Biology subjects

Ji, F.

Publications and source records attributed to Ji, F..

At least 19 recordsLinked to original sources

bioRxiv2026

Diet Quality from Midlife to Later Life Relates to Late-Life Brain Health and Verbal Memory in the SG70 Cohort

Healthy diet across adulthood is associated with better late-life cognition, but how life-course diet quality relates to brain integrity, and whether brain measures mediate diet-cognition associations, remains unclear as studies with long-term diet records and detailed neurocognitive measures are lacking. We studied 892 participants from the SG70 study, nested within the Singapore Chinese Health Study, with adherence to the Dietary Approaches to Stop Hypertension diet (DASH) assessed between 1993--2025. Dietary quality during midlife, ages 44--55 years, and early elderhood, ages 61--73 years, was examined in relation to seven cognitive domains, brain morphometry, white matter hyperintensities and free-water MRI markers in late life, ages 68--82 years. Higher DASH adherence at both life stages was significantly associated with better late-ife verbal memory, and remained so when both life stages were modelled jointly. Higher midlife DASH adherence was associated with greater white matter volume in association tracts, whereas higher early-elderhood DASH adherence was associated with lower white matter hyperintensity (deep basal ganglia and anterior periventricular regions) and lower frontal and occipital grey matter free water, suggesting lower neurovascular and inflammatory burden. Mediation analyses indicated that white matter volume accounted for 12.3% in mediating the midlife DASH--verbal memory association, while cortical free water accounted for 12.5% in mediating the early-elderhood DASH--verbal memory association. Importantly, participants whose DASH adherence improved from lower adherence in midlife to better adherence in later life showed better verbal memory and more favourable brain integrity than those with persistently low adherence. These findings identify midlife and post-midlife diet quality as modifiable life-course exposures associated with late-life cognitive resilience through differences in macrostructural and microstructural brain integrity.

neuroscience↗

bioRxiv2026

Spatial and Multi-Omics Analysis of Human Breast Cancer Reveals the Spatiotemporal Dynamics of Basal Layer Disruption

When breast cancer invasion begins and how tumor cells breach the basal barrier remain poorly defined. We profiled normal mammary ducts, ductal hyperplasia (DH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma using spatial transcriptomics, spatial proteomics and five bulk-omics layers, alongside an independent longitudinal lesion cohort. Cross-sectionally, basal/myoepithelial continuity declined most between DH and DCIS, accompanied by extracellular-matrix remodeling and altered fibroblast- and macrophage-associated signaling. EGFR-positive luminal progenitor-like cells were enriched at manually annotated basal discontinuities and were molecularly distinct, nominating a candidate leader-like population without establishing causality. In the longitudinal cohort, expression of GABRG3, TAGLN, MLPH and AZGP1 in initially benign lesions was associated with subsequent ipsilateral malignancy. These findings support a model in which progression-relevant breast tissue remodeling may begin at the DH stage and nominate cellular states and candidate biomarkers for prospective validation in breast cancer risk stratification among patients with DH.

cancer biology↗

bioRxiv2026

Active non-redundancy and viral orchestration sustain diel microbial successions in the coastal ocean

Ecosystem resilience in dynamic coastal oceans is conventionally ascribed to functional redundancy, where taxonomically distinct microbes buffer environmental fluctuations through interchangeable metabolic roles. In this study, we reveal a deterministic succession architecture sustained by active non redundancy and temporal metabolic coupling, uncovered via autonomous drone array metatranscriptomic sampling in Daya Bay, China. By resolving the transcriptional landscape into six chronometrically phased modules rather than simple time points, we demonstrate a near total renewal of the active gene pool, with greater than 90% of transcribed clusters showing phase exclusivity within approximatively a two-hour window. This radical functional reshaping exposes a tight, scale dependent taxonomic functional coupling where community composition is a strong, linear predictor of metabolic output, peaking at the genus level (p < 0.0001). Functional continuity is maintained not by redundant generalists, but by a precisely sequential relay of specialists, each optimized for transient microniches with minimal overlap between successive phases. Deep learning structural adjudication of the psbA gene pool further reveals viral orchestration of this temporal coupling, where incoming cyanophages introduce structurally distinct protein variants that sustain photosynthetic electron flow under peak irradiance. These findings redefine coastal microbiome stability as a fine-tuned rapid succession of temporal specialists rather than a redundant backdrop. We propose a fundamental revision of marine ecosystem models, shifting from passive buffering frameworks to deterministic, clock driven architectures, which may prove to be critical for forecasting microbiome responses to accelerating short term climate variability.

