Frontiers in Cell and Developmental Biology

Integrating multi-omics, EWAS, and reverse network toxicology to explore environmental pollutant risks in erectile dysfunction

2026-04-02

Qingtao Yang, Qi Yu, Wei Li, Xi Wei, Jiang Shi, Jun Qiao, Changshi Gu, Fa Sun, Tao Li

BackgroundErectile dysfunction (ED) is increasingly prevalent worldwide, arising from complex interactions between genetic susceptibility and environmental exposure. Real-world exposure involves complex chemical mixtures that may induce synergistic toxicity, which traditional methods struggle to elucidate. This study integrates multi-omics data with reverse network toxicology to systematically identify causal molecular targets and environmental pollutants underlying ED risk, thereby clarifying their mechanisms.MethodsWe performed summary data-based Mendelian randomization (SMR) integrating proteomic (pQTL), transcriptomic (eQTL), and DNA methylation (mQTL) data to identify plasma proteins, gene expression levels, and methylation sites causally linked to ED, with false positives excluded via HEIDI tests. The identified targets were used to screen environmental pollutants in the Comparative Toxicogenomics Database Toxicity was predicted using ADMETlab 3.0 and ProTox-III, followed by molecular docking to validate interactions. Functional assays in HUVECs assessed the role of FIS1 and the effects of benzo[a]pyrene.ResultspQTL-SMR analysis identified 28 plasma proteins significantly associated with ED risk, with consistent effects in both discovery and validation cohorts. Integrated eQTL and mQTL analyses further prioritized FIS1, TNFSF12, and CNP as core targets linked to ED at the protein, gene expression, and methylation. Multi-omics evidence revealed that distinct methylation sites within these genes differentially regulate transcription and translation, exerting different impacts on ED. Using these targets, we screened four environmental pollutants—bisphenol F, tetrabromobisphenol A, benzo[a]pyrene, and chlorpyrifos—as potential regulators. Toxicity predictions indicated mutagenic, cytotoxic, or endocrine-disrupting potential for these compounds. Molecular docking confirmed stable binding to the target proteins (binding free energy ΔG < −5.0 kcal/mol). In vitro experiments showed that inhibition of FIS1 expression suppressed HUVEC proliferation and mitochondrial function, and exposure to benzo[a]pyrene similarly impaired these processes and reduced FIS1 expression.ConclusionThis study delineates a potential “environmental pollutant–molecular target–ED” mechanistic pathway, offering new insights into the environmental etiology of ED and establishing a theoretical basis for risk assessment and targeted prevention strategies.

Precision nutrition for NAFLD: a mechanistic rationale for targeting the cytokine landscape

2026-04-01

Amin Ullah, Shanshan Hu, Bairong Shen

Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden with limited approved pharmacotherapies. This therapeutic gap necessitates exploration of alternative strategies targeting the underlying inflammatory drivers of disease progression. NAFLD pathogenesis is characterized by chronic dysregulation of the cytokine milieu, promoting the transition from simple steatosis to steatohepatitis and fibrosis. This review critically evaluates mechanistic evidence for specific nutraceuticals—omega-3 fatty acids (EPA/DHA), vitamins D, E, and B, and curcumin—in modulating these immunometabolic pathways. Accumulating evidence indicates that these agents suppress pro-inflammatory mediators (e.g., IL-6, IL-1β) and enhance anti-inflammatory signals (e.g., IL-10) through inhibition of central regulators such as NF-κB and the NLRP3 inflammasome. However, their efficacy is context-dependent, with DHA demonstrating relatively consistent anti-fibrotic effects in preclinical models, curcumin exhibiting formulation- and bioavailability-dependent benefits, and EPA and vitamin D showing variable responses across studies and disease stages. Collectively, these findings highlight cytokine-targeted precision nutrition as a promising strategy for NAFLD management and underscore the need for robust clinical trials to establish personalized therapeutic protocols.

Regulation of zygotic genome activation by the nucleocytoplasmic ratio

2026-04-01

Lily Acker, Hui Chen

During early development, embryos undergo the maternal-to-zygotic transition (MZT), when control of development shifts from maternal factors to the newly activated zygotic genome. Decades of studies in various model organisms suggest that the nucleocytoplasmic (N/C) ratio is a key regulator of zygotic genome activation (ZGA), though this relationship is more nuanced in some organisms than others. Changing the nuclear content, nucleus size or cell size has been shown to shift the timing of ZGA. Mechanistically, the N/C ratio is linked to fundamental cellular processes that regulate genome activities, including nuclear import, repressor titration, activator accumulation, cell cycle lengthening, and chromatin remodeling. In this review, we summarize the experimental evidence supporting the N/C ratio as a regulator of ZGA and describe the associated molecular mechanisms. We also discuss the limitations of the N/C ratio model, highlight species-specific differences, and examine outstanding questions.

