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MC1R contributes to ferroptosis resistance and tumor aggressiveness in colorectal cancer by activating Notch signaling

Cancer Gene Therapy volume 33, pages 26–38 (2026)Cite this article

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Abstract

Ferroptosis, a form of iron-dependent cell death, is emerging as a potential therapeutic target due to its ability to inhibit tumor growth and enhance immune responses. However, the mechanisms regulating ferroptosis and tumor metastasis, particularly in colorectal cancer (CRC), remain poorly understood. In this study, bioinformatics analysis identified MC1R as a key regulator of ferroptosis-related genes. In vitro experiments showed MC1R overexpression in CRC cell lines promotes cell proliferation and migration while inhibiting ferroptosis via downregulating ACSL4 expression, with opposite effects seen in MC1R knockdown. In vivo experiments also found MC1R-knockdown CRC cells resulted in xenograft tumors with lower volume and weight. Mechanistically, MC1R activates the Notch signaling pathway, leading to ACSL4 inhibition, which inhibits ferroptosis and, in turn, cell growth and migration. High MC1R expression in CRC correlates with poor prognosis and is negatively associated with ferroptosis levels. Targeting MC1R could offer a novel strategy to enhance ferroptosis in CRC, potentially improving patient outcomes. This study elucidates the complex interactions between MC1R, Notch signaling, and ferroptosis, providing insights for developing targeted therapies in CRC.

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Fig. 1: MC1R is associated with ferroptosis in CRC.
Fig. 2: Knocking down MC1R inhibits CRC cell proliferation and migration.
Fig. 3: Impact of MC1R on ferroptosis in CRC cells.
Fig. 4: Downregulation of MC1R inhibits Notch signaling and upregulates ACSL4 expression.
Fig. 5: MC1R influences ferroptosis in CRC cells via ACSL4.
Fig. 6: MC1R regulates CRC cell proliferation and migration via ACSL4.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72:338–44.

    PubMed  Google Scholar 

  2. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lei G, Zhuang L, Gan B. The roles of ferroptosis in cancer: tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell. 2024;42:513–34.

    CAS  PubMed  Google Scholar 

  5. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18:280–96.

    CAS  PubMed  Google Scholar 

  6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008;15:234–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Liu Y, Liu J, Kang R, Tang D. NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochem Biophys Res Commun. 2020;531:581–7.

    CAS  PubMed  Google Scholar 

  9. Geng N, Shi BJ, Li SL, Zhong ZY, Li YC, Xua WL, et al. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. Eur Rev Med Pharm Sci. 2018;22:3826–36.

    CAS  Google Scholar 

  10. Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478:1338–43.

    CAS  PubMed  Google Scholar 

  11. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–98.

    CAS  PubMed  Google Scholar 

  12. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.

    CAS  PubMed  Google Scholar 

  13. Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26:420–432.e429.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.

    PubMed  PubMed Central  Google Scholar 

  15. Qiao L, Wong BC. Role of Notch signaling in colorectal cancer. Carcinogenesis. 2009;30:1979–86.

    CAS  PubMed  Google Scholar 

  16. Tyagi A, Sharma AK, Damodaran C. A review on Notch signaling and colorectal cancer. Cells 2020; 9:1549.

  17. Hayakawa Y, Tsuboi M, Asfaha S, Kinoshita H, Niikura R, Konishi M, et al. BHLHA15-positive secretory precursor cells can give rise to tumors in intestine and colon in mice. Gastroenterology. 2019;156:1066–81.e1016.

    CAS  PubMed  Google Scholar 

  18. Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell. 2019;36:319–336.e317.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jackstadt R, Sansom OJ. Mouse models of intestinal cancer. J Pathol. 2016;238:141–51.

