bims-instec 2025-03-30 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2025–03–30
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.
Colorectal Organoids: Models, Imaging, Omics, Therapy, Immunology, and Ethics.
FASN promotes lipid metabolism and progression in colorectal cancer via the SP1/PLA2G4B axis.
NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer.
Multiomic traits reveal that critical irinotecan-related core regulator FSTL3 promotes CRC progression and affects ferroptosis.
Methionine Metabolism Dictates PCSK9 Expression and Antitumor Potency of PD-1 Blockade in MSS Colorectal Cancer.
The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers.
Obese adipose tissue extracellular vesicles activate mitochondrial fatty acid β-oxidation to drive colonic stemness.
High Glycolysis and Lipid Metabolism Status Predicts Poor Prognosis in Colorectal Cancer Patients.
HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.
Intestinal estrogen receptor beta modulates the murine colon tumor immune microenvironment.
Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy.
Vagal pathway activation links chronic stress to decline in intestinal stem cell function.
CHI3L1 mediates radiation resistance in colorectal cancer by inhibiting ferroptosis via the p53/SLC7A11 pathway.

Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00215-3. [Epub ahead of print]44(4): 115444

KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.

Konstantin Budagyan, Alexa C Cannon, Adam Chatoff, Dorothy Benton, Alison M Kurimchak, Daniela Araiza-Olivera, Anastasiia Gerasimova, Nathaniel W Snyder, James S Duncan, Cristina Uribe-Alvarez, Jonathan Chernoff.

  Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and linked to poor prognosis and therapeutic resistance. Emerging evidence suggests that specific KRAS mutations differentially influence treatment responses. In this study, we generate isogenic Apc-null mouse colon epithelial cells with four common KRAS mutations. Transcriptomic and proteomic analyses reveal significant enrichment of cholesterol and lipid metabolism pathways in KRAS G12V cells, driven by increased SREBP1 expression and mTORC1 activation. Furthermore, KRAS G12V cells exhibit elevated ACSS2 expression and greater dependence on ACSS2 for proliferative advantage compared to other mutants. Inhibition of ACSS2 uniquely sensitizes KRAS G12V cells to MEK inhibition, highlighting a distinct therapeutic vulnerability. Finally, ACSS2 plays a critical role in early KRAS G12V adenoma development, unlike in KRAS G12D adenomas. These findings highlight mutation-specific metabolic reprogramming in KRAS-driven CRC and identify ACSS2 as a potential therapeutic target.

Keywords:  ACSS2; CP: Cancer; KRAS; acetate; acetyl-CoA; acetylation; adenoma; colorectal cancer; drug resistance; metabolism; signal transduction

DOI:  https://doi.org/10.1016/j.celrep.2025.115444
Cells. 2025 Mar 19. pii: 457. [Epub ahead of print]14(6):

Colorectal Organoids: Models, Imaging, Omics, Therapy, Immunology, and Ethics.

Martina Taglieri, Linda Di Gregorio, Serena Matis, Chiara Rosa Maria Uras, Massimo Ardy, Sara Casati, Monica Marchese, Alessandro Poggi, Lizzia Raffaghello, Roberto Benelli.

  Colorectal epithelium was the first long-term 3D organoid culture established in vitro. Identification of the key components essential for the long-term survival of the stem cell niche allowed an indefinite propagation of these cultures and the modulation of their differentiation into various lineages of mature intestinal epithelial cells. While these methods were eventually adapted to establish organoids from different organs, colorectal organoids remain a pioneering model for the development of new applications in health and disease. Several basic and applicative aspects of organoid culture, modeling, monitoring and testing are analyzed in this review. We also tackle the ethical problems of biobanking and distribution of these precious research tools, frequently confined in the laboratory of origin or condemned to destruction at the end of the project.

Keywords:  PDO; colon–rectum; culture models

DOI:  https://doi.org/10.3390/cells14060457
Cell Death Discov. 2025 Mar 28. 11(1): 122

FASN promotes lipid metabolism and progression in colorectal cancer via the SP1/PLA2G4B axis.

Xin Liu, Jiachun Lu, Xiangyu Ni, Yuxin He, Jiayu Wang, Zilin Deng, Guangbo Zhang, Tongguo Shi, Weichang Chen.