microbiology↗

bioRxiv2026

Tetrabromobisphenol A (TBBPA) inhibits Bacillus subtilis as a Membrane Active Antibacterial Agent

Antimicrobial resistance (AMR) is a pressing global public health crisis, necessitating novel antimicrobial agents and mechanistic insights. Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, exhibits potent activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) without inducing resistance, yet its mode of action remains unclear. Using Bacillus subtilis as a model, we investigated TBBPAs antibacterial mechanism via extensive bacterial cytological profiling, fluorescence imaging, and mutant validation. We found that TBBPA causes membrane depolarization and disruption, based on Thioflavin T release, MinD mislocalization, FM5-95 fluorescence aggregation, and propidium iodide penetration. In fact, TBBPA can destabilizes giant unilamellar lipid vesicles in vitro. The induced membrane damage triggers several downstream effects, including MreB immobilization, which impairs cell wall synthesis, inhibition of DNA replication and translation, and increased autolysin activation leading to cell lysis. In conclusion, this study suggests that TBBPA directly targets the cell membrane, causing disruption of multiple essential processes, and leads to activation of autolysins, resulting in lysis. These findings highlight TBBPAs prospective utility as an anti-Gram-positive agent; nevertheless, concerns over its potential side effects necessitate further investigations into its safety profile prior to clinical translation.

microbiology↗

bioRxiv2025

Multilevel Regulation of Skeletal Muscle Ferroptosis in Aging: Sex- and Exercise-Dependent Effects on Histological, Molecular, and Genetic Markers

BackgroundFerroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a key contributor to aging-associated skeletal muscle degeneration and dysfunction. However, the interactive effects of aging, sex, and exercise modality on ferroptosis regulatory markers at the histological, protein, and gene expression levels remain poorly understood. MethodsMale (n = 23) and female (n = 23) mice aged 7 (young) and 17 (aged) months were assigned to sedentary control, voluntary wheel running, or forced treadmill exercise. Ferroptosis in the quadriceps muscle was assessed using histological markers (e.g., fibrosis, Fe3 accumulation, 4-HNE, MDA), protein-level markers (e.g., GPX4, SLC7A11, p-AMPK, MDA, GSH/GSSG), and gene expression markers (e.g., SLC7A11, GSS, ACSL4, POR). ResultsAging significantly elevated histological indicators of ferroptosis--fibrosis, lipid peroxidation, and iron overload--regardless of sex. At the protein and gene levels, sex-dependent differences were evident: aged females exhibited lower MDA and GSSG levels and upregulation of antioxidant-related genes, compared with aged males. Both exercise interventions modulated ferroptosis markers, with forced exercise exerting more pronounced effects than voluntary exercise. Notably, aged females demonstrated the most substantial reductions in ferroptosis-related markers in response to forced exercise, indicating a significant sex-by-exercise interaction. ConclusionAging markedly increases ferroptosis-related changes in skeletal muscle, with partial sex-specific differences at the molecular level. Forced exercise provides more robust regulatory effect against ferroptosis than voluntary exercise, especially in aged females. These findings underscore the therapeutic potential of sex-specific, targeted exercise interventions for mitigating ferroptosis-mediated muscle deterioration during aging.

physiology↗

bioRxiv2025

ABCG transporter gene PstABCG2 contributes to multidrug resistance in Puccinia striiformis