    PubMed  Google Scholar 

  20. Kranenburg O. Prometastatic NOTCH signaling in colon cancer. Cancer Discov. 2015;5:115–7.

    CAS  PubMed  Google Scholar 

  21. Banu MA, Dovas A, Argenziano MG, Zhao W, Sperring CP, Cuervo Grajal H, et al. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma. EMBO J. 2024;43:4492–521.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cui Y, Miao Y, Cao L, Guo L, Cui Y, Yan C, et al. Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity. Nat Commun. 2023;14:5740.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Su DG, Djureinovic D, Schoenfeld D, Marquez-Nostra B, Olino K, Jilaveanu L, et al. Melanocortin-1 receptor expression as a marker of progression in melanoma. JCO Precis Oncol. 2024;8:e2300702.

    PubMed  Google Scholar 

  24. Bohm M, Stegemann A. Bleomycin-induced fibrosis in MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice further supports a modulating role for melanocortins in collagen synthesis of the skin. Exp Dermatol. 2014;23:431–3.

    PubMed  Google Scholar 

  25. Hill RP, MacNeil S, Haycock JW. Melanocyte stimulating hormone peptides inhibit TNF-alpha signaling in human dermal fibroblast cells. Peptides. 2006;27:421–30.

    CAS  PubMed  Google Scholar 

  26. Hiramoto K, Kobayashi H, Ishii M, Sato E, Inoue M. Increased alpha-melanocyte-stimulating hormone (alpha-MSH) levels and melanocortin receptors expression associated with pigmentation in an NC/Nga mouse model of atopic dermatitis. Exp Dermatol. 2010;19:132–6.

    CAS  PubMed  Google Scholar 

  27. Kleiner S, Braunstahl GJ, Rudrich U, Gehring M, Eiz-Vesper B, Luger TA, et al. Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo. Clin Exp Allergy. 2016;46:1066–74.

    CAS  PubMed  Google Scholar 

  28. Luo LF, Shi Y, Zhou Q, Xu SZ, Lei TC. Insufficient expression of the melanocortin-1 receptor by human dermal fibroblasts contributes to excess collagen synthesis in keloid scars. Exp Dermatol. 2013;22:764–6.

    CAS  PubMed  Google Scholar 

  29. Muffley LA, Zhu KQ, Engrav LH, Gibran NS, Hocking AM. Spatial and temporal localization of the melanocortin 1 receptor and its ligand alpha-melanocyte-stimulating hormone during cutaneous wound repair. J Histochem Cytochem. 2011;59:278–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Guida S, Guida G, Goding CR. MC1R functions, expression, and implications for targeted therapy. J Invest Dermatol. 2022;142:293–302.e291.

    CAS  PubMed  Google Scholar 

  31. Tan T, Mouradov D, Gibbs P, Sieber OM. Protocol for generation of and high-throughput drug testing with patient-derived colorectal cancer organoids. STAR Protoc. 2024;5:103090.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell. 2018;33:890–904 e895.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV. Iron and cancer: recent insights. Ann N Y Acad Sci. 2016;1368:149–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ebrahimi N, Adelian S, Shakerian S, Afshinpour M, Chaleshtori SR, Rostami N, et al. Crosstalk between ferroptosis and the epithelial-mesenchymal transition: implications for inflammation and cancer therapy. Cytokine Growth Factor Rev. 2022;64:33–45.

    CAS  PubMed  Google Scholar 

  37. Vucetic M, Daher B, Cassim S, Meira W, Pouyssegur J. Together we stand, apart we fall: how cell-to-cell contact/interplay provides resistance to ferroptosis. Cell Death Dis. 2020;11:789.

    PubMed  PubMed Central  Google Scholar 

  38. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of cancer. Cancer Cell. 2018;34:21–43.

    CAS  PubMed  Google Scholar 

  39. Lei S, Chen C, Han F, Deng J, Huang D, Qian L, et al. AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis. Cell Rep. 2023;42:113110.

    CAS  PubMed  Google Scholar 

  40. Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020;585:113–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019;10:1617.