Abnormal metabolic reprogramming is essential for tumorigenesis, metastasis, and the regulation of immune responses. Fatty acid synthase (FASN), a key enzyme in lipid metabolism, plays a crucial role in these processes. However, the relationship between FASN-mediated lipid reprogramming and the immune response in colorectal cancer (CRC) remains unclear. The present study demonstrated that FASN expression is elevated in CRC tissues and is significantly associated with poor prognosis. Functional experiments revealed that FASN promotes proliferation, migration, invasion, and phosphatidylcholine (PC) production in CRC cells. Additionally, in vivo experiments revealed that FASN knockdown significantly inhibits tumor growth and the spread of CRC cells to the lungs. Mechanistically, FASN, which is upregulated in CRC tissues, drives cancer cell proliferation, metastasis, and PC metabolism through the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of natural killer (NK) cells in a PC-dependent manner. These findings provide new insights into lipid metabolism and the immunobiology of CRC, suggesting potential targets for the treatment and prevention of CRC. Schematic diagram showing the mechanism by which FASN promotes cancer cell proliferation, metastasis, and PC metabolism in CRC via the SP1/PLA2G4B axis, subsequently suppressing the antitumor response of NK cells in a PC-dependent manner. FFA free fatty acid, LPA lysophosphatidic acid, PA phosphatidate, DAG diglyceride, PC phosphatidylcholine, LPC lysophosphatidylcholine, CE cholesterol ester, TAG triacylglycerol.

DOI: https://doi.org/10.1038/s41420-025-02409-9
World J Gastroenterol. 2025 Mar 21. 31(11): 100785

NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer.

Ya-Ru Niu, Mi-Dan Xiang, Wen-Wei Yang, Yu-Ting Fang, Hai-Li Qian, Yong-Kun Sun.

   BACKGROUND: Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.
AIM: To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells.
METHODS: We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays.
RESULTS: Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition.
CONCLUSION: SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.

Keywords:  Chemotherapy resistance; Colorectal cancer; Glycolysis; NAD+; SIRT1

DOI:  https://doi.org/10.3748/wjg.v31.i11.100785
Cancer Cell Int. 2025 Mar 26. 25(1): 115

Multiomic traits reveal that critical irinotecan-related core regulator FSTL3 promotes CRC progression and affects ferroptosis.

Chengyi Huang, Bufu Tang, Wenjuan Chen, Jinggang Chen, Huojun Zhang, Minghua Bai.

   BACKGROUND: Irinotecan is a widely used chemotherapy drug in colorectal cancer (CRC). The evolution and prognosis of CRC involve complex mechanisms and depend on the drug administered, especially for irinotecan. However, the specific mechanism and prognostic role of irinotecan-related regulators remain to be elucidated.
METHODS: Data from public databases were used to explore the multiomic traits of irinotecan-related regulators through bioinformatics analysis. RT‒qPCR, western blotting, transmission electron microscopy and flow cytometry were used as experimental validations.
RESULTS: Iriscore (irinotecan-related score) was constructed based on irinotecan-related regulators, and a high iriscore predicted a poor prognosis, poor therapeutic response and the MSS/MSI-L status. Single-cell analysis revealed that FSTL3 and TMEM98 were mainly expressed in CRC stem cells. Potential transcription factors (E2F1, STAT1, and TTF2) and therapeutic drugs (telatinib) that target irinotecan-related regulators were identified. FSTL3 was the core risk irinotecan-related regulator. Some ferroptosis regulators (GPX4, HSPB1 and RGS4) and related metabolic pathways (lipid oxidation and ROS metabolism) were correlated significantly with FSTL3. In vitro, irinotecan inhibited the expression of FSTL3 and ferroptotic defence proteins (GPX4 and SLC7A11), and induced lipid peroxidation and intracellular Fe (2+) ions concentration increased.
CONCLUSIONS: We confirmed that irinotecan-related regulators, especially FSTL3, have effective prognostic value in CRC and speculated that FSTL3 may promote CRC progression and affect ferroptosis, which is beneficial for identifying candidate targeted irinotecan-related regulators and accurate individualized treatment strategies for CRC.

Keywords:  Colorectal cancer; Ferroptosis; Irinotecan; Multi-omic traits; Prognosis

DOI:  https://doi.org/10.1186/s12935-025-03753-7
Adv Sci (Weinh). 2025 Mar 24. e2501623

Methionine Metabolism Dictates PCSK9 Expression and Antitumor Potency of PD-1 Blockade in MSS Colorectal Cancer.

Qi-Long Wang, Zijie Chen, Xiaofei Lu, Huizhen Lin, Huolun Feng, Nuozhou Weng, Liwen Chen, Mengnan Liu, Li Long, Lingjun Huang, Yongmei Deng, Kehong Zheng, Xiaojun Zheng, Yong Li, Ting Cai, Jiabin Zheng, Wei Yang.

