The transition from milk to solid feed after birth drives the metabolic reprogramming of the liver in mammals, yet the underlying transcriptional regulatory mechanisms remain poorly understood. In this study, we characterized the dynamic transcriptomic profiles of liver tissues in goat kids from birth to post-weaning (1 d, 2 wk, 4 wk, 8 wk, and 12 wk of age) to elucidate the competing endogenous RNA (ceRNA) regulatory network underlying metabolic adaptation. Weighted gene co-expression network analysis revealed that differentially expressed genes, including PPARG, FASN, FABP3, SCD, ELOVL5, and ELOVL6, were significantly enriched in the PPAR signaling pathway and fatty acid biosynthesis pathway and exhibited high expression during the suckling period. This expression pattern suggests active hepatic lipogenesis supporting rapid growth in suckling kids, while the reliance on endogenous lipid synthesis decreased after weaning. Additionally, we identified 567 differentially expressed long non-coding RNAs (DELs). Among these, target genes of DELs in Cluster 12 and Cluster 14 were significantly enriched in immune-related pathways, such as NF-κB and Th17 cell differentiation. Their dynamic expression patterns suggest potential roles in mediating the transition from passive to active immunity and in responding to weaning stress. Furthermore, a lipid metabolism-associated ceRNA network was constructed, including miR-154b-3p/miR-197-3p-ACACB-MSTRG.10418.2 and miR-497-5p-FASN-MSTRG.9465.3 axes. The targeting relationship within the miR-497-5p-FASN-MSTRG.9465.3 axis was experimentally validated. These findings provide novel insights into the regulatory mechanisms underlying early liver development and metabolic adaptation in ruminants.

Generation of Trp53-knockout; Klf5-overexpressing murine endodermal organoids, related to Figure 1

Cross-species transcriptomics revealed similarity between LUSC and PK-organoids, related to Figure 4

Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.

Klf5 activation boosts proliferation of colon organoids but not alveolar organoids, related to Figure 1

Activation of Ribi/OXPHOS pathways in KLF5-high LUSC samples and Klf5-overexpressing PK organoids, related to Figure 5

Mammary gland involution in dairy goats critically governs subsequent lactation initiation and milk quality, with microRNAs (miRNAs) serving as pivotal molecular regulators. This study elucidates the mechanistic interplay among chi-miR-345-3p, caspase-9 (CASP9), and transforming growth factor-β3 (TGFβ3) in regulating the proliferation and apoptosis of goat mammary epithelial cells. Results showed that chi-miR-345-3p expression was significantly downregulated in mammary tissues during late-lactation and dry periods relative to late gestation, concurrently suppressing CASP9 and TGFβ3 through direct targeting. Functionally, chi-miR-345-3p promoted proliferation of GMECs and inhibited apoptosis, whereas CASP9/TGFβ3 exerted pro-apoptotic effects. Notably, a positive feedback loop was identified between TGFβ3 and CASP9, and this axis inhibits phosphorylation of the PI3K/AKT and p38-MAPK, thereby causing cell cycle arrest and promoting GMECs apoptosis. Chi-miR-345-3p targeted CASP9/TGFβ3 to alleviate their inhibition of these pathways, up-regulate cyclin D1 (CCND1) and down-regulate p53, thereby reducing cell cycle arrest and inhibiting apoptosis, and maintaining mammary epithelial cell homeostasis. This study reveals a bidirectional regulatory loop involving chi-miR-345-3p and CASP9/TGFβ3, which precisely regulates mammary involution by integrating the inhibitory action of chi-miR-345-3p with the positive feedback between CASP9 and TGFβ3. This discovery provides potential molecular targets for extending lactation persistency and improving milk production performance in dairy goats (or dairy livestock).

Excessive STING activation underlies the pathogenesis of diverse inflammatory diseases, yet conventional inhibitors often fail to restore its physiological degradation. To address this, we designed a biomimetic STING-directed autophagy-targeting chimera (STING-ATTEC) that recapitulates the endogenous ESCRT-mediated degradation pathway, with computational modeling providing preliminary guidance for molecular optimization. The optimized STING-ATTEC was encapsulated within folate-modified cationic lipid nanoparticles (FA-LNP+), formulated with DOTAP to enhance autophagic activity and promote lysosomal trafficking. This combined strategy synergistically amplified STING degradation, leading to potent suppression of inflammatory signaling, mitigation of tissue damage, and promotion of tissue regeneration across multiple disease models. These findings illustrate a cooperative material-based strategy that enhances autophagy and enables targeted protein degradation, positioning lysosome-targeting degraders as a promising translational modality for immunomodulatory therapy.