    PubMed  PubMed Central  Google Scholar 

  42. Brown CW, Amante JJ, Goel HL, Mercurio AM. The alpha6beta4 integrin promotes resistance to ferroptosis. J Cell Biol. 2017;216:4287–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019;572:402–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Li X, Li Y, Zhang W, Jiang F, Lin L, Wang Y, et al. The IGF2BP3/Notch/Jag1 pathway: a key regulator of hepatic stellate cell ferroptosis in liver fibrosis. Clin Transl Med. 2024;14:e1793.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu S, Wu H, Zhang P, Zhou H, Wu D, Jin Y, et al. NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC. Sci Rep. 2025;15:10193.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ni Y, Liu L, Jiang F, Wu M, Qin Y. JAG1/Notch pathway inhibition induces ferroptosis and promotes cataractogenesis. Int J Mol Sci. 2025; 26:307.

  47. D’Orazio J, Jarrett S, Amaro-Ortiz A, Scott T. UV radiation and the skin. Int J Mol Sci. 2013;14:12222–48.

    PubMed  PubMed Central  Google Scholar 

  48. Weber JM, Forsythe SR, Christianson CA, Frisch BJ, Gigliotti BJ, Jordan CT, et al. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006;39:485–93.

    CAS  PubMed  Google Scholar 

  49. Boardman R, Pang V, Malhi N, Lynch AP, Leach L, Benest AV, et al. Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway. Am J Physiol Heart Circ Physiol. 2019;316:H1065–H1075.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Angulo-Rojo C, Manning-Cela R, Aguirre A, Ortega A, Lopez-Bayghen E. Involvement of the Notch pathway in terminal astrocytic differentiation: role of PKA. ASN Neuro. 2013;5:e00130.

    PubMed  PubMed Central  Google Scholar 

  51. Zhu S, Zou M, Li C, Tang Y, Luo H, Dong X. MC1R regulates T regulatory cell differentiation through metabolic reprogramming to promote colon cancer. Int Immunopharmacol. 2024;138:112546.

    CAS  PubMed  Google Scholar 

  52. Fender AW, Nutter JM, Fitzgerald TL, Bertrand FE, Sigounas G. Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. J Cell Biochem. 2015;116:2517–27.

    CAS  PubMed  Google Scholar 

  53. Xiong Y, Zhang YY, Wu YY, Wang XD, Wan LH, Li L, et al. Correlation of over-expressions of miR-21 and Notch-1 in human colorectal cancer with clinical stages. Life Sci. 2014;106:19–24.

    CAS  PubMed  Google Scholar 

  54. Li G, Zhou Z, Zhou H, Zhao L, Chen D, Chen H, et al. The expression profile and clinicopathological significance of Notch1 in patients with colorectal cancer: a meta-analysis. Future Oncol. 2017;13:2103–18.

    CAS  PubMed  Google Scholar 

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Funding

This research was funded by the Natural Science Foundation of Hubei Province, grant number 2022CFB138 to Huili Li; by the Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, grant number 2023zsyx003 to Huili Li; by the Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College,Huazhong University of Science and Technology, grant number 202415 to Huili Li; by the Natural Science Foundation of Hubei Province, grant number 2025AFB304 to Xiangwei Zeng.

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Author notes

  1. These authors contributed equally: Xiangwei Zeng, Lujian Jiang, Huili Li.

Authors and Affiliations

  1. College of Medicine and Health Science, Wuhan Polytechnic University, Wuhan, 430000, Hubei, PR China

    Xiangwei Zeng & Jiamou Wang

  2. Tianjin Academy of Traditional Chinese Medicine affiliated Hospital, Tianjin, 300120, PR China

    Lujian Jiang

  3. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, PR China

    Huili Li

  4. Renmin Hospital of Wuhan University, Wuhan, 430000, Hubei, PR China

    Xuan He

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  1. Xiangwei Zeng
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XZ, LJ, and HL performed the experiments, wrote the paper, and analyzed the data. JW helped analyze the data. XH designed and supervised the study. All authors read and approved the final paper.

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Correspondence to Xuan He.

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Zeng, X., Jiang, L., Li, H. et al. MC1R contributes to ferroptosis resistance and tumor aggressiveness in colorectal cancer by activating Notch signaling. Cancer Gene Ther 33, 26–38 (2026). https://doi.org/10.1038/s41417-025-00942-4

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