  Nutrient metabolisms are vitally interrelated to cancer progression and immunotherapy. However, the mechanisms by which nutrient metabolisms interact to remodel immune surveillance within the tumor microenvironment remain largely unexplored. Here it is demonstrated that methionine restriction inhibits the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol homeostasis and a potential target for cancer immunotherapy, in colorectal cancer (CRC) but not in the liver. Mechanistically, methionine is catabolized to S-adenosylmethionine (SAM), promoting mRNA transcription of PCSK9 through increased DNA methyltransferase 1 (DNMT1)-mediated DNA methylation and suppression of sirtuin 6 (SIRT6) expression. Furthermore, both PCSK9 inhibition and dietary methionine restriction (DMR) potentiate PD-1 blockade therapy and foster the infiltration of CD8+ T cells in Colon 26 tumor-bearing mice-a proficient mismatch repair (pMMR)/microsatellite stable (MSS) CRC model that exhibits limited response to anti-PD-1 therapy. Moreover, combining 5-fluorouracil (5-FU) chemotherapy with PCSK9 inhibition and PD-1 blockade further augments therapeutic efficacy for MSS CRC. The findings establish a mechanistic link between amino acid metabolism and cholesterol metabolism within the tumor microenvironment where tumor cells sense methionine to regulate PCSK9 expression, highlighting promising combination therapeutic strategies that may greatly benefit MSS CRC patients.

Keywords:  MSS colorectal cancer; PCSK9; immunotherapy resistance; methionine metabolism

DOI:  https://doi.org/10.1002/advs.202501623
Cell Death Differ. 2025 Mar 27.

The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers.

Vida Kufrin, Annika Seiler, Silke Brilloff, Helen Rothfuß, Sandra Küchler, Silvia Schäfer, Elahe Rahimian, Jonas Baumgarten, Li Ding, Frank Buchholz, Claudia R Ball, Martin Bornhäuser, Hanno Glimm, Marius Bill, Alexander A Wurm.

Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

DOI: https://doi.org/10.1038/s41418-025-01479-7
Cell Mol Gastroenterol Hepatol. 2025 Mar 21. pii: S2352-345X(25)00045-1. [Epub ahead of print] 101504

Obese adipose tissue extracellular vesicles activate mitochondrial fatty acid β-oxidation to drive colonic stemness.

Parsa S Haque, Desiree Goodman, Thor Kuusivuori-Robinson, Christina Coughlan, Yaritza Delgado-Deida, Joseph C Onyiah, Janos Zempleni, Arianne L Theiss.

   BACKGROUND AND AIMS: Patients with obesity and mouse models of obesity exhibit abnormalities in intestinal epithelial cells, including enhanced stemness. Adipose tissue (AT) is the largest endocrine organ secreting cytokines, hormones, and extracellular vesicles (EVs). Here, we characterized EV protein cargo from obese and non-obese AT and demonstrate the role of obese adipose-derived EVs in enhancing colonic stemness.
METHODS: EVs were isolated from visceral AT from mice fed high-fat diet to induce obesity or control matched-diet. EV cargo was characterized by unbiased proteomics. Mouse colonoids were treated with EVs and analyzed for fatty acid β-oxidation (FAO), expression of stem marker genes, stem function, and β-catenin expression and acetylation. Mice deficient in adipocyte-specific Tsg101 expression were generated to alter adipocyte EV protein cargo and colonic stemness was measured.
RESULTS: EVs secreted from obese visceral AT (Ob EVs) were significantly enriched with acyl-CoA dehydrogenase long chain (ACADL), an initiator enzyme of FAO. Compared to non-obese EVs, colonoids treated with Ob EVs exhibited increased exogenous ACADL protein expression, FAO, growth, persistence of stem/progenitor function, and increased β-catenin protein expression and acetylation that was abolished by FAO inhibition. Mice deficient in adipocyte-specific Tsg101 expression exhibited Ob EVs with altered protein expression profiles and were protected from obesity-induced enhanced colonic stemness.
CONCLUSIONS: The contents of Ob EVs are poised to fuel FAO and to promote obesity-induced stemness in the colon. Alteration of metabolism is a key mechanism of adipose-to-intestinal tissue communication elicited by EVs, thereby influencing basal colonic stem cell homeostasis during obesity.