Inhalable particulate matter (PM) has emerged as a critical yet underappreciated carcinogenic factor in lung cancer, especially affecting non-smokers and populations residing in heavily polluted regions. Epidemiological research has confirmed the link between PM exposure and lung cancer risk, but the underlying biological pathways and clinical relevance are still not well understood. Here, we provide a comprehensive synthesis of current advances in PM-associated lung carcinogenesis, from population-level risk patterns to molecular pathogenesis and translational strategies. We outline the epidemiological burden and unique clinical features of PM-related lung cancer. We then propose a "Hallmarks of PM-associated lung cancer" framework, summarizing 12 features of how lung cancer evolves under PM exposure. This involves a complex interplay of cell-intrinsic oncogenic traits induced by PM (genetic alterations, epigenetic reprogramming, metabolic remodeling, stemness) and microenvironment reshaped by PM (inflammatory responses, immune suppression, angiogenesis, and pre-metastatic niche formation). Moreover, we critically examine the technical challenges in mechanistic studies and propose future solutions. Finally, we highlight urgent opportunities for integrating PM exposure into lung cancer screening, risk stratification, and prevention policies. This review offers a comprehensive framework for strategies to downsize the impact of air pollution on global lung health.

Due to late diagnosis, high molecular diversity, and limited response to therapeutic intervention, gastrointestinal (GI) cancers result in a considerable number of cancer-related deaths. Classic clinicopathological classification and single omics analysis fail to adequately convey the extensive biological complexity related to progression of disease, developed therapy resistance and recurrence of the disease. As a result, the recent introduction of integrated multi-omics including genomics, epigenomics, transcriptomics, proteomics, metabolomics and spatial profiling as well as the emerging use of liquid biopsy is substantially reshaping our understanding of and clinical approach to GI cancers. This review summarizes developments to illustrate how the incorporation of multi-omics across GI tumors offers a better understanding of GI cancers and providing more precise and less costly ways to detect disease earlier, develop molecular subtypes of the tumors with greater accuracy for the purpose of developing an individualized risk stratification system for patients. Furthermore, the article will discuss the growing use of minimal residual disease monitoring and the use of ctDNA in guiding a patient's post-operative surveillance and treatment decision-making process. In addition, this review focuses on the value of using multi-omics-based knowledge of a tumor's microenvironment to better predict how effective immunotherapy will be and support the effective combination of drugs for the treatment of GI cancers and how targeted therapy will broaden the clinical practice landscape for developing therapeutics containing new vulnerable targets. Finally, the review provides an overview of current barriers to the implementation of multi-omics and point out to future opportunities. Collectively, emerging omics data suggest a meaningful shift toward precision oncology in gastrointestinal cancers, though widespread clinical implementation remains an active area of investigation.

Suppression of ribosome biogenesis and oxidative phosphorylation hinders the proliferation of LUSC cell lines in vitro, related to Figure 6

Background:The cachexia index (CXI) has emerged as a recognized prognostic biomarker of cancer cachexia. However, the dynamic progression of cachexia may not be fully captured by a single assessment. This study examined the impact of integrating the CXI with BMI trajectories on the survival prognosis of patients with cancer cachexia to enable early identification of high-risk populations. Methods:This is a retrospective review of clinical and pathological data from 147 patients diagnosed with cancer cachexia at Xuzhou Central Hospital between January 2019 and May 2024. Based on computed tomography images at the time of initial cancer cachexia diagnosis to calculate the L3-SMI, the CXI was calculated using serum albumin (ALB) level, neutrophil-to-lymphocyte ratio (NLR), and skeletal muscle index (SMI). Using X-tile software, gender-specific optimal cutoff values for CXI were determined, and patients were divided into low and high CXI groups. Multiple BMI measurements were collected, and BMI dynamic trajectory subtypes were identified using latent category growth mixture modeling (GMM). Cox regression analysis was performed to identify independent risk factors for overall survival (OS); Kaplan-Meier survival curves were plotted; and subgroup interactions were analyzed according to cancer type, BMI trajectory subtype, ECOG PS, and TNM stage. A heterogeneity analysis of CT-based body composition was conducted to evaluate the relationship between muscle and adipose tissue. Results:GMM revealed two types of BMI decline trajectories: Class 1 (low reserve-slow decline BMI, 58%) and Class 2 (high reserve-accelerated decline BMI, 42%). The low CXI group had a considerably shorter median OS compared to the high CXI group (4.5 vs. 8.3 months, p < 0.001), with the low CXI and Class 1 subgroup having the poorest prognosis (median OS 3.5 months vs. other subgroups, p < 0.001). Multivariate Cox regression analysis identified low CXI, ECOG PS 2-3, and TNM Stage III-IV as independent risk factors for OS (p < 0.05). Subgroup analysis showed that low CXI significantly increased the risk of death in patients with gastrointestinal cancer, Class 1, and TNM Stage III-IV (p < 0.05), and there was no interaction with cancer type, BMI trajectory subtype, ECOG PS, or TNM Stage (p > 0.05). The third lumbar spinal muscle area (L3-SMA) was weakly positively correlated with subcutaneous fat thickness (SFT) (Spearman r = 0.256, p = 0.0018). Conclusion:The combination of low CXI and Class 1 trajectory was identified as an exceedingly high-risk phenotype with markedly poor survival, mandating early intensive intervention. This novel composite model provides a critical foundation for early risk stratification and precise intervention strategies in cancer cachexia, with the potential to significantly improve patient prognosis.

