionally rich in substrate and cofactor nutrients for methylation pathways, and components known to alter DNA-methyltransferase (DNMT) enzyme activity. In line with prior EWAS studies with small sample sizes where FDR-significant findings are unlikely, we used pre-specified nominal P-value thresholds (0.001, 0.0001) for the exploratory analyses. RESULTS: At P < 0.001 (unadjusted), 676 differentially methylated loci (DML) were identified in the intervention group versus 286 in controls. At P < 0.0001 (unadjusted), 50 DML were identified in the intervention group compared to 13 in controls. Fifteen DML were in transcription start site-proximal regions of genes including those involved in zinc homeostasis and nutrient sensing, development and pluripotency, proteostasis and genome stability, tumor suppression, and synaptic function. A group-by-time interaction analysis identified 70 intervention-specific DML at P < 0.0001, with nominal enrichment including autophagy, mTOR signaling, and chromatin remodeling pathways. A regional DMR analysis identified 128 within-group and 129 interaction-specific DMRs. DMR functional enrichment analyses revealed convergent nominal associations with lipid metabolism (alpha-linolenic acid, lipoic acid, biosynthesis of unsaturated fatty acids, PPAR signaling, cholesterol homeostasis), central energy metabolism (TCA cycle, glycolysis/gluconeogenesis, pentose phosphate, pyruvate), and nutrient sensing (PI3K-Akt, mTOR, AMPK, autophagy as well as other pathways). As expected for the limited cohort size and short intervention duration, none of the single CpG findings or enrichment analyses survived multiple test correction and are therefore considered exploratory and hypothesis-generating only. CONCLUSION: This EWAS identified a larger number of nominally changing CpGs in the intervention group compared to controls as well as biologically coherent methylation changes. These findings provide mechanistic hypotheses for previously observed epigenetic age attenuation. Replication in larger cohorts, longer intervention durations, and functional validation remain essential.

DNA methylation↗

PubMed2026

Transcriptome analysis of brown adipose tissue in Brandt's vole treated with tannic acid under cold exposure.

BACKGROUND: Tannic acid (TA) is a hydrolysable plant secondary metabolite known to influence multiple physiological processes in animals; however, its role in regulating brown adipose tissue (BAT) thermogenesis remains poorly understood. Notably, the overwinter food caches of Brandt's voles predominantly consist of Artemisia species, which are rich in TA. This study aimed to determine whether TA contributes to cold tolerance in Brandt's voles by activating BAT thermogenesis. Adult male voles were administered TA, after which the masses of BAT and inguinal white adipose tissue (iWAT) were measured, and temperature changes in BAT, the body surface, and the rectum were recorded following exposure to - 20 °C. In addition, transcriptomic analyses of BAT were performed, and the expression and protein levels of key thermogenic markers were assessed. RESULTS: The results showed that TA reduced iWAT mass while exerting minimal effects on BAT mass. TA-treated voles exhibited significantly elevated temperatures in BAT, the body surface, and the rectum after cold exposure. Histological analyses revealed that TA treatment reduced adipocyte area in iWAT while increasing the number of nuclei in brown adipocytes in BAT. In BAT, differentially expressed genes (DEGs) in voles receiving a low TA dose were significantly enriched in pathways related to fat digestion and absorption and peroxisome proliferator-activated receptor (PPAR) signaling. In contrast, DEGs in voles administered a high TA dose were predominantly associated with brown adipocyte differentiation and the upregulation of cold-induced thermogenesis. Moreover, TA administration increased the expression of FFAR4 and UCP1, as well as the protein levels of PGC-1α, PPARγ, and UCP1 following cold exposure. CONCLUSIONS: Collectively, these findings demonstrate that TA enhances cold tolerance in Brandt's voles by promoting thermogenic gene expression and stimulating brown adipocyte differentiation in BAT, providing novel insights into the role of plant secondary metabolites in mammalian cold adaptation and herbivore-plant interactions.

Animals↗

PubMed2025

Gain-of-function PPM1D mutations attenuate ischemic stroke.

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d-/-) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d-/- mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke. Gain-of-function PPM1D mutations attenuate ischemic cerebral injury. Whole-genome sequencing data of 10,241 ischemic stroke patients from the Third Chinese National Stroke Registry (CNSR-III) identified eight patients with gain-of-function mutations in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene (17q23.2). These mutation carriers displayed improved peripheral inflammation, decreased fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Ppm1d-deficient (Ppm1d-/-) mice exhibited exacerbated stroke outcomes, characterized by enlarged infarct volumes, disrupted cerebrovascular architecture, and enhanced neuro-inflammation. Mechanistically, Ppm1d deficiency induced the disturbance of endothelial fatty acid metabolism involving the PPARα pathway. Through integrated computational modeling, virtual screening, and in vitro validation, T2755 was identified as a small molecule PPM1D stabilizer. Pharmacological PPM1D stabilization with T2755 significantly attenuated ischemic brain injury in murine models.

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