bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–12–21
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Pirin Transcriptionally Regulates PLA2G4A To Inhibit Ferroptosis in Colorectal Cancer via Lipid Profile Remodeling.
  2. Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
  3. Aneuploidy patterns in colorectal cancer.
  4. Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer.
  5. Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner.
  6. The LPA2 receptor PDZ domain affects canonical Wnt signaling in colon cancer cells.
  7. Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.
  8. ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway.
  9. Identification of intestinal enteroendocrine cell subtypes and their associated hormones in zebrafish.
  10. A cellular basis for heightened gut sensitivity in females.
  11. Targeting CTGF overcomes resistance to CSF1R inhibitors by preventing CAF activation in colorectal cancer.
  12. USP11 promotes colorectal cancer progression by stabilizing EGFR and TRAF6: a potential therapeutic target in EGFR- and TLR-driven tumorigenesis.
  1. Adv Sci (Weinh). 2025 Dec 16. e16385
    Pirin Transcriptionally Regulates PLA2G4A To Inhibit Ferroptosis in Colorectal Cancer via Lipid Profile Remodeling.
    Wei Shi, Yue Qi Ong, Prativa Majee, Esther Sm Wong, Amhed Missael Vargas Velazquez, Kerem Fidan, Pierce Kah-Hoe Chow, Wai Leong Tam, Ker Kan Tan, Iain Beehuat Tan, Vinay Tergaonkar.
      Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is a promising therapeutic target in colorectal cancer (CRC); however, its regulation remains unclear. Here, Pirin (PIR) is recognized as a ferroptosis suppressor that acts through lipid remodeling. PIR is upregulated in CRC tissues, correlating with reduced ferroptosis sensitivity and enhanced tumor growth, whereas PIR loss restricts CRC progression in vivo and in vitro. Intestinal epithelium-specific PIR deletion limits AOM/DSS-induced tumorigenesis by increasing lipid peroxidation and promoting ferroptosis. Mechanistically, ferroptosis triggers a compensatory NRF2-PIR axis, in which NRF2 binds to the PIR promoter to induce its expression. PIR deficiency downregulates PLA2G4A (encoding cPLA2α), a key arachidonic-acid-metabolizing enzyme involved in ferroptosis control. Lipidomics has shown that PIR loss increases polyunsaturated fatty acid (PUFA)-containing phospholipids and decreases monounsaturated (MUFA) and saturated (SFA) species, shifting membranes toward a ferroptosis-permissive state. Restoration of PLA2G4A rescues ferroptosis resistance in PIR-deficient cells. Targeting this pathway, either by pharmacologic inhibition of PLA2G4A with AACOCF3 or by genetic disruption of the PIR-PLA2G4A axis, enhances the efficacy of ferroptosis inducers and suppresses CRC progression. This study defines an NRF2-PIR-PLA2G4A circuit that governs ferroptosis susceptibility via lipidome remodeling and highlights its therapeutic potential in CRC.
    Keywords:  PLA2G4A; Pirin; colorectal cancer; ferroptosis; lipid metabolism
    DOI:  https://doi.org/10.1002/advs.202516385
  2. Nat Genet. 2025 Dec 18.
    Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
    Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B Malla, Nadia Nasreddin, Patricia P Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L Baird, Kathryn Pennel, June Munro, Joseph A Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A Ridgway, Crispin Miller, John R P Knight, Andrew D Campbell, Philip D Dunne, John Le Quesne, Joanne Edwards, Peter J Park, Martin Bushell, Owen J Sansom.
      Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02408-7
  3. Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01493-7. [Epub ahead of print]45(1): 116721
    Aneuploidy patterns in colorectal cancer.
    Irene C Zaalberg, Steven L C Ketelaars, Henriette C Jodal, Magnus Løberg, Mette Kalager, Gerrit A Meijer, Beatriz Carvalho, Susanne M A Lens.
      Colorectal cancers (CRCs) display recurrent, non-random patterns of chromosome gains and losses, yet the functional contribution of these aneuploidies to colorectal tumorigenesis remains unclear. Mechanistic insights into the oncogenic driver potential of aneuploidy require improved experimental models that recapitulate CRC patient-relevant aneuploidy patterns. Developing such models demands a clear understanding of how aneuploidy evolves during the progression from pre-malignant adenoma to carcinoma and how aneuploidy patterns vary across CRC subtypes. In this review, we highlight and discuss context-dependent alterations in the aneuploidy landscape of CRC, examining associations with tumor subtype, tumor stage, whole-genome doubling, TP53 status, and metastatic organotropism. Through a synthesis of the current literature and meta-analysis of publicly available bulk sequencing datasets of colorectal carcinomas and colorectal adenomas, this review provides a comprehensive CRC aneuploidy framework to guide future studies aimed at unraveling the mechanistic and clinical implications of these copy-number alterations.