The low response rate of current immune checkpoint inhibitors in cancer has necessitated the development of new immune targets.Survival and public databases analyses were performed to determine the clinical significance of immunoglobulin-like transcript 3 (ILT3). The impact of ILT3 and apolipoprotein E (APOE) on tumor-associated macrophage (TAM) recruitment and polarization were evaluated by transwell assay, flow cytometry (FCM), and real-time PCR, while their impact on T cell survival and cytotoxicity was detected by CFSE, apoptotic assay, FCM and ELISA. These pro-tumoural activity of (an ortholog of ILT3 in mouse) were verified in vivo models.Survival and public databases analyses revealed that high ILT3 expression was significantly associated with worse prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma. The same association was observed with its ligand, APOE. In vitro assays demonstrated that tumor-derived ILT3/APOE promoted recruitment and M2-like polarization of TAMs in LUAD and directly inhibited T cell proliferation and cytotoxicity. In vivo knockdown of gp49b enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell-induced tumor microenvironment immunosuppression. Furthermore, combined inhibition of gp49b and programmed cell death ligand 1 (PD-L1) showed the most drastic tumor regression in C57BL/6 mice models.Tumor-derived ILT3 overexpression suppresses anti-tumor immunity by recruiting M2-like TAMs and impairing T cell activities, while ILT3 inhibition counteracts this immunosuppression and enhances the efficacy of PD-L1 blockade in LUAD. Thus, ILT3 could be a promising novel immunotherapeutic target for combined immunotherapy.

Background: Tonsillar squamous cell carcinoma (TSCC) is characterized by a high tendency to metastasize to lymph nodes, significantly impacting the treatment modality and recurrence rates in head and neck cancer patients. Therefore, the development of accurate predictive models, such as nomograms, is imperative for the early identification of risk factors associated with lymph node involvement. Various lymph node classification systems, including the number of positive lymph nodes (NPLNs), the ratio of positive lymph nodes (pLNRs), and the logarithm of the odds of positive lymph nodes (LODDS), have been proposed to provide prognostic information. However, the optimal system for classifying lymph nodes remains uncertain, necessitating further investigation to determine which system offers the most accurate prediction of patient outcomes. Thus, our objective was to identify the most effective prognostic nomogram for predicting outcomes in TSCC patients. Material and Methods: In this study, we retrospectively analyzed data from 1,775 TSCC patients extracted from the Surveillance, Epidemiology, and End Results (SEER) database, following predefined criteria for inclusion. We evaluated the performance of prognostic models using Harrell's concordance index (C-index) and Akaike information criterion (AIC). Subsequently, variables were utilized to construct nomograms for predicting cancer-specific survival and overall survival. Nomograms' predictive capabilities were assessed using Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI). Results: The nomogram comprising pLNR, LODDS, and NPLN showed superior efficacy in predicting the survival outcome of patients with laryngectomy for TSCC. Conclusion: The nomograms developed in this study have the potential to serve as valuable tools for forecasting patient survival following surgical interventions for TSCC.

