Cancer metastasis is a leading cause of cancer-related deaths, while its underlying mechanisms remain incompletely understood. To colonize distant organs, cancer cells reprogram their metabolism to adapt to diverse environmental challenges. Therefore, elucidating the metabolic pathways that drive cancer metastasis will uncover novel biomarkers and therapeutic targets. In this study, we integrated published datasets and systematically analyzed metabolites across multiple cancer cell lines. This large-scale bioinformatic analysis revealed distinct metabolites and metabolic pathways associated with organ-specific metastasis, and underscored the crucial role of tissue of origin in shaping the metabolic landscape of metastatic tumors. Notably, the transsulfuration pathway (also known as the cysteine and methionine metabolism) was strongly enriched in cancer cells with high metastatic potential. We validated this finding in pancreatic cancer, where the pathway enzyme cystathionine β-synthase (CBS) and its metabolic products were highly expressed in metastatic cancer cells. Targeting the transsulfuration pathway either by methionine deprivation or pharmacological inhibition of CBS significantly impaired the migration and invasion of metastatic pancreatic cancer cells. Taken together, our study not only provides a global view of the altered metabolic landscape in metastasis, but also identifies the transsulfuration pathway as an oncogenic driver and a therapeutic target for pancreatic cancer metastasis.

Rice, a staple food for more than half of the global population, represents a major dietary source of toxic heavy metal(loid) exposure. Accurate quantification of the associated health risks is crucial for effective food safety management. The total concentrations of eight heavy metal(loid)s (Cr, Ni, Cu, Zn, As, Cd, Hg, and Pb) in Chinese commercial rice and their bioaccessible concentrations in cooked rice were measured. A probabilistic health risk assessment (HRA) was performed using Monte Carlo simulation, incorporating bioaccessible concentrations in cooked rice and refined exposure parameters for Chinese population. Most heavy metal(loid) concentrations in commercial rice were below national maximum allowable limits. Risk assessment based on bioaccessible concentrations in cooked rice provided estimates closer to potential exposure levels than assessments using total concentrations. The probabilistic HRA indicated potential non-carcinogenic and carcinogenic health risks associated with long-term rice consumption. Adult females and children emerged as priority groups for protection, while Cd and As were identified as key elements requiring control. A refined, bioaccessibility-based HRA framework that is more closely aligned with real-world exposure was established. A differentiated management approach integrating "Zoned Management and Tiered Control" is proposed to mitigate health risks from heavy metal(loid)s in Chinese commercial rice.

The Hippo pathway is a conserved signaling cascade that regulates development, regeneration, tissue homeostasis, and organ size through a network of protein-protein interactions (PPIs). Since its discovery in Drosophila, PPI studies have significantly contributed to defining its core kinase cascade and transcriptional machinery. Over the past two decades, advances in mass spectrometry (MS)-based proteomics have transformed Hippo pathway research from targeted assays to unbiased interactome mapping, largely expanding its regulatory and functional landscapes. In this work, we introduce MS-based biochemical approaches commonly used for analyzing PPIs, summarize historical and methodological progress in characterizing Hippo-related PPIs, highlight applications of the Hippo interactome for signaling and disease studies, and discuss future directions for improving Hippo interactome-based biological discoveries and therapeutic development. Collectively, these advances establish the Hippo pathway as a valuable model for demonstrating how MS-driven interactome analysis accelerates biological research.

Ferroptosis evasion contributes to therapeutic resistance in intrahepatic cholangiocarcinoma (ICC), yet the ubiquitin-dependent mechanisms governing this process remain poorly defined. Here, we identify ubiquitin-specific protease 5 (USP5) as a clinically relevant ferroptosis suppressor in ICC. USP5 was frequently upregulated in human ICC specimens, and elevated USP5 expression was associated with adverse clinicopathological features and poor outcomes. Mechanistically, USP5 directly interacted with heat shock protein beta-1 (HSPB1) and stabilizes HSPB1 by deubiquitination, thereby attenuating lipid peroxidation-driven ferroptosis. USP5 depletion destabilizes HSPB1, sensitizes ICC cells to ferroptosis, and limits tumor growth, whereas USP5 overexpression promotes ferroptosis resistance and tumor progression. Structure-guided virtual screening and functional validation identified hellebrigenol (Hel) as a candidate USP5 inhibitor that increases HSPB1 ubiquitination and proteasome-dependent turnover, inducing ferroptosis and suppressing ICC progression. Notably, Hel potentiated gemcitabine efficacy, resulting in pronounced tumor inhibition and improved survival. Collectively, these findings establish the USP5-HSPB1 axis as a ferroptosis checkpoint in ICC and suggest pharmacologic USP5 inhibition as a strategy to improve chemotherapy response.