    Keywords:  CP: cancer; CP: genomics; adenoma; aneuploidy; chromosomal instability; colorectal cancer; tumor evolution
    DOI:  https://doi.org/10.1016/j.celrep.2025.116721
  4. Gut. 2025 Dec 18. pii: gutjnl-2024-332243. [Epub ahead of print]
    Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer.
    Annika Osswald, Esther Wortmann, David Wylensek, Stephanie Kuhls, Olivia I Coleman, Kenneth Peuker, Anne Strigli, Quinten R Ducarmon, Martin Larralde, Wei Liang, Nicole S Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Chun-Jun Guo, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Jason M Ridlon, Rizlan Bernier-Latmani, Georg Zeller, Sebastian Zeissig, Dirk Haller, Krzysztof Flisikowski, Thomas Clavel, Soeren Ocvirk.
       BACKGROUND: Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking.
    OBJECTIVE: Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.
    DESIGN: We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.
    RESULTS: Western diet exacerbated the CRC phenotype in APC 1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta.
    CONCLUSION: This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.
    Keywords:  BILE ACID; BILE ACID METABOLISM; COLORECTAL CANCER; DIETARY - COLON CANCER; MICROBIOME
    DOI:  https://doi.org/10.1136/gutjnl-2024-332243
  5. JCI Insight. 2025 Dec 17. pii: e181032. [Epub ahead of print]
    Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner.
    Rosemary C Callahan, Jillian C Curry, Geetha Bhagavatula, Alyse W Staley, Rachel Em Schaefer, Faiz Minhajuddin, Liheng Zhou, Rane M Neuhart, Shaikh M Atif, David J Orlicky, Ian M Cartwright, Mark E Gerich, Calen A Steiner, Arianne L Theiss, Caroline Ht Hall, Sean P Colgan, Joseph C Onyiah.
      Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 is induced during colitis and tumorigenesis. We also found that HO-1 is upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids, and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and non-oxidative toxicity from heme. In vivo, epithelial HO-1 deficient mice developed significantly fewer and smaller tumors compared to littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from knockout mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: protective against acute heme toxicity, but promoting iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.
    Keywords:  Cell biology; Cell stress; Colorectal cancer; Gastroenterology; Inflammatory bowel disease
    DOI:  https://doi.org/10.1172/jci.insight.181032
  6. Cell Signal. 2025 Dec 17. pii: S0898-6568(25)00733-8. [Epub ahead of print] 112318
    The LPA2 receptor PDZ domain affects canonical Wnt signaling in colon cancer cells.
    M Cristina Castañeda-Patlán, Juan Carlos Martínez- Morales, Marco Antonio Morquecho-León, Paola Briseño-Díaz, K Helivier Solís, M Teresa Romero-Ávila, J Adolfo García-Sáinz, Martha Robles-Flores.
      Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA1 is expressed at high levels and LPA2 is low in non-malignant 112CoN cells, the opposite occurs in malignant cells, with colon cancer cells showing low LPA1 levels and high LPA2 levels. We also observed that both LPA and Wnt-3a induce strong ERK activation in all colon cell lines; these effects are not additive. Additionally, LPA and Wnt-3a stimulate β-catenin transcriptional activity and its phosphorylation at residues S552 and S675, again in a non-additive manner. We further found that LPA2 and the Wnt effectors Dvl2 and Dvl3 co-precipitate in colon cancer cells, and that the PDZ-interacting motif in the carboxyl terminus of the LPA2 receptor is critical for their direct interaction. Moreover, expressing a mutated LPA2-PDZminus receptor inhibited cell migration while increasing proliferation. Remarkably, the LPA2-PDZminus receptor negatively affected its ability to activate canonical Wnt signaling and unexpectedly, it also impaired the Wnt-3a ligand-induced activation of canonical Wnt signaling in colon cancer cells.
    Keywords:  Colon cancer; LPA(1); LPA(2); Lysophosphatidic acid; Wnt pathway; β-catenin
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112318
  7. Nat Commun. 2025 Dec 13.
    Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.
    Heming Zhou, Huarong Chen, Weixin Liu, Cong Liang, Shiyan Wang, Kai Yuan, Alvin Ho Kwan Cheung, Yuet Wu, Wei Kang, Henley Cheung, Yanqiang Ding, Qinyao Wei, Hao Su, Tianhui Li, Weimei Luo, Sujun Chen, Chi Chun Wong, Jun Yu.