Keywords:  ACADL; Lgr5; colon; epithelial cells; metabolism; obesity; stem cells

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101504
Curr Mol Med. 2025 Mar 25.

High Glycolysis and Lipid Metabolism Status Predicts Poor Prognosis in Colorectal Cancer Patients.

Meng Li, Maoyi Yue, Yao Chen, Gang Zhao.

   BACKGROUND: The prognosis of patients with stage III colorectal cancer (CRC) shows significant variations. The purpose of this study was to investigate the role of key regulatory proteins in glycolysis and lipid metabolism for the prognostic evaluation of stage III CRC patients.
METHODS: Utilizing the Cancer Genome Atlas (TCGA) database, we analyzed the expression of various key regulatory genes in glycolysis and lipid metabolism pathways in CRC, as well as the relationship between gene expression levels and overall survival. We selected the top two key genes exhibiting differential expression patterns in glycolysis and lipid metabolism, namely, glucose transporter type 1 (GLUT1), pyruvate kinase M2 (PKM2), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), as targets for subsequent exploration. We analyzed the effects of GLUT1, PKM2, FASN, and SCD1 on the proliferation, migration, and drug sensitivity of CRC cells in vitro. These proteins were detected by immunohistochemistry (IHC) in the clinical tissues of stage III CRC patients. Based on the intensity of IHC staining for GLUT1, PKM2, FASN and SCD1, the cumulative score from these 4 target proteins for each sample was calculated (score range from 0 to 8). The relationships between high (scores of 6-8) or low (scores of 0-5) expression of glycolysis and lipid metabolism molecules and the clinicopathological characteristics, and survival of patients were analyzed.
RESULTS: The expression disparities of the GLUT1, PKM2, FASN, and SCD1 genes were the most prominent between tumor and normal tissues. Overexpression of GLUT1, PKM2, FASN, or SCD1 significantly promoted CRC cell growth and migration, as evidenced by CCK-8, colony formation, and Transwell assays. Exogenous introduction of GLUT1, PKM2, FASN, or SCD1 increased oxaliplatin IC50 values, enhanced cell survival, and reduced early apoptosis in CRC cells exposed to oxaliplatin. High glycolysis and lipid metabolism status were associated with poor tumor differentiation, vascular or nerve invasion, and shorter overall survival. The status of glycolysis and lipid metabolism was an independent prognostic factor for stage III CRC patients.
CONCLUSION: High glycolysis and lipid metabolism status are correlated with a poor prognosis in patients with stage III colorectal cancer.

Keywords:  Colorectal cancer; combined analysis; glycolysis and lipid metabolism molecules; prognostic evaluation.

DOI:  https://doi.org/10.2174/0115665240369037250319000043
Autophagy. 2025 Mar 24. 1-22

HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.

Yan Gao, Shenao Fu, Yinghui Peng, Yulai Zhou, Jiang Zhu, Xiangyang Zhang, Changjing Cai, Ying Han, Hong Shen, Shan Zeng.

  Chemotherapy remains the primary treatment for unresectable or advanced postoperative colorectal cancers. However, its effectiveness is compromised by chemoresistance, which adversely affects patient outcomes. Dysregulated macroautophagy/autophagy is a proposed mechanism behind this resistance, with ubiquitination playing a key regulatory role. In this study, we identify the transcription factor HMBOX1 (homeobox containing 1) as a critical regulator of chemoresistance in colorectal cancer. RNA sequencing revealed that HMBOX1 is downregulated in drug-resistant colorectal cancer cells and tissues, with its low expression linked to poor prognosis. An integrated analysis of genes associated with autophagy and 5-fluorouracil (5-FU) resistance was conducted, verified in the colorectal cancer tissues of patients by single-cell RNA sequencing and immunostaining. Mass-spectrometry-based proteomics and RNA sequencing were used to elucidate the underlying molecular mechanisms. Functionally, upregulation of HMBOX1 enhances the sensitivity of colorectal cancer cells to the first-line treatment with 5-FU by inhibiting autophagy. Mechanistically, HMBOX1 promotes the transcription of the E3 ubiquitin ligase HACE1, which in turn enhances ATG5 K63-ubiquitination and subsequent proteasome-mediated degradation. This results in decreased ATG5 levels, inhibiting autophagy and thus reducing 5-FU resistance in colorectal cancer cells both in vitro and in vivo. Furthermore, we confirm that HMBOX1 expression positively correlates with HACE1 expression and inversely correlates with autophagy levels in clinical colorectal cancer tissues. Our findings suggest that HMBOX1 downregulation drives 5-FU resistance through autophagy enhancement in colorectal cancer, highlighting HMBOX1 as a potential target for improving chemosensitivity and patient prognosis.Abbreviation: 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; ATG: autophagy related; CASP3: caspase 3; C-CASP3: cleaved caspase 3; C-PARP: cleaved PARP; CCK8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CNV: copy number variation; co-IP: co-immunoprecipitation; COAD: colorectal adenocarcinoma; CQ: chloroquine; CRC: colorectal cancer; CR: complete response; FHC: fetal human colon; GEO: Gene Expression Omnibus; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; HMBOX1: homeobox containing 1; IHC: immunohistochemistry; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mIHC: multiplexed immunohistochemistry; MUT: mutant; NC: negative control; OS: overall survival; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PFS: progression-free survival; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TF: translation factor; USP22: ubiquitin specific peptidase 22; WT: wild type.