Investigation of the mechanisms underlying the development and evolution of the mammalian cerebrum using gyrencephalic ferrets

2026-04-01

Mayuko Yoshino, Angelina I. Mosiagina, Daisuke Sano, Reona Dei, Mao Yoshida, Hiroshi Kawasaki

The mammalian cerebrum has changed notably during evolution, with increases in neurons and glial cells accompanied by its expansion and folding. Although these evolutionary changes are thought to be crucial for the acquisition of higher cognitive functions, the molecular and cellular mechanisms underlying the development and evolution of the mammalian cerebrum are still not fully understood. This is partly because of the difficulty in analyzing these mechanisms using mice only. To overcome this problem, genetic manipulation techniques for the cerebrum of gyrencephalic carnivore ferrets have been established. Gene knockout in the ferret cerebrum has also been achieved using the CRISPR/Cas9 system. In this review, we summarize recent research into the mechanisms underlying the development and evolution of the cerebrum using ferrets.

Functions and mechanisms of circular RNAs in cancer stem cells and therapy resistance

2026-04-01

Yixiao Yuan, Dahang Zhang, Juan Wang, Xiulin Jiang, Lincan Duan

Cancer stem cells (CSCs) play a central role in tumor initiation, progression, recurrence, and therapy resistance. Their abilities for self-renewal, multi-lineage differentiation, and strong resistance make conventional chemotherapy, targeted therapy, and radiotherapy insufficient to completely eradicate tumors. In recent years, circular RNAs (circRNAs), a class of novel non-coding RNAs, have been shown to regulate CSC properties through multiple mechanisms, including acting as miRNA sponges, interacting with proteins, modulating signaling pathways, and encoding small peptides. Accumulating evidence indicates that circRNAs are aberrantly expressed in CSCs across various tumor types, including liver cancer, lung cancer, breast cancer, gastric cancer, prostate cancer, ovarian cancer, glioma, and acute myeloid leukemia, influencing stemness and drug sensitivity via specific signaling pathways or regulatory networks. CircRNAs have potential as biomarkers for diagnosis, prognosis, and therapy resistance prediction, as well as promising therapeutic targets. Strategies targeting oncogenic circRNAs, such as siRNA or shRNA delivered via liposomes, can effectively suppress CSC stemness and resistance and may be combined with chemotherapy, targeted therapy, or immunotherapy. Despite challenges such as incomplete mechanistic understanding, CSC heterogeneity, and limited clinical validation, advances in single-cell sequencing, circRNA interference, and nanocarrier delivery provide new opportunities for clinical translation. Overall, circRNAs play critical roles in maintaining CSC stemness, modulating drug resistance, and promoting tumor progression, offering novel avenues for overcoming therapy-resistant CSCs and for early diagnosis, prognosis assessment, and personalized treatment.

Keeping it centered: decoding the activities that regulate yeast histone H3 variant Cse4 and confine it to centromeres

2026-04-01

Martina Greco, Joanna Klim, Peter De Wulf

The field of centromere biology was launched in 1980 with the isolation of a 120-bp centromeric DNA fragment from Saccharomyces cerevisiae. Fifteen years later, the discovery that the yeast histone H3 variant Cse4 is the conserved counterpart of human CENP-A established both proteins as the defining epigenetic marks of centromeres. Subsequent genetic screens, biochemical and molecular biology studies have elucidated how Cse4 is specifically targeted to and stably maintained at centromeres. The mislocalization of Cse4 beyond centromeres disrupts transcriptional programs and drives chromosomal instability and aneuploidy. This review traces Cse4 research from its early breakthroughs to current insights into its regulatory pathways. Although derived from yeast, these mechanistic advances provide a conceptual framework for understanding analogous, and likely conserved, processes in humans, where CENP-A biology remains less well defined but is increasingly being implicated in cancer and therapy resistance when perturbed.

Editorial: Advancements in solid tumor immunotherapy: enhancing efficacy and overcoming resistance

2026-03-31

Yi Jiang, ShaoDong Wang, Leqi Zhou, Tao Zhang, Haoran Feng, Tao Zhang

Chronic kidney disease as an active driver of digestive tract tumors: mechanistic insights and emerging management strategies

2026-03-31

Hanchi Dong, Hongliang Cao, Yirou Gong, Zihan Zhao, Keyan Wang, Xincheng Zhang, Fengchun Zhang