Microbial metabolites can act as systemic signals that connect gut dysbiosis to tumor immune remodeling. Recently, Li et al. showed that gut microbiota-derived deoxycholic acid activates the farnesoid X receptor-nuclear factor κB-interleukin-6 axis in breast cancer cells, promoting the recruitment of granulocytic myeloid-derived suppressor cells, T helper polarization, and tumor progression. These findings offer new insights into microbial bile acid signaling in the tumor microenvironment.

Macrophage dysfunction is hallmark of atherosclerotic disease, characterized by inflammation and uptake of oxidized low-density lipoproteins. We investigate the role of the epigenetic reader bromodomain-containing protein 4 (BRD4) in orchestrating macrophage responses through interactions with the mechanosensitive transcriptional coactivators YAP/TAZ. Suppression of BRD4 via bromodomain and extra-terminal motif (BET) protein inhibitors (BETi) unveils a remarkable capacity to mitigate YAP/TAZ-driven inflammation. Knockdown of YAP, TAZ, or BRD4 in macrophages shows a significant convergence of inflammatory genes under the regulatory purview of these transcriptional regulators. In addition, persistent activation of YAP and TAZ initiates a partial inflammatory phenotype in macrophages, which is effectively ameliorated with BETi. Notably, CD36 and low-density lipoprotein receptor-1 (LOX1), pivotal receptors involved in uptake of oxidized low-density lipoprotein, emerge as direct YAP/TAZ targets. We employed a BD2-specific BETi, ABBV-744, in an AAV-PCSK9-induced atherosclerosis model to test the therapeutic potential of BET inhibition. Although reduction in cholesterol levels is modest, BETi substantially curtails plaque formation, diminishing macrophage infiltration, and suppressing the upregulation of YAP/TAZ and oxidized low-density lipoprotein uptake receptors associated with atherogenesis. Intriguingly, even in conditions marked by heightened YAP/TAZ expression induced by myeloid cell-targeted YAP/TAZ overexpression, BETi effectively dampens inflammation, mitigates foam cell formation, and disease progression. Our work underscores the considerable promise of targeting the YAP/TAZ-BRD4 axis as a therapeutic strategy for averting atherosclerosis, thereby disrupting the relentless cycle of inflammation, mechanosensory responses, and oxLDL uptake characteristic of atherosclerosis progression.

Thyroid disorders profoundly disrupt metabolism, development, growth, pubertal timing, and fertility in domestic animals. Gonadotropin-inhibitory hormone (GnIH), a key inhibitory neuropeptide regulating reproductive function, has been implicated in metabolic dysfunction-associated infertility as well as thyroid dysfunction-related pubertal abnormalities. These observations suggest potential crosstalk between GnIH and thyroid hormones (THs), positioning GnIH as a possible integrative regulator linking the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-gonadal (HPG) axes. However, the role of GnIH in the modulation of thyroid function remains poorly defined. Using the pig as a translationally relevant model for neuroendocrine research, we investigated the peripheral effects of GnIH on TH synthesis and elucidated the underlying mechanisms in female piglets. Untargeted metabolomic analysis revealed a significant reduction in serum thyroxine levels following chronic intraperitoneal administration of GnIH compared with vehicle-treated controls. Furthermore, colocalization and pharmacological analyses demonstrated that peripheral GnIH directly suppresses TH synthesis in the thyroid gland, leading to decreased circulating TH levels and activation of the negative feedback regulation within the HPT axis. These results suggest that the thyroid gland is a primary peripheral target for GnIH-induced hypothyroidism. Subsequent in vivo and in vitro studies confirmed that peripheral GnIH disrupts mitochondrial function, inducing apoptosis and oxidative stress in thyroid follicular epithelial cells and ultimately causing hypothyroidism, while its effects on proliferation followed an opposite trend. These results establish that GnIH directly inhibits TH synthesis through mitochondrial dysfunction and follicular epithelial cell apoptosis, thereby contributing to hypothyroidism pathogenesis. Our study identifies GnIH as a novel neuroendocrine regulator of thyroid function and suggests that GnIH agonists or antagonists may offer therapeutic potential for thyroid disorders and related conditions.