Keywords:  5-fluorouracil resistance; HMBOX1 (homeobox containing 1); autophagy; colorectal cancer; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2025.2477443
Cancer Lett. 2025 Mar 20. pii: S0304-3835(25)00227-7. [Epub ahead of print] 217661

Intestinal estrogen receptor beta modulates the murine colon tumor immune microenvironment.

Madeleine Birgersson, Matilda Holm, Carlos J Gallardo-Dodd, Baizhen Chen, Lina Stepanauskaitė, Linnea Hases, Claudia Kutter, Amena Archer, Cecilia Williams.

  Chronic inflammation contributes to the development of colorectal cancer, partly through its regulation of the microenvironment and antitumor immunity. Interestingly, women have a lower incidence of colorectal cancer, and estrogen treatment has been shown to reduce the occurrence of colorectal tumors. While intestinal estrogen receptor beta (ERβ, Esr2) can protect against colitis and colitis-induced cancer in mice, its role in shaping the tumor microenvironment remains unknown. In this study, we performed RNA sequencing to analyze the transcriptome of colonic epithelia and tumors from azoxymethane/dextran sulfate sodium-treated wild-type and intestinal ERβ knockout (ERβKOVil) mice and vehicle-treated controls. This revealed significant differences in gene expression and enriched biological processes influenced by sex and genotype, with immune-related responses being overrepresented. Deconvolution supported differential immune cell abundance and immunostaining showed that tumors from ERβKOVil mice displayed significantly increased macrophage infiltration, decreased T cell infiltration, and impaired natural killer cell infiltration. Further, ERβ mRNA levels in clinical colorectal tumors correlated with immune signaling profiles and better survival. Our findings indicate that intestinal ERβ promotes an antitumor microenvironment and could potentially affect the effectiveness of immunotherapy. These insights highlight the importance of ERβ in modulating antitumor immunity and underscore its therapeutic potential in colorectal cancer.

Keywords:  RNA sequencing; colorectal cancer; estrogen receptor beta; inflammation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217661
Cell Death Dis. 2025 Mar 25. 16(1): 206

Hypomethylation induced overexpression of PLOD3 facilitates colorectal cancer progression through TM9SF4-mediated autophagy.

Renzhong Zhu, Chuanxin Tian, Nan Gao, Zhiqiang Li, Sheng Yang, Yue Zhang, Ming Zhou, Yueming Sun, Chuan Zhang, Kangpeng Jin.

Colorectal cancer (CRC) ranks among the primary causes of human mortality globally. Numerous studies have highlighted the significant role of PLOD3 in the progression of various cancers. However, the exact function and underlying mechanisms of PLOD3 in CRC remains incompletely understood. To investigate the expression of PLOD3, qRT‒PCR, immunohistochemistry and western blotting were utilized to analyze the expression of PLOD3 in CRC tissues and adjacent normal tissues. Functional assays were conducted to assess the roles of PLOD3 both in vitro and in vivo. To elucidate the potential mechanism of PLOD3 in CRC, a range of techniques, including coimmunoprecipitation, immunofluorescence, CHX pulse-chase, and ubiquitination assays were used. As the results indicated, hypomethylation of the PLOD3 promoter leads to its over- expression in CRC, and elevated PLOD3 levels are associated with a poor prognosis. Both in vitro and in vivo models demonstrated that PLOD3 enhances CRC cell proliferation, invasion, and migration. Furthermore, through mechanistic studies, TM9SF4 was identified as a protein that interacts with PLOD3 and contributes to CRC progression by promoting autophagy. Additionally, PLOD3 could be secreted by CRC cells and secreted PLOD3 could promote CRC cells migration and invasion. These results demonstrated that PLOD3 promotes CRC progression through the PLOD3/TM9SF4 axis and could be a potential biomarker and treatment target for CRC.