The hypothalamus is a critical organ that regulates sexual development in animals. However, current research on the hypothalamic regulation of sexual maturation in female goats remains limited. In this study, we conducted metabolomic and transcriptomic analyses on the hypothalamic tissues of female Jining grey goats at different stages of sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). A total of 418 differential metabolites (DAMs) were identified in this study, among which the abundance of metabolites such as anserine, L-histidine, carnosine, taurine, and 4-aminobutyric gradually increased with the progression of sexual development. These metabolites may regulate neuronal development and hormone secretion processes by influencing the metabolism of histidine and phenylalanine. Through combined transcriptomic and metabolomic analyses, we identified that differentially expressed genes such as mitogen-activated protein kinase kinase kinase 9 (MAP3K9), prune homolog 2 with BCH domain (PRUNE2), and potassium voltage-gated channel interacting protein 4(KCNIP4) may jointly regulate the development and energy metabolism of hypothalamic Gonadotropin-releasing hormone neurons in conjunction with DAMs, including LPC22:5, 2-Arachidonyl Glycerol ether, LPE22:5, and Lysops22:5. Additionally, we elucidated the molecular mechanism through which glutathione metabolism regulates sexual maturation in goats. In summary, this study illustrates the dynamic changes in metabolites and mRNA within hypothalamic tissue during postnatal sexual maturation in female Jining grey goats. This research may provide significant scientific insights for future animal breeding.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

Objective: The study aimed to investigate the effectiveness of the intervention on psychological resilience, negative emotions, and overall well-being of subjects with non-small cell lung cancer (NSCLC) in middle and advanced stages utilizing happiness therapy combined with positive thinking-meditation expected to provide a basis for clinical psychological intervention. Methods: One hundred patients with stage III/IV SCLC were chosen as the study population. The participants were assigned into two groups randomly, depending on a random number table: a control cohort (n = 50) and an intervention cohort (n = 50). The control group received systemic anti-tumour therapy and daily care, while the intervention group received an additional 4-week psychosocial intervention of happiness therapy and positive thinking meditation on top of the systemic anti-tumour therapy and daily care. The study used the Hospital Anxiety and Depression Scale (HADS), the Psychological Resilience Scale (CD-RISC), and the General Well-Being Scale (GWB) as assessment tools to comprehensively evaluate psychological state before and after therapy, respectively. Patients in the 2 groups were also reviewed at a 6-month follow-up to record progression-free survival (PFS) in both groups. Results: Data analysis illustrated that following intervention, the psychological resilience score (78.30 +/- 8.47) and the general well-being score (81.06 +/- 3.43) of the patients within the intervention cohort were significantly higher than the control (t = -11.13, -10.14, P < 0.001). Anxiety and depression scores in patients of the intervention group (17.80 +/- 3.47) were notably lower than those in the control group (t = 5.30, P < 0.001), and there was a different median progression-free survival (PFS) time (171.00 vs. 219.00 days, P = 0.037). Conclusion: Present study demonstrated that happiness therapy combined with positive thinking meditation as psychological intervention can improve psychological significantly enhance their overall sense of well-being, delay disease progression.

Background: Eukaryotic Initiation Factor 3C (EIF3C) represents a pivotal translational initiation factor in eukaryotes and has been shown to facilitate the progression of various neoplasms. However, its mechanistic role in ovarian cancer remains elusive. Methods: In this research, the expression of EIF3C in ovarian cancer tissues was investigated using immunohistochemistry. In addition, the assessments were made on changes in cellular proliferation, invasion, and apoptotic abilities by reducing the expression of EIF3C in ovarian cancer cells. By utilizing microarray analysis, a comparison was performed between the downregulated EIF3C group and the control group of ovarian cancer cells, revealing the genes that were expressed differently. Furthermore, the signalling pathways associated with cellular proliferation were validated. The functional role of EIF3C in vivo was investigated using a xenograft tumour model. Results: The immunohistochemical analysis showed that elevated levels of EIF3C are linked to a negative prognosis in patients with ovarian cancer. Suppression of EIF3C greatly hindered the growth and spread of SK-OV-3 and HO-8910 cells while enhancing cellular programmed cell death. Following KEGG and GSEA enrichment analyses of differentially expressed genes, the p53 signalling pathway was found to be associated with EIF3C. Suppression of EIF3C resulted in the upregulation of the p53 signalling pathway, leading to the inhibition of cell proliferation and invasion and the promotion of apoptosis. In vivo experiments demonstrated that EIF3C knockdown suppressed the growth of subcutaneous tumours in nude mice. Conclusion: There is a correlation between overexpression of EIF3C in tumour tissues of ovarian cancer patients and this is associated with a poorer prognosis. By influencing the p53 signaling pathway, EIF3C facilitates the growth and infiltration of cells in ovarian cancer.