The emergence of triadimefon resistance in Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust, poses a growing threat to global food security. While the novel SDHI fungicide flubeneteram exhibits high efficacy against Pst, the molecular mechanisms governing resistance to both fungicides remain largely unknown. Here, we identify the ABC transporter PstABCG2 as a key mediator of multidrug resistance (MDR) through combined transcriptomic, genetic, and biochemical analyses. First, time-series transcriptomics revealed sustained upregulation of PstABCG2 under fungicide stress, with silencing via in planta RNAi and HIGS significantly enhancing Pst sensitivity to both triadimefon and flubeneteram. Heterologous expression of PstABCG2 in a Fusarium graminearum {Delta}FgABCG2 mutant restored fungicide tolerance, confirming its efflux function. Crucially, saturation mutagenesis and structural modeling pinpointed E1184 as a critical residue for fungicide binding: the E1184Y mutation disrupted triadimefon affinity (validated by MST/ITC, {Delta}G reduced from -7.1 to -6.5 kcal/mol) but minimally impacted flubeneteram binding due to adaptive halogen-bond networks. Furthermore, we discovered that the GATA-family transcription factor PstGATA directly activates PstABCG2 expression by binding to promoter cis-elements, and silencing PstGATA phenocopied the hypersensitivity of PstABCG2-silenced isolates. The results may provide a theoretical foundation for elucidating multidrug resistance mechanisms in Pst, field resistance management, and novel fungicide target development.

pathology↗

bioRxiv2025

A global genetic interaction map of a human cell reveals conserved principles of genetic networks

We generated a genome-scale, genetic interaction network from the analysis of more than 4 million double mutants in the haploid human cell line, HAP1. The network maps [~]90,000 genetic interactions, including thousands of extreme synthetic lethal and genetic suppression interactions. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes, pathways, biological processes, and cellular compartments. Comparative analyses showed that general principles of genetic networks are conserved from yeast to human cells. A genetic interaction network mapped in a single genetic background complements the DepMap gene co-essentiality network, recapitulating many of the same biological connections and also capturing unique functional information to reveal roles of uncharacterized genes and molecular determinants of specific cancer cell line genetic dependencies.

systems biology↗

bioRxiv2025

Fbxl10/Kdm2b is required for Kmt2b/Mll2 binding across thegenome and regulates H3K4 methylation on bivalent promoters

The presence of histone modifications associated with both transcriptional repression (H3K27me3) and activation (H3K4me3) on key developmental promoters in embryonic stem cells results from the co-localization of repressive Polycomb group (PcG) and activating Trithorax group (TrxG) protein complexes. Functional interactions between PcG and TrxG on these promoters are not fully understood. Here we focus on the relationships between Fbxl10/Kdm2b, a component of a PcG complex PRC1, and Kmt2b/Mll2, an essential component of TrxG at bivalent promoters. Computational analysis of previously published data revealed genome-wide correlation between chromatin occupancies of these two proteins, suggesting potential crosstalk between Kdm2b and Mll2 at both active and repressed promoters. We tested this hypothesis experimentally and found that loss of Kdm2b resulted in depletion of Mll2 at promoters genome-wide, suggesting that Kdm2b is required for Mll2 occupancy at both bivalent and active promoters. Loss of Kdm2b or the core PRC1 component Ring1b also resulted in the reduction of H3K4me3 specifically at bivalent promoters. These findings provide a direct pathway for cooperation between PcG and TrxG at bivalent promoters, suggesting an unexpected modification to the current model of bivalency. In addition, these findings reveal genome-wide role of Kdm2b independent of the full PRC1 complex.

molecular biology↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

Super-omics and PCAS reveal rheumatoid arthritis as a tumor-like disease

Rheumatoid arthritis (RA) is a debilitating systemic autoimmune disorder that significantly impairs quality of life. To elucidate the molecular alterations in RA progression, we performed comprehensive super-omics analyses on synovial tissues from patients with joint trauma, arthritis, and RA. These analyses included transcriptomics, proteomics, metabolomics, microbiomics, and fourteen PTMs (phosphorylation, acetylation, lactylation, O-GlcNAc glycosylation, arginine monomethylation, lysine monomethylation, lysine dimethylation, lysine trimethylation, succinylation, malonylation, glutarylation, tyrosine nitration, N-glycosylation, and O-glycosylation). Additionally, we developed a protein-centered association study (PCAS) method to integrate these complex datasets. Using this approach, we identified key proteins, such as STK17B, and its interactors, which may be crucial in RA pathogenesis. Tumor-like features, including aberrant angiogenesis and epithelial-mesenchymal transition, were observed in RA, alongside the potential involvement of oncogenes and tumor suppressor genes. Finally, we constructed a molecular interaction blueprint of RA, providing a comprehensive framework for advancing RA pathogenesis, diagnosis, and therapy.

