bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–04–12
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells.
  2. Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.
  3. Small nucleolar RNA Snora61 drives self-renewal of intestinal stem cells via initiation of Lgr5 transcription.
  4. Ferroptosis as an approach to leverage cancer metabolism.
  5. Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression.
  6. LGR5: from stem cell marker to therapeutic target.
  7. Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer.
  8. Dissecting Complex Interactions Between Ferroptosis and the Proteasome.
  9. Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.
  10. Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy.
  11. Targeting HIF-1α promotes ferroptosis and boosts antitumor immunity in MSS colorectal cancer.
  1. Cell Death Dis. 2026 Apr 11.
    Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells.
    Laura di Blasio, Marianela Vara-Messler, Barbara Peracino, Elena Masti, Vanesa Cepas-López, Livio Trusolino, Alberto Puliafito, Andrea Bertotti, Valentina Monica, Luca Primo.
      Several epidemiological and preclinical studies suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) exert anticancer activity at multiple stages of colorectal cancer (CRC) progression. However, inconsistent clinical evidence and the lack of a clearly defined molecular mechanism underlying the antitumor effects of n-3 PUFAs have raised doubts about their efficacy as anticancer therapies. To address these issues, we investigated the effects of the n-3 PUFA docosahexaenoic acid (DHA) in a collection of CRC patient-derived tumor organoids (PDTOs), a powerful platform for functional analysis of patient-specific tumors. DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without inducing apoptosis. CRC-derived PDTOs exhibited pronounced sensitivity to DHA, irrespective of KRAS or TP53 mutational status, whereas organoids from normal colon tissue were less affected. Mechanistically, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation and partial rescue by ferroptosis inhibitors. Fluorescently labeled DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress. Moreover, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models. Together, these findings indicate that exploiting the intrinsic oxidative vulnerability of cancer cells with DHA may represent a promising, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41419-026-08744-8
  2. Am J Physiol Gastrointest Liver Physiol. 2026 Apr 09.
    Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.
    Yuezhong Zhang, Yinzhi Ying, Wesley Huang, Zoe A Rosenfeld, Marwa O El-Derany, Zheng Hong Lee, Cristina Castillo, Tae Gyu Oh, Joel K Greenson, Yatrik M Shah.
      Broad antioxidant strategies in inflammatory bowel disease have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species (ROS). In our recent work, we demonstrated that fibroblast-specific overexpression of acyl-CoA synthetase long-chain family member 4 (ACSL4) reprogrammed lipid metabolism and sensitized adjacent epithelial cells to ferroptosis in IBD models, pointing to heterocellular lipid crosstalk as a driver of epithelial injury. Building on that insight, here we test the hypothesis that fibroblast glutathione peroxidase 4 (GPX4), a key enzyme detoxifying lipid hydroperoxides, is critical in restraining fibroblast-mediated lipid peroxidation and consequent epithelial ferroptosis during colitis. We generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice and subjected them to acute DSS colitis. Fibroblast-specific GPX4 deletion did not alter basal colon morphology but significantly aggravated DSS-induced injury. Increased histological scores, greater weight loss, and colon shortening versus littermate control mice. In vitro, GPX4-deficient fibroblasts exhibited elevated lipid peroxidation in response to ferroptosis inducers, reversible by liproxstatin-1. Critically, liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient animals, restoring colon length, weight loss, and histologic injury. Together, these findings identify fibroblast GPX4 as a gatekeeper that limits stromal lipid peroxidation and suppresses epithelial ferroptosis under inflammatory stress. Targeting fibroblast-mediated lipid peroxidation may offer a refined therapeutic axis in IBD.
    Keywords:  GPX4; inflammatory bowel disease; lipid peroxidation
    DOI:  https://doi.org/10.1152/ajpgi.00387.2025
  3. Nat Commun. 2026 Apr 07.
    Small nucleolar RNA Snora61 drives self-renewal of intestinal stem cells via initiation of Lgr5 transcription.
    Jiacheng He, Yufei Lan, Yuwei Xu, Zhen Xiong, Zhibin Yi, Hui Guo, Jiahang Zhang, Ziheng Zhou, Ying Du, Fan Pan, Zusen Fan.