The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis, and organ size, and its dysregulation promotes tumorigenesis. However, the precise mechanisms of its regulation in both normal physiology and cancer remain incompletely understood. Here, we identify STK38 and STK38L (also known as NDR1 and NDR2), previously proposed as redundant kinases of LATS, as negative regulators of the Hippo pathway. STK38/L inhibit LATS by competitively binding to MOB1 and disrupting the LATS-MOB1 complex, a process independent of their kinase activity. This inhibitory mechanism is evolutionarily conserved, as the Drosophila ortholog Tricornered similarly impairs Warts-Mats complex formation, resulting in enlarged fly wing size. Pathologically, STK38L is highly expressed in ovarian cancer and required for ovarian tumor growth, and its amplification correlates with YAP activation and increased tumor sensitivity to TEAD inhibitors. Taken together, our study reveals a conserved role of STK38/L in Hippo pathway regulation, providing new insights into Hippo-dependent growth control and cancer development.

Gut microbes play a crucial role in regulating the tumor microenvironment (TME) of colorectal cancer (CRC). Nevertheless, the deep mechanism between the microbiota-TME interaction has not been well explored. In this study, we for the first time discovered that Lactobacillus intestinalis (L. intestinalis) effectively suppressed tumor growth both in the AOM/DSS-induced CRC model and the ApcMin/+ spontaneous adenoma model. Our investigation revealed that L. intestinalis increased the infiltration of immune cells, particularly dendritic cells (DC), in the TME. Mechanically, the tumor-derived CCL5 induced by L. intestinalis recruited DC chemotaxis through the NOD1/NF-κB signaling pathway. In clinical samples and datasets, we found positive correlation between L. intestinalis, CCL5 level, and the DC-related genes. Our study provided a new strategy for microbial intervention for CRC and deepened the understanding of the interaction between tumor cells and the immune microenvironment modulated by gut microbes.

Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide, driven by late-stage diagnoses and poor survival outcomes. Leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) are increasingly recognized as critical players in GC pathophysiology, though their exact roles are not fully understood. LIF, a multifunctional cytokine in the interleukin-6 family, signals through the LIFR/gp130 complex and activates oncogenic pathways such as JAK/STAT3, MAPK/ERK, and Hippo-YAP. Emerging evidence indicates that LIF drives tumor progression by promoting epithelial-mesenchymal transition, immune evasion, and chemoresistance. Clinically, high LIF expression is associated with poor prognosis, peritoneal metastasis, and resistance to chemotherapy and immunotherapy. This review explores the molecular mechanisms of LIF/LIFR signaling in GC, highlighting its potential as a prognostic biomarker and therapeutic target. MINI ABSTRACT CONCLUSION: The LIF/LIFR pathway contributing to gastric cancer is complex with context-dependent pro- versus anti-tumorigenic roles in GC progression, marking it as a significant biomarker and target for future therapies.

Glutamine homeostasis plays a crucial role in fundamental cellular processes and is often dysregulated in cancer cells; however, the underlying mechanisms governing this homeostasis remain unclear. Here, we demonstrate that enriched glutamine activates the Hippo pathway. Mechanistically, glutamine synthetase (GS) interacts with LATS1, leading to its downregulation via increased ubiquitin degradation. Glutamine supplementation reduces the expression of GS and stabilizes LATS1, leading to YAP phosphorylation and inhibition. Clinically, GS expression is associated with clinical outcomes and inversely correlated with LATS1 expression and YAP1 phosphorylation. Taken together, these results not only uncover a previously undescribed mechanism by which glutamine homeostasis regulates the Hippo pathway but also suggest a potential therapeutic strategy by targeting glutamine metabolism and key growth-related signaling pathways for cancer treatment.

Polycomb Repressive Complex 2 (PRC2) establishes H3K27me3 marks to shape spatiotemporal gene expression during embryogenesis. While its dysregulation is linked to developmental disorders, cancer, and aging, the mechanisms guiding PRC2 to specific genomic loci remain a subject of ongoing debate. A prevailing model proposes that PRC2 recruitment occurs via its intrinsic affinity for chromatin rather than through sequence-specific transcription factors. Here, we provide evidence that the maternally deposited pioneer transcription factor Foxh1 plays a critical role in directing PRC2 to specific genomic loci during zygotic genome activation in Xenopus. Foxh1 is a critical transcription factor mediating Nodal signaling, but it also plays an earlier role by pre-binding enhancers prior to signaling activation. This pre-binding is essential for forming enhanceosome complexes that trigger mesendodermal gene expression and drive gastrulation, in cooperation with other maternal transcription factors. Using maternal Foxh1-null embryos, we demonstrate that Foxh1 directly recruits Ezh2, the catalytic subunit of PRC2, to Foxh1-bound loci. Loss of Foxh1 impairs Ezh2 recruitment, leading to a global reduction in H3K27me3. These findings support a dual-function model in which Foxh1 not only activates endodermal gene expression in endoderm, but also recruits PRC2 to silence the same genes in ectoderm. This dual activity of Foxh1 allows the spatially coordinated epigenetic states of the endodermal gene regulatory program during early embryogenesis.