immunology↗

bioRxiv2024

Evaluation of Brain Age as a Specific Marker of Brain Health

Brain age is widely regarded as a powerful marker of general brain health. Brain age models are typically trained on large datasets to predict chronological age, which may offer advantages in predicting specific health outcomes, much like the success of finetuning large language models for specific applications. However, it is also well-accepted that machine learning models trained to directly predict specific outcomes (i.e., direct models) often outperform those trained on surrogate objectives. Therefore, despite their much larger training data, it is unclear whether brain age models outperform direct models in predicting specific brain health outcomes. Here, we compare large-scale brain age models (pretrained on 53,542 participants) and direct models for predicting specific health outcomes related to Alzheimers Disease (AD) dementia. Using anatomical T1 scans from three continents (N = 1,848), we find that summarizing brain age with a single scalar (i.e., brain age gap) led to poor prediction performance. Using higher-dimensional intermediate representations of brain age models led to better prediction, but was still worse than direct models without finetuning. Using intermediate representations of finetuned brain age models was necessary to achieve similar performance as direct models. Overall, our results do not discount brain age as a useful marker of general brain health, but suggest that using chronological age as a pretraining target might be suboptimal for predicting specific health outcomes.

neuroscience↗

bioRxiv2024

WMH-DualTasker: A Dual-Task Deep Learning Model with Self-supervised Consistency for Automated Segmentation and Visual Rating of White matter Hyperintensities - a Multicentre study

BackgroundWhite matter hyperintensities (WMH) are neuroimaging markers linked to an elevated risk of cognitive decline. WMH severity is typically assessed via visual rating scales and through volumetric segmentation. While visual rating scales are commonly used in clinical practice, they offer limited descriptive power. In contrast, supervised volumetric segmentation requires manually annotated masks, which is labor-intensive and challenging to scale for large studies. Therefore, our goal was to develop an automated deep learning model that can provide accurate and holistic quantification of WMH severity with minimal supervision. MethodsWe developed WMH-DualTasker, a deep learning model that simultaneously performs voxel-wise segmentation and visual rating score prediction. The model employs self-supervised learning with transformation-invariant consistency constraints, using WMH visual ratings (ARWMC scale, range 0-30) from clinical settings as the sole supervisory signal. Additionally, we assessed its clinical utility by applying it to identify individuals with mild cognitive impairment (MCI) and to predict dementia conversion. FindingsThe volumetric quantification performance of WMH-DualTasker was either superior to or on par with existing supervised methods, as demonstrated on the MICCAI-WMH dataset (N=60, Dice=0.602) and the SINGER dataset (N=64, Dice=0.608). Furthermore, the model exhibited strong agreement with clinical visual rating scales on an external dataset (SINGER, MAE=1.880, K=0.77). Importantly, WMH severity metrics derived from WMH-DualTasker improved predictive performance beyond conventional clinical features for MCI classification (AUC=0.718, p<0.001), MCI conversion prediction (AUC=0.652, p<0.001) using the ADNI dataset. InterpretationsWMH-DualTasker substantially reduces the reliance on labor-intensive manual annotations, facilitating more efficient and scalable quantification of WMH severity in large-scale population studies. This innovative approach has the potential to advance preventive and precision medicine by enhancing the assessment and management of vascular cognitive impairment associated with WMH. Code and model weights are publicly available at https://github.com/hzlab/WMH-DualTasker.

neuroscience↗

bioRxiv2024

TiFM2.0 - Versatile mechanical measurement and actuation in live embryos

During development, spatial-temporally patterned tissue-level stresses and mechanical properties create diverse tissue shapes. To understand the mechanics of small-scale embryonic tissues, precisely controlled sensors and actuators are needed. Previously, we reported a control-based approach named tissue force microscopy (TiFM1.0), which combines dynamic positioning and imaging of an inserted cantilever probe to directly measure and impose forces in early avian embryos. Here we present an upgraded system (TiFM2.0) that utilises interferometer positioning to minimise probe holder footprint, enhancing accessibility and imaging signal. This new design enables a double-probe configuration for bidirectional stretching, compression and stress propagation experiments. As proof-of-concept, we showcase a variety of examples of TiFM2.0 applications in chicken and zebrafish embryos, including the characterization of mechanical heterogeneities important for the morphogenesis of the chicken posterior body axis. We also present simplified designs and protocols for the replication of TiFM systems with minimal custom engineering for developmental biology labs.

developmental biology↗

bioRxiv2024

Capturing sclera anisotropy using direct collagen fiber models. Linking microstructure to macroscopic mechanical properties.