      The role of RNA N6-methyladenoine (m6A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m6A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquitination and degradation. By boosting CSCs, ALKBH5 overexpression elicit chemoresistance in CSCs, PDOs and transgenic mice. Targeting of ALKBH5 by knockout or VNPs-siALKBH5 synergizes with chemotherapy to trigger tumor regression in CSCs-/PDOs-derived xenografts and ALKBH5 knockout mice. Together, we reveal that ALKBH5 is essential for colorectal CSCs and is a therapeutic target for overcoming CRC chemoresistance.
    DOI:  https://doi.org/10.1038/s41467-025-67502-0
  8. Cell Signal. 2025 Dec 15. pii: S0898-6568(25)00734-X. [Epub ahead of print] 112319
    ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway.
    Xuan He, Ming Li, Jianpeng Liu, Xiangwei Zeng.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, characterized by complex metabolic alterations and aberrant signaling pathways. Although ADAMTSL2 has been associated with tumor progression, its functional role in CRC remains unclear. In this study, we identified elevated ADAMTSL2 expression in CRC tissues from the TCGA-COADREAD cohort, where it correlated with poor patient survival. Functional experiments using HCT116 and SW620 cell lines, along with patient-derived organoids, demonstrated that ADAMTSL2 knockdown suppressed proliferation and migration. These findings were further supported by reduced tumor growth in ADAMTSL2-silenced xenograft models. Mechanistically, we uncovered a novel ADAMTSL2-Notch-ACLY axis, through which ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming. Our results establish ADAMTSL2 as a key prognostic biomarker and a potential therapeutic target in CRC, highlighting the clinical relevance of its regulation of Notch-ACLY-mediated metabolic plasticity.
    Keywords:  ACLY; ADAMTSL2; Colorectal cancer; Lipid metabolism; Notch signaling pathway
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112319
  9. PLoS Biol. 2025 Dec;23(12): e3003522
    Identification of intestinal enteroendocrine cell subtypes and their associated hormones in zebrafish.
    Margaret Morash, Richard G Kay, Erik J Soderblom, Grace H MacLean, Jia Wen, Peyton J Moore, Colin R Lickwar, Mujahid Ali Shah, Julia Ganz, Fiona M Gribble, Frank Reimann, Rodger A Liddle, John F Rawls.
      Enteroendocrine cells (EECs) are rare sensory cells in the intestinal epithelium that coordinate digestive physiology by secreting a diverse repertoire of peptide hormones. These hormones are the main effectors of EEC function, and their characterization requires direct observation by mass spectrometry due to the specialized protein cleavage and posttranslational modifications that yield their mature forms. Based on the distinct subset of hormones they predominantly secrete, EECs can be categorized into subtypes. How each EEC subtype is specified, however, remains poorly understood. Here, we describe EEC subtype differentiation and hormone production in the zebrafish. Using single-cell RNA sequencing data, we identified EEC progenitors and six EEC subtypes in zebrafish and revealed that their expression profiles are consistent across larval and adult stages. Mass spectrometry analysis of isolated zebrafish EECs identified highly processed peptides derived from 19 of 23 hormone-coding genes expressed by EECs, including a previously undescribed zebrafish secretin ortholog. We assembled reporters for zebrafish EEC subtypes to test the lineage relationships between EEC subtypes and the EEC progenitor population, which expresses neurogenin 3 (neurog3). Despite its essential role in mammalian EEC differentiation, we found that selective cytotoxic ablation of neurog3+ cells in zebrafish only reduced a subset of EEC subtypes and loss of the neurog3 gene had no impact on EEC numbers. Finally, we discovered that selective ablation of ghrelin+ EECs reduced a different subset of EEC subtypes, together suggesting that neurog3+ and ghrelin+ cells serve as distinct precursors for separate EEC subtypes. We anticipate these observations and resources will facilitate future studies in the zebrafish to discern the developmental biology, physiology, and endocrinology of EEC subtypes.
    DOI:  https://doi.org/10.1371/journal.pbio.3003522
  10. Science. 2025 Dec 18. 390(6779): 1285-1291
    A cellular basis for heightened gut sensitivity in females.
    Archana Venkataraman, Eric E Figueroa, Joel Castro, Fernanda Castro Navarro, Deepanshu Soota, Stuart M Brierley, David Julius, Holly A Ingraham.