DOI: https://doi.org/10.1038/s41419-025-07503-5
Cell Stem Cell. 2025 Mar 20. pii: S1934-5909(25)00084-0. [Epub ahead of print]

Vagal pathway activation links chronic stress to decline in intestinal stem cell function.

Guoying Zhang, Yannan Lian, Qingguo Li, Shudi Zhou, Lili Zhang, Liting Chen, Junzhe Tang, Hailong Liu, Ni Li, Qiang Pan, Yongqiang Gu, Naiheng Lin, Hanling Wang, Xuege Wang, Jiacheng Guo, Wei Zhang, Zige Jin, Beitao Xu, Xiao Su, Moubin Lin, Qi Han, Jun Qin.

  Chronic stress adversely affects intestinal health, but the specific neural pathways linking the brain to intestinal tissue are not fully understood. Here, we show that chronic stress-induced activation of the central amygdala-dorsal motor nucleus of the vagus (CeA-DMV) pathway accelerates premature aging and impairs the stemness of intestinal stem cells (ISCs). This pathway influences ISC function independently of the microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, the immune response, and the sympathetic nervous system (SNS). Under chronic stress, DMV-mediated vagal activation prompts cholinergic enteric neurons to release acetylcholine (ACh), which engages ISCs via the M3 muscarinic acetylcholine receptor (CHRM3). This interaction activates the p38 mitogen-activated protein kinase (MAPK) pathway, triggering growth arrest and mitochondrial fragmentation, thereby accelerating an aging-like decline in ISCs. Together, our findings provide insights into an alternative neural mechanism that links stress to intestinal dysfunction. Strategies targeting the DMV-associated vagal pathway represent potential therapeutic approaches for stress-induced intestinal diseases.

Keywords:  aging; chronic stress; intestinal stem cells; p38; the brain-gut axis; vagus

DOI:  https://doi.org/10.1016/j.stem.2025.02.016
J Transl Med. 2025 Mar 21. 23(1): 357

CHI3L1 mediates radiation resistance in colorectal cancer by inhibiting ferroptosis via the p53/SLC7A11 pathway.

Ming Jin, Hui Liu, Zhen Zheng, Shuai Fang, Yang Xi, Kaitai Liu.

   BACKGROUND: Radiotherapy is a key treatment for colorectal cancer (CRC), particularly rectal cancer; however, many patients are resistant to radiation. While it has been shown that CHI3L1 is associated with CRC progression, its specific function and regulatory mechanisms in radiation resistance remain unclear.
METHODS: The levels of CHI3L1 in CRC and normal tissue samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. To assess the effects of CHI3L1 on CRC cell proliferative, migratory, and invasive capacities, Cell Counting Kit-8 (CCK-8) and Transwell assays were performed. Radiation resistance in CRC cells with varying CHI3L1 expression levels was evaluated through colony formation assay. Western blot and immunofluorescence analyses were conducted to explore the correlation between CHI3L1 and p53 expression levels. Ferroptosis was assessed by determining reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) concentrations in cells with different CHI3L1 expression levels, and a xenograft mouse model was used to identify the molecular mechanisms of ferroptosis in vivo.
RESULTS: Significant CHI3L1 upregulated was observed in CRC tissues and was associated with promotion of malignant cell behaviors. The number of colonies in CHI3L1-overexpressing groups was significantly greater than that in the control groups following radiation, indicating increased radiation resistance in the former group. Furthermore, CHI3L1 overexpression was associated with p53 downregulation and elevated p53 ubiquitination. Notably, CHI3L1 inhibited the ferroptosis of CRC cells by suppressing p53 expression through the p53/SLC7A11 signaling pathway.
CONCLUSIONS: CHI3L1 overexpression promotes the proliferation, migration, invasion, and radiation resistance of CRC cells. Elevated CHI3L1 expression is associated with increased p53 ubiquitination and SLC7A11 upregulation. CHI3L1 promotes radiation resistance by suppressing ferroptosis in CRC cells through the p53/SLC7A11 axis.

Keywords:  CHI3L1; Colorectal cancer; Ferroptosis; P53; Radiation resistance; SLC7A11

DOI:  https://doi.org/10.1186/s12967-025-06378-6