      Intestinal epithelium relies on intestinal stem cells (ISCs) for rapid and precise tissue replenishment to maintain gut normal function. The self-renewal maintenance of ISCs is finely regulated by multiple stemness factors and signaling pathways. However, the transcription mechanisms of some key stemness factors remain poorly understood. Here, we identify that small nucleolar RNA Snora61 is highly expressed in ISCs. Snora61 is mainly distributed in the nucleoplasm. Snora61 knockout impairs ISC self-renewal and intestinal regeneration. Mechanistically, Snora61 binds to the promoter region of Lgr5 gene and engages with RNA-binding protein RBMX to recruit HMGB2 onto Lgr5 promoter, leading to Lgr5 transcription and expression. Snora61 promotes the self-renewal of small intestinal stem cells, which in turn enhances the proliferation of differentiated epithelial cells, thereby contributing to the maintenance of intestinal homeostasis. Conversely, Snora61 knockout causes reduced LGR5 expression. Deletion of Lgr5 with Snora61 displays more severely impaired ISC self-renewal and intestinal regeneration. Our findings reveal a regulatory mechanism of Lgr5 transcription underlying ISC self-renewal maintenance.
    DOI:  https://doi.org/10.1038/s41467-026-71620-8
  4. Trends Cell Biol. 2026 Apr 09. pii: S0962-8924(26)00039-5. [Epub ahead of print]
    Ferroptosis as an approach to leverage cancer metabolism.
    Jenny Jin, Jiachen Hu, Mingyue Li, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Ferroptosis is a cell death process defined by the iron-mediated peroxidation of membrane phospholipids that overwhelms the cell's innate antioxidant capabilities. Sitting at the nexus of iron, lipid, reactive oxygen species stress responses, and cellular metabolism, ferroptosis is intricately tied to these pathways. The burgeoning field of cancer metabolism has revealed that cancer cells exhibit changes in ferroptosis-relevant metabolic pathways, thereby opening an important avenue of investigation into whether tumors can have characteristic metabolic alterations that render them exquisitely sensitive to ferroptotic cell death. In this review, we highlight recent findings in the metabolic pathways linking ferroptosis and oncogenesis, as well as implications for future cancer therapeutic strategies.
    Keywords:  cancer metabolism; ferroptosis; lipid metabolism; lipidomics; metabolomics; oncogenic signaling
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.008
  5. Cell Death Dis. 2026 Apr 10.
    Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression.
    Lili Li, Taekyu Ha, Jing-Xin Feng, Michael DiPrima, Dunrui Wang, Parthav Jailwala, Thomas Meyer, Justin Lack, Hidetaka Ohnuki, Giovanna Tosato.
      Despite therapeutic advances, metastatic colorectal cancer remains a therapeutic challenge as most patients will develop resistance to therapy and will progress. Epigenetic mechanisms are implicated in enabling the acquisition of new phenotypic traits as drivers of colorectal cancer progression, rather than new genetic mutations or expansion of existing mutant clones. It remains unclear, however, which epigenetic mechanisms sustain colorectal cancer plasticity, how they are induced, and how this plasticity generates subclonal diversity that drives the aggressive cancer phenotype. Here we identify the integrated stress response as an inducer of colorectal cancer cell plasticity, subclonal diversity, and tumor progression in the stress-surviving cells. Combined analysis of chromatin accessibility and gene transcription profiling in these cells found the emergence of an endogenous interferon response as a key phenotypic trait associated with subclonal colorectal cancer cell diversity, treatment resistance and heightened aggressiveness. We unveil a new experimental approach to successfully prevent treatment-resistant colorectal cancer progression by combining epigenetic modulators with a cereblon-dependent degrader of GSPT1, a regulator of protein synthesis, to normalize chromatin accessibility and induce colorectal cancer cell death. Collectively, our study identifies the integrated stress response as an inducer of epigenetic and transcriptional plasticity in colorectal cancer cells and highlights a successful approach to therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41419-026-08720-2
  6. Trends Cancer. 2026 Apr 06. pii: S2405-8033(26)00037-3. [Epub ahead of print]
    LGR5: from stem cell marker to therapeutic target.
    Peyton C High, Maya G Cappellino, Tiffani A Blackburn, Kendra S Carmon.
      Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an established marker of normal and cancer stemlike cells. LGR5 has been implicated in promoting cancer cell plasticity that drives tumorigenesis, metastasis, and therapeutic resistance. LGR5 rapidly and constitutively internalizes and potentiates Wnt (Wingless/Int-1)/β-catenin and adhesion signaling pathways, though its precise mechanisms and interacting partners remain unresolved. An improved understanding of LGR5 signaling may provide invaluable insight into its intricate and important functions in cancer progression. Moreover, several LGR5-targeting therapies, including peptibody- and antibody-drug conjugates and bispecific antibodies, are showing promising efficacy and tolerability in colorectal cancer and other tumor types. This review discusses the cancer-related functions of LGR5 and explores the preclinical and clinical approaches to therapeutically target this enigmatic protein.
    Keywords:  LGR5; Wnt/β-catenin signaling; antibody–drug conjugate; bispecific antibody; cancer cell plasticity; colorectal cancer
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.006
  7. Nat Commun. 2026 Apr 04.
    Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer.
    Senlin Zhao, Jing Zhang, Yushuai Mi, Bin Quan, Zijuan Hu, Xinyang Zhong, Ye Xu, Sanjun Cai, Xinxiang Li, Ping Wei, WanJun Chen, Yuping Zhu, Jianqiang Tang, Dawei Li.
      Serum bile acids (BAs) emerge as risk factors for cancer, but their roles in colorectal cancer (CRC) remain unclear. We show that glycocholic acid (GCA), a primary BA, is elevated in the serum of CRC patients. In a mouse CRC model, GCA promotes tumor programmed death-ligand 1 (PD-L1) expression in tumors, suppressing CD8⁺ T cell-mediated antitumor immunity and facilitating tumor growth. Mechanistically, GCA inhibits the BA receptor farnesoid X receptor (FXR), a transcriptional repressor for SRY-box transcription factor 14 (SOX14). Loss of FXR repression upregulates SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9), thereby reducing PD-L1 palmitoylation and stabilization. Silencing SOX14 or DHHC9, or activating FXR, synergizes with anti-PD-1 therapy, reducing tumor growth in GCA-treated mice. These findings uncover a mechanism that GCA remodels the tumor microenvironment to mediate CRC resistance to immunotherapy, highlighting therapeutic opportunities targeting the FXR-PD-L1 axis in CRC patients with elevated serum GCA.
    DOI:  https://doi.org/10.1038/s41467-026-71403-1
  8. bioRxiv. 2026 Mar 30. pii: 2026.03.28.714855. [Epub ahead of print]
    Dissecting Complex Interactions Between Ferroptosis and the Proteasome.
    Magdalena B Murray, Rishi Upadhyay, Krystina Szylo, Aastha Gautam, Judith Goncalves, Giovanni Forcina, Ananya Vinayak, Onn Brandmann, Scott J Dixon.
      The proteasome is an essential multiprotein complex whose inhibition can lead to apoptosis. Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. How proteasome function regulates ferroptosis sensitivity is poorly understood and difficult to study given the essential nature of the proteasome. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining direct cell death imaging, cell death pathway-specific inhibitors, and mathematical modeling. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system x - inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. This work demonstrates a complex role for proteasome function in ferroptosis regulation and establishes new methods to dissect cross-talk between ferroptosis and essential cellular processes.
    DOI:  https://doi.org/10.64898/2026.03.28.714855
  9. Cell Death Dis. 2026 Apr 10.
    Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.
    Dorottya Károlyi, Sólyom Bálint Bótor, Natali Neuhauser, András Rubics, Janka Szinyákovics, Tibor Kovács, Mária Péter, Gábor Balogh, Fergal O'Farrell, Szabolcs Takáts.
      Biosynthesis of lipids and fatty acids (FAs) is essential for the normal functioning of cellular processes, and lipid availability determines the progression of multiple malignant tumor types. To date, the roles of individual steps in lipid biosynthesis during tumor growth and their interaction with intracellular signaling pathways are not well understood. Our study demonstrates that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. In vivo tumor cell-specific silencing of components of the neutral lipid biosynthetic apparatus revealed that loss of several enzymes involved in FA and diacylglycerol synthesis inhibited tumor growth. Specifically, acetyl-CoA carboxylase (ACC), which catalyzes the first step of FA synthesis, drives late-stage tumor growth. FA synthesis perturbation led to inactivation of TORC1 (mechanistic Target of Rapamycin Complex 1)-accompanied by activation of the catabolic process autophagy. Moreover, TORC1 activity cannot be fully restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC-deficient tumor cells, but supplementation with ectopic oleic acid can partially increase TORC1 activity and tumor progression. In addition to their metabolic value, the role of FAs in promoting TORC1 gives us new insight into cancer cell dependence on de novo FA synthesis.