      Visceral pain disorders, such as irritable bowel syndrome, exhibit a marked female prevalence. Enhanced signaling between enterochromaffin (EC) cells in the gut epithelium and mucosal sensory nerve fibers likely contributes to this sex bias. We identified an estrogen-responsive paracrine pathway in which two enteroendocrine cell types, peptide YY (PYY)-expressing L cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that estrogen signaling up-regulates the bacterial metabolite short-chain fatty acid receptor Olfr78 on colonic L cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells by means of NPY1R, thereby enhancing serotonin release and gut pain. We propose that hormonal fluctuations, in conjunction with internal (stress) or environmental (diet) factors, amplify this local estrogen-responsive colonic circuit, resulting in maladaptive gut sensitivity.
    DOI:  https://doi.org/10.1126/science.adz1398
  11. Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00553-1. [Epub ahead of print]6(12): 102480
    Targeting CTGF overcomes resistance to CSF1R inhibitors by preventing CAF activation in colorectal cancer.
    Bojun Wang, Yingjue Li, Mengde Shi, Yuanyu Liao, Yuli Ruan, Shuling Han, Yue Ma, Xin Guan, Rui Yang, Tianjiao Dang, Tong Wu, Zhuo Chen, Junyi Duan, Futing Bai, Yanqiao Zhang, Chao Liu.
      Targeting the colony-stimulating factor 1 receptor (CSF1R) pathway to deplete tumor-associated macrophages (TAMs) represents a promising strategy to overcome immunotherapy resistance in colorectal cancer (CRC). However, resistance to CSF1R inhibitors limits effectiveness. We find that CSF1R inhibition, while effectively reducing TAM abundance, fails to suppress tumor growth. Through imaging mass cytometry (IMC), we further reveal that the CSF1R inhibitor PLX3397 indirectly activates cancer-associated fibroblasts (CAFs), impedes T cell infiltration, and suppresses T cell function. Mechanistically, CSF1R inhibitors unexpectedly activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, which promotes connective tissue growth factor (CTGF) release and subsequent CAF activation. Critically, anti-CTGF therapy rescues CSF1R inhibitor efficacy in vivo. The addition of checkpoint immunotherapy to CSF1R inhibitor and anti-CTGF in animal models leads to complete tumor regression. This combination strategy presents a potential approach to enhance the efficacy of immune checkpoint inhibitors in CRC.
    Keywords:  CSF1R inhibitor; CTGF; cancer-associated fibroblasts; colorectal cancer; immunotherapy; stromal reprogramming
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102480
  12. Cell Death Dis. 2025 Dec 19. 16(1): 894
    USP11 promotes colorectal cancer progression by stabilizing EGFR and TRAF6: a potential therapeutic target in EGFR- and TLR-driven tumorigenesis.
    Ji Hye Shin, Ji Young Kim, Seo Hyun Kim, Yeeun Kang, Ha-Jeong Lee, Mi-Jeong Kim, Jimin Choi, Soo-Kyung Jeong, Si-On Park, Yong Beom Cho, Kyeong Kyu Kim, Jae-Hyuck Shim, Eunyoung Chun, Ki-Young Lee.
      Ubiquitin-specific proteases (USPs) are key regulators of protein homeostasis and have been implicated in various aspects of cancer development, including colorectal cancer (CRC). In this study, we investigated the role of USP11 in CRC pathogenesis. RNA-seq analysis of tumor and matched normal tissues from 35 CRC patients identified USP11 as significantly overexpressed in tumor samples. Elevated USP11 expression was correlated with reduced patient survival, suggesting its prognostic significance. Functional experiments using USP11-knockout and USP11-overexpressing CRC cell lines (HCT-15 and HT-29) revealed that USP11 promotes tumor cell proliferation, migration, colony formation, and 3D spheroid growth. Biochemical assays demonstrated that USP11 stabilizes EGFR and TRAF6 by removing K48-linked ubiquitin chains, thereby preventing their proteasomal degradation. These interactions potentiate both EGFR and Toll-like receptor (TLR) signaling pathways, contributing to CRC tumorigenesis. Loss of USP11 led to significant reductions in EGFR and TRAF6 protein levels, resulting in impaired tumorigenic behavior in vitro and in mouse xenograft models. Furthermore, USP11 deficiency suppressed tumor spheroid formation in response to EGF, HKLM (a TLR2 agonist), and LPS (a TLR4 agonist), whereas USP11 overexpression amplified these effects. Importantly, pharmacological inhibition of USP11 with mitoxantrone markedly decreased spheroid growth in both EGFR- and TLR-driven models, supporting its therapeutic potential. Overall, our findings reveal that USP11 contributes to CRC progression by stabilizing EGFR and TRAF6, thereby enhancing oncogenic signaling. These insights identify USP11 as a promising molecular target for CRC treatment and support the repurposing of mitoxantrone as an inhibitor of USP11-driven tumor growth.
    DOI:  https://doi.org/10.1038/s41419-025-08266-9
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