Because of the crucial role of collagen fibers on soft tissue mechanics, there is great interest in techniques to incorporate them in computational models. Recently we introduced a direct fiber modeling approach for sclera based on representing the long-interwoven fibers. Our method differs from the conventional continuum approach to modeling sclera that homogenizes the fibers and describes them as statistical distributions for each element. At large scale our method captured gross collagen fiber bundle architecture from histology and experimental intraocular pressure-induced deformations. At small scale, a direct fiber model of a sclera sample reproduced equi-biaxial experimental behavior from the literature. In this study our goal was a much more challenging task for the direct fiber modeling: to capture specimen-specific 3D fiber architecture and anisotropic mechanics of four sclera samples tested under equibiaxial and four non-equibiaxial loadings. Samples of sclera from three eyes were isolated and tested in five biaxial loadings following an approach previously reported. Using microstructural architecture from polarized light microscopy we then created specimen-specific direct fiber models. Model fiber orientations agreed well with the histological information (adjusted R2s>0.89). Through an inverse-fitting process we determined model characteristics, including specimen-specific fiber mechanical properties to match equibiaxial loading. Interestingly, the equibiaxial properties also reproduced all the non-equibiaxial behaviors. These results indicate that the direct fiber modeling method naturally accounted for tissue anisotropy within its fiber structure. Direct fiber modeling is therefore a promising approach to understand how macroscopic behavior arises from microstructure.

bioengineering↗

bioRxiv2024

Comparing continuum and direct fiber models of soft tissues.An ocular biomechanics example reveals that continuum models may artificially disrupt the strains at both the tissue and fiber levels

Collagen fibers are the main load-bearing component of soft tissues but difficult to incorporate into models. Whilst simplified homogenization models suffice for some applications, a thorough mechanistic understanding requires accurate prediction of fiber behavior, including both detailed fiber-level strains and long-distance transmission. Our goal was to compare the performance of a continuum model of the optic nerve head (ONH) built using conventional techniques with a fiber model we recently introduced which explicitly incorporates the complex 3D organization and interaction of collagen fiber bundles [1]. To ensure a fair comparison, we constructed the continuum model with identical geometrical, structural, and boundary specifications as for the fiber model. We found that: 1) although both models accurately matched the intraocular pressure (IOP)-induced globally averaged displacement responses observed in experiments, they diverged significantly in their ability to replicate specific 3D tissue-level strain patterns. Notably, the fiber model faithfully replicated the experimentally observed depth-dependent variability of radial strain, the ring-like pattern of meridional strain, and the radial pattern of circumferential strain, whereas the continuum model failed to do so; 2) the continuum model disrupted the strain transmission along each fiber, a feature captured well by the fiber model. These results demonstrate limitations of the conventional continuum models that rely on homogenization and affine deformation assumptions, which render them incapable of capturing some complex tissue-level and fiber-level deformations. Our results show that the strengths of explicit fiber modeling help capture intricate ONH biomechanics. They potentially also help modeling other fibrous tissues. Statement of SignificanceUnderstanding the mechanics of fibrous tissues is crucial for advancing knowledge of various diseases. This study uses the ONH as a test case to compare conventional continuum models with fiber models that explicitly account for the complex fiber structure. We found that the fiber model captured better the biomechanical behaviors at both the tissue level and the fiber level. The insights gained from this study demonstrate the significant potential of fiber models to advance our understanding of not only glaucoma pathophysiology but also other conditions involving fibrous soft tissues. This can contribute to the development of therapeutic strategies across a wide range of application

bioengineering↗

bioRxiv2024

Muscle Type-Specific Modulation of Autophagy Signaling in Obesity: Effects of Caloric Restriction and Exercise