    DOI:  https://doi.org/10.1038/s41419-026-08738-6
  10. bioRxiv. 2026 Mar 14. pii: 2026.03.11.711115. [Epub ahead of print]
    Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy.
    Kenji M Fujihara, Azmi Aziz, Behnia Akbari, Maria Gutierrez-Perez, Gregory Francis, Siham Zentout, Kameng Wu, Nicholas J Clemons, Erdem M Terzi, Michael E Pacold, Richard Possemato.
      Ferroptosis is a cell death mechanism characterized by the accumulation of iron-catalyzed lipid peroxides in membrane lipid acyl chains and subsequent loss of membrane integrity. 1 Despite thorough investigation of its mechanisms in cultured cells, induction of ferroptosis has unresolved clinical utility in cancer therapy. Here, we systematically evaluate ferroptosis induction via multiple mechanisms, in both cell and tumor models, using focused genetic screens, genetic loss-of-function systems, and pharmacological perturbations. Through this analysis we identify cancer cell line subsets with distinct responses to canonical ferroptosis inducers and suppressors and define the underpinnings of each. Inhibition of central in vitro ferroptosis suppressors GPX4, GCLC, or SLC7A11 across these multiple models fails to impact established tumor growth. In contrast, deficiency in the cytosolic thioredoxin reductase and pharmacologic GCLC inhibition potently induces tumor regression and triggers a form of non-ferroptotic cell death regulated by cystine availability and translation. These analyses further reveal that the principal essential function of environmental cystine in cultured cells is to support selenoprotein function, identified through investigating our finding that β-mercaptoethanol supports exponential growth in cystine-free conditions. Thus, while ferroptosis activation may be efficacious alone or in combination with other therapies in specific tumor contexts, cell culture systems greatly overestimate the potential anti-cancer effects of ferroptosis induction via the GPX4 axis.
    DOI:  https://doi.org/10.64898/2026.03.11.711115
  11. Redox Biol. 2026 Apr 01. pii: S2213-2317(26)00149-7. [Epub ahead of print]93 104151
    Targeting HIF-1α promotes ferroptosis and boosts antitumor immunity in MSS colorectal cancer.
    Zhiying Yang, Rui Ma, Weili Wu, Ying Shi, You Chen, Xiaotong Luo, Kai Li, Liangcai Wu, Bo Wang, Boyu Zhang, Ping Yuan.
      The lack of effective therapeutic options available for microsatellite stable (MSS) colorectal cancer (CRC) remains a significant clinical challenge. Interestingly, chemotherapy-resistant cancer cells can be induced to undergo ferroptosis, prompting our investigation into RSL3, a potent ferroptosis inducer, in MSS CRC cells. Our findings revealed that while RSL3 suppressed the growth of MSS CRC cells, a subset displayed resistance. Single-cell sequencing uncovered an aberrant activation of hypoxia pathways in RSL3-resistant MSS CRC cells. Inhibiting HIF-1α, the key transcription factor driving hypoxia signaling, restored RSL3 sensitivity in these resistant cells; moreover, this sensitivity was attenuated upon HIF-1α overexpression. Chromatin immunoprecipitation assays further demonstrated that in RSL3-resistant cells, HIF-1α was enriched at the promoter of P4HA1, a gene implicated in ferroptosis resistance, thereby enhancing its expression. Additionally, in vivo experiments using syngeneic transplantation of CT26 cells in mice revealed that combining RSL3 with an HIF-1α inhibitor markedly enhanced tumor suppression and metastasis prevention, concomitant with increased intratumoral infiltration of CD8+ T cells and CD86+ macrophages. Notably, the combination enhanced the antitumor response of anti-PD1, a treatment otherwise ineffective on this tumor. These findings suggest that targeting HIF-1α represents a promising therapeutic strategy when used in conjunction with a ferroptosis inducer for the treatment of MSS CRC.
    Keywords:  Colorectal cancer; Ferroptosis; HIF-1α; Microsatellite stable
    DOI:  https://doi.org/10.1016/j.redox.2026.104151
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