The growing demand for high-quality pork has prompted studies on dietary supplements like Eucommia ulmoides leaf extract (ELE). This research evaluated ELE’s impact on antioxidants, meat quality, and cecal microflora in finishing pigs. A total of 120 healthy pigs (Duroc × Large White × Landrace, 150-d old, body weight 91.50 ± 0.33 kg) was assigned to four groups, each receiving a basal diet or diet containing 0.015%, 0.030%, and 0.050% ELE. The experimental period lasted 45 d. E. ulmoides leaf extract did not affect growth performance but significantly reduced serum low density lipoprotein and total cholesterol levels (P < 0.05), and increased the glutathione levels of serum and liver (P < 0.001). Additionally, ELE decreased malondialdehyde in serum and the longissimus dorsi muscle (LDM) (P < 0.05), and enhanced superoxide dismutase activities of liver (P = 0.026) and LDM (P = 0.018). Meat quality was improved by ELE, as evidenced by a reduced drip loss (P = 0.017), while increased LDM pH, redness (a∗) value, oleic acid content, and total monounsaturated fatty acids content at the highest ELE dose (P < 0.05). Moreover, a 0.050% ELE diet significantly enhanced muscle fiber density (P = 0.034) and showed a trend towards elevating intramuscular fat content (P = 0.069). These findings revealed that 0.050% ELE up-regulated the expression of myosin heavy chain (MyHC) IIa, peroxisome proliferator activated receptor gamma, fatty acid binding protein 4, and ATP citrate lyase, while down-regulating the expression of MyHCIIb and hormone-sensitive lipase genes, confirmed by real-time quantitative PCR (RT-qPCR) validation. And ELE significantly enriched beneficial bacteria and reduced harmful bacteria at both phylum and genus levels (P < 0.05). Spearman’s analysis indicated a correlation between microflora and health and meat quality. Overall, ELE supplementation improved antioxidative status, meat quality, and structure of cecal microbiota in finishing pigs, and meat quality was correlated with the improvement in cecal microbiota.

With the unprecedented pace of global population aging, there has been a parallel epidemiological shift marked by increasing incidence rates of ulcerative colitis (UC) in geriatric populations, imposing a substantial disease burden on healthcare systems globally. The etiopathogenesis of UC in the elderly remains poorly delineated, while current therapeutic strategies require further optimization to accommodate the unique pathophysiological characteristics of elderly patients. This review systematically elucidates the three barrier dysfunction - encompassing the gut microbiota ecosystem, mucosal epithelial integrity, and immunoregulatory network - that collectively drives UC pathogenesis during biological senescence. We emphasize the therapeutic potential of barrier-targeted interventions, particularly highlighting emerging modalities including fecal microbiota transplantation, intestinal organoid regeneration techniques, mesenchymal stem cell-mediated immunomodulation, and precision-engineered Chimeric Antigen Receptor T-cell therapies. Through this multidimensional analysis, we propose a paradigm-shifting approach to UC management in the elderly, advocating for the development of tailored and evidence-based therapeutic interventions that address the complex interplay between age-related biological changes and intestinal barrier homeostasis in elderly patients.

Glutamine homeostasis plays a crucial role in fundamental cellular processes and is often dysregulated in cancer cells; however, the underlying mechanisms governing this homeostasis remain unclear. Here, we demonstrate that enriched glutamine activates the Hippo pathway. Mechanistically, glutamine synthetase (GS) interacts with LATS1, leading to its downregulation via increased ubiquitin degradation. Glutamine supplementation reduces the expression of GS and stabilizes LATS1, leading to YAP phosphorylation and inhibition. Clinically, GS expression is associated with clinical outcomes and inversely correlated with LATS1 expression and YAP1 phosphorylation. Taken together, these results not only uncover a previously undescribed mechanism by which glutamine homeostasis regulates the Hippo pathway but also suggest a potential therapeutic strategy by targeting glutamine metabolism and key growth-related signaling pathways for cancer treatment.