BackgroundObesity causes metabolic dysregulation and contributes to various diseases, with autophagy playing a pivotal role in this process. Autophagy, a cellular recycling mechanism, is influenced by factors beyond obesity, like caloric restriction (CR) and CR combined with exercise (CR+Ex), which modulate autophagy in obesity management. However, the regulation of autophagy in skeletal muscle under conditions of obesity, CR, and CR+Ex remains poorly understood. MethodMice were divided into six groups: normal diet, normal diet CR, normal diet CR+Ex, high-fat diet, high-fat diet CR, and high-fat diet CR+Ex. All mice were fed ad libitum with either a normal or high-fat diet for the first four months, followed by the respective interventions for the subsequent four months. Body composition, motor function, and skeletal muscle autophagy signaling were assessed. ResultsObesity resulted in increased total mass, lean mass, fat mass, and fat percentage in tissue; decreased grip strength and endurance capacity. Notably, CR+Ex reduced total mass, lean mass, and fat mass in obese mice. In both normal and obese conditions, the expression of autophagy markers p62, LC3B-I, and LC3B-II is significantly higher in red muscle. Obesity leads to a reduction in cathepsin L expression, while CR further increased LC3B-I expression in red muscle. ConclusionCR+Ex proves to be an effective strategy for counteracting the adverse changes in body composition associated with obesity. Unlike red muscle, white muscle exhibits lower baseline autophagic levels and may necessitate elevated expression of autophagy-related proteins, such as cathepsin L, to mitigate the negative effects of obesity.

physiology↗

bioRxiv2024

The Impact of Frailty Syndrome on Skeletal Muscle Histology and the Preventive Effects of Exercise

Aging-induced frailty syndrome significantly impairs skeletal muscle health, yet its impact on muscle histology remains unclear. This study investigates the histological alterations in muscle associated with frailty syndrome and evaluates the preventive effects of exercise. Mice were divided into groups based on age and condition, including an exercised group. Evaluated variables include body weight, lean mass ratio, myofiber size and number, extracellular matrix (ECM) content, and myosin heavy chain isoforms. Findings indicate that frailty syndrome increases body weight and ECM content, while reducing myofiber size and number, highlighting its negative impact on skeletal muscle histology. Notably, exercise effectively mitigated these adverse changes, suggesting its potential role in preventing skeletal muscle dysfunction associated with frailty syndrome.

physiology↗

bioRxiv2024

Regulation of Ferroptosis in Obesity: Muscle Type-Specific Effects of Dietary Restriction and Exercise

BackgroundObesity is a significant global health issue and a risk factor for numerous diseases. Ferroptosis, an iron-dependent regulated cell death, is triggered by iron overload and the excessive accumulation of lipid peroxidation mediated by reactive oxygen species. Studies has identified a strong association between ferroptosis and obesity. Additionally, dietary restriction (DR) and DR combined with exercise (DR+Ex) are effective strategies for managing obesity and ferroptosis. However, the regulation of ferroptosis and its signaling pathways in skeletal muscle under conditions of obesity, DR, and DR+Ex remains poorly understood. MethodsMice were divided into four groups: normal diet, high-fat diet, high-fat DR, and high-fat DR+Ex. All mice were fed ad libitum with either a normal or high-fat diet for the first 14 weeks, followed by the respective interventions for the subsequent 8 weeks. Mice muscle ferroptosis were examined by immunohistochemistry, Hematoxylin & Eosin, Massons trichrome, Prussian blue staining, and Western-Immunoblot. ResultsThe high-fat diet resulted in increased inflammatory cell infiltration, fibrosis, and iron accumulation. Red and white muscle showed increased expression of 4-HNE, regulated by GPX4 and NCAO4, respectively. DR and DR+Ex reduced downstream 4-HNE expression by regulating GPX4 in red muscle. ConclusionDue to metabolic differences, obesity-induced ferroptosis in skeletal muscle and the regulation by DR+Ex exhibiting fiber type-specificity. Specifically, red and white muscle respond to obesity-induced ferroptosis through different pathways; red muscle can inhibit obesity-induced ferroptosis through DR+Ex by GPX4. This deepens the understanding of mechanisms related to skeletal muscle cell death and provides scientific data support for the personalized treatment of related diseases.

physiology↗