ArticleCell death & disease2025
Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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Who cites it
99 citing papers in PubMed.
- Ferroptosis-Pyroptosis Crosstalk in Spinal Cord Injury: Molecular Mechanisms, Emerging Connectors, and Staged Therapeutic Perspectives.Journal of molecular neuroscience : MN · 2026Review
- Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.Molecular biology reports · 2026Review
- Lactylation and regulated cell death: the substrate defines the outcome.Apoptosis : an international journal on programmed cell death · 2026Article
- Review
- New and emerging strategies for targeting cancers: Challenges and opportunities (Review).Oncology letters · 2026Review
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- PCK2 Inhibition Reverses Cisplatin Resistance of Non-Small Cell Lung Cancer by Triggering Ferroptosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Lactate-dependent regulation of ferroptosis: redox homeostasis, lactylation, and translational perspectives.Apoptosis : an international journal on programmed cell death · 2026Review
- Review
- Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments.Molecular biomedicine · 2026Review
- Glutathione Biology in Neurodegenerative and Metabolic Diseases: Molecular Mechanisms, Pathophysiological Roles, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease.Cell proliferation · 2026Review
- Beyond a Metabolite: Lactylation as a Pivotal Regulator of Colorectal Cancer Pathogenesis and Treatment Resistance.Journal of biochemical and molecular toxicology · 2026Review
- Unveiling Lactylation: A Novel Frontier in Cancer Stemness and Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The glycolysis-H4K12la-PKM2 positive feedback loop drives M2 polarization of macrophages in colorectal cancer.Clinical epigenetics · 2026Article
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- HDAC3 as an Immunometabolic Rheostat: Molecular Mechanisms of Deacylation Plasticity, Lactylation Dynamics, and Spatiotemporal Regulation.Biomolecules · 2026Review
- Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities.Genes & diseases · 2026Review
- Clinical implications of lactylation modification in digestive system tumors (Review).Oncology letters · 2026Review
39 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors.
Funding
Abstract
Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is a post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate that histone lactylation enhances CCSC chemoresistance both in vitro and in vivo. Furthermore, our findings showed that p300 catalyzes the lactylation of histone H4 at K12, whereas HDAC1 facilitates its delactylation in CCSCs. Notably, lactylation at H4K12 (H4K12la) upregulates GCLC expression and inhibits ferroptosis in CCSCs, and the inhibition of p300 or LDHA decreases H4K12la levels, thereby increasing the chemosensitivity of CCSCs. Additionally, the GCLC inhibitor BSO promotes ferroptosis and sensitizes CCSCs to oxaliplatin. Taken together, these findings suggest that histone lactylation upregulates GCLC to inhibit ferroptosis signaling, thus enhancing CCSC chemoresistance. These findings provide new insights into the relationship between cellular metabolism and chemoresistance and suggest potential therapeutic strategies targeting p300, LDHA, and GCLC. We showed that histones H4K12 lactylation promoted chemoresistance in CSCs. p300 catalyzes the lactylation of histone H4 at K12, HDAC1 inhibits the histone lactylation at the same site. H4K12la in CSCs regulates the expression of the ferroptosis-related gene GCLC, thereby inhibiting ferroptosis and leading to chemoresistance. Targeting the p300, LDHA, or GCLC may be overcome tumor chemoresistance.
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