Digestive tract tumors (DTT), particularly gastric cancer (GC) and colorectal cancer (CRC), remain among the leading causes of cancer-related morbidity and mortality worldwide. Accumulating epidemiological evidence indicates that patients with chronic kidney disease (CKD) exhibit a significantly increased risk of developing gastrointestinal malignancies and experience worse clinical outcomes. However, the biological mechanisms underlying this association have not been comprehensively synthesized. In this review, we integrate clinical and experimental evidence to delineate how CKD functions as a systemic pro-tumorigenic condition rather than a passive comorbidity. We highlight three interrelated mechanistic axes linking CKD to DTT: (i) persistent systemic inflammation and oxidative stress, (ii) metabolic and endocrine dysregulation driven by uremic toxin accumulation, vitamin D deficiency, and mineral imbalance, and (iii) immune perturbations associated with dialysis modalities and post-transplant immunosuppression. These processes converge to disrupt gastrointestinal barrier integrity, reshape the gut microbiota, impair antitumor immune surveillance, and promote malignant transformation and tumor progression. Importantly, we discuss how CKD-specific interventions, including dialysis strategies, kidney transplantation, dietary management, and modulation of gut microbiota, may further modify gastrointestinal cancer risk. Finally, we propose CKD-oriented preventive and screening strategies for GC and CRC, emphasizing the need for risk stratification based on renal function, proteinuria, and metabolic profiles. By framing CKD as an active driver of gastrointestinal carcinogenesis, this review provides a novel integrative framework that synthesizes interconnected mechanistic pathways and explicitly links them to CKD-specific clinical management strategies, a translational perspective that informs early detection, prevention, and integrated care of DTT in patients with CKD.

The regulation of pedicle initiation by androgens in sika deer (Cervus nippon)

2026-03-31

Zhen Liu, Xiongzhi Li, Qianqian Guo, Guangyu Li, Hongmei Sun, Jiangbin Zou, Baorui Xing, Rana Waseem Akhtar, Yingyan Guo, Haiping Zhao

BackgroundDeer antlers have the potential to contribute to a range of novel biomedical models. Although androgen is undoubtedly an undisputed prerequisite for pedicle initiation (initial stage of antler formation), the molecular mechanisms underlying androgen stimulation remain unclear.MethodsFour juvenile male deer (Cervus nippon) were selected: one intact individual and three castrated ones. The castrates were further divided to receive either testosterone or vehicle injections. The antlerogenic periosteum (AP) tissues overlying each frontal crest were collected at successive time points for subsequent analyses. Proteomic analysis was performed using two-dimensional difference gel electrophoresis (2D-DIGE), while cell proliferation and differentiation were assessed through ex vivo tissue explant cultures, in vitro osteoblast induction, and transcriptomic analyses.ResultsExogenous androgen induced pedicle initiation. Among the differentially-expressed proteins (DEPs) identified, ACTB, VIM, p53, RNASEL, and CALR were notable for their direct interactions with the androgen receptor (AR). Pathways related to the cell cycle, gene expression, protein metabolism, and signal transduction were found to play key roles in activating pedicle initiation. In serum-free medium, testosterone promoted the proliferation of AP cells in ex vivo tissue explant cultures; however, it showed no effect on osteogenic differentiation of these cells.ConclusionOur findings indicate that testosterone serves as the key factor triggering pedicle initiation. However, this effect likely occurs through the promotion of AP cell proliferation rather than their osteogenic differentiation. Furthermore, the results suggest that CALR may play a pivotal role in regulating the transcription of AR downstream genes during pedicle initiation. These results provide new insights into androgen-regulated mechanisms in deer pedicle initiation.

Age-related lncRNA alterations of SDHAP2_miR-17-5p/miR-20b-5p_RAB11FIP1 ceRNA network in donor-derived human limbal epithelial cells

2026-03-30

Shangkun Ou, Shaoxia Ye, Shengpeng Zhang, Sijie Lin, Yi Mao, Liying Zhang, Xiaodong Liu, Lingyu Zhang, Huping Wu, Yiming Wu

BackgroundLimbal epithelial cells (LECs) play a crucial role in preserving ocular surface stability and ensuring the normal function of the corneal epithelium. The functional capacity of LECs diminishes with age, playing a part in the onset of ocular diseases linked to aging. Although long non-coding RNAs (lncRNAs) are key regulators of gene expression and are known to be involved in numerous ocular pathologies, their expression dynamics during aging in LECs are not yet well characterized.MethodsHigh-throughput RNA sequencing and computational analysis were utilized to characterize age-related differences in mRNA and lncRNA in human LECs derived from young and old donors. 90 lncRNAs and 177 mRNAs with significant age-associated expression changes were identified. Functional enrichment was assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A competing endogenous RNA (ceRNA) network was constructed using Cytoscape and cytoHubba, focusing on the interaction between lncRNAs, miRNAs and mRNAs.ResultsThe study identified the potential ceRNA network, SDHAP2_miR-17-5p/miR-20b-5p_RAB11FIP1, that might be crucial in age-related changes of the LECs. Quantitative RT-PCR validated the expression for SDHAP2 (downregulated), miR-17-5p (upregulated), miR-20b-5p (upregulated), and RAB11FIP1 (downregulated) in the old group, consistent with transcriptome data. Functional analysis suggested this network may be involved in oxidative stress responses and cellular senescence.ConclusionOur findings reveal age-associated lncRNA and mRNA expression alterations in human LECs and highlight the SDHAP2_miR-17-5p/miR-20b-5p_RAB11FIP1 ceRNA network as a potential molecular indicator and therapeutic entry point for age-related ocular surface diseases.