The MAP4K family, consisting of seven kinases (MAP4K1–7), plays crucial roles in regulating diverse cellular processes, including proliferation, differentiation, migration and apoptosis. Recent studies have highlighted their involvement in multiple signaling pathways such as mitogen-activated protein kinase, Jun N-terminal kinase and Hippo, implicating them in conditions such as cancer, autoimmune and metabolic disorders and neurodegenerative diseases. Notably, MAP4K proteins have demonstrated significant roles in cancer development and progression, including tumor growth, metastasis and immune modulation. Here we summarize current insights into the roles of individual MAP4K members in cancer and other diseases, emphasizing their distinct and overlapping functions within key signaling networks. Furthermore, we discuss the therapeutic potential of targeting MAP4K family members for cancer treatment. These kinases represent promising targets for developing novel therapies for cancer and related diseases. Future research is essential to clarify the specific molecular mechanisms of MAP4K proteins in cancer and to explore their broader relevance in health and disease. The MAP4K family of proteins plays a crucial role in various cellular processes, including cell growth and survival. The Review explores how different MAP4K proteins contribute to cancer progression and other diseases. Researchers used various methods, including genetic analysis and experiments on cell lines, to investigate the roles of MAP4K proteins. They found that these proteins are involved in key signaling pathways that regulate cell behavior. For example, MAP4K1 affects immune cell activation, whereas MAP4K4 is linked to cancer cell movement and growth. The Review highlights that MAP4K proteins can act as both promoters and suppressors of cancer, depending on the context. This dual role makes them potential targets for new cancer therapies. The researchers suggest that developing specific inhibitors for these proteins could lead to more effective treatments for cancer and other diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

The platinum-based compounds are widely used in treating various types of cancer through their heavy metal component platinum. However, the development of chemoresistance often limits their clinical effectiveness. In this study, we report the roles of heavy metal response and its associated Hippo pathway in regulating platinum-based chemotherapy. Our data show that the MTF1-dependent heavy metal response induces cancer cell resistance to platinum-based compounds both in vitro and in vivo. This resistance is mitigated by Hippo pathway-mediated phosphorylation of MTF1. Moreover, pharmacological activation of the Hippo pathway sensitizes cancer cells to platinum-based compounds. Clinically, lung adenocarcinoma (LUAD) patients with high MTF1 activity exhibit poor overall survival rates, and Hippo pathway inactivation is positively correlated with elevated MTF1 transcriptional activity in platinum-treated LUAD patients. Collectively, our findings not only unveil a critical role of the Hippo-MTF1 pathway in regulating the response to platinum-based chemotherapy, but also suggest new strategies to enhance its efficacy by targeting the heavy metal response.

Background Tissue-resident memory T (TRM) cells are a distinct subset of memory T cells that persist in non-lymphoid tissues, providing localized and rapid immune responses to infection and malignancy. Unlike circulating memory T cells, TRM cells have unique homing and functional characteristics that are shaped by the tissue microenvironment. In the gut, TRM cells play a pivotal role in maintaining mucosal immunity, exhibiting phenotypic and functional heterogeneity in different intestinal compartments and in response to aging and pathological conditions. Aim of review This review aims to systematically examine the definition, spatial heterogeneity and functional roles of intestinal TRM (iTRM) cells. It highlights their contributions to physiological immunity, their involvement in pathological processes such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their age-related dynamics. The review also explores emerging therapeutic implications of modulating iTRM cells for intestinal health and disease management. Key scientific concepts of review iTRM cells are defined by surface markers like CD69 and CD103, transcriptional regulators such as Hobit, Runx3, Blimp-1, as well as cytokine signals including TGF-β, IFN-β, IL-12. They exhibit spatial and functional heterogeneity across intestinal layers (epithelium versus lamina propria) and regions (small intestine versus colon). In IBD, iTRM cells play a dual role, contributing to both inflammation and tissue repair, whereas in CRC, specific subsets of iTRM cells (e.g., CD8+ CD103+ CD39+) are associated with enhanced antitumor immunity. Aging impacts iTRM functionality, with shifts in the CD4+/CD8+ ratio and reduced cytokine production in elderly individuals. Insights into the metabolic, transcriptional, and environmental regulation of iTRM cells provide avenues for targeted therapies in intestinal diseases, cancer immunotherapy, and interventions to delay intestinal aging.

FMD prolongs life, improves cognition and slows the ageing of the intestines. Microbiota and gut immunity may play a role.