The lysosomal iron rheostat: Orchestrating ferroptosis in cancer plasticity

Abstract

Iron is indispensable for cellular metabolism yet potentially cytotoxic, making its intracellular handling a fundamental determinant of cell fate decisions. The endo-lysosomal system has recently emerged as a central iron rheostat that integrates transferrin uptake, ferritinophagy, and lysosomal iron export to control iron bioavailability for mitochondria and other iron-dependent pathways. Growing studies further show that lysosomal iron is not merely permissive for ferroptosis but can directly initiate lipid damage through localized iron activation, lysosomal lipid peroxidation, and lysosomal membrane permeabilization. At the same time, emerging studies on organelle contact sites reveal that ferroptosis arises from the failure of a coordinated multi-organellar communication system, in which lysosomes, the endoplasmic reticulum, and mitochondria exchange iron, lipids, and redox signals in an effort to metabolically adapt to stress. This perspective is particularly relevant to drug-tolerant persisters and mesenchymal cancer cell states, which rely on rewired lysosomal iron trafficking to sustain plasticity while becoming highly susceptible to ferroptosis. In this minireview, we discuss emerging insights into the spatial organization of iron metabolism and propose a model in which ferroptosis sensitivity depends on the intracellular routing, chemical reactivity, and release dynamics of iron, highlighting lysosomal iron handling as a key therapeutic vulnerability in minimal residual disease.

Keywords

Lysosomes / iron / ferroptosis / membrane contact sites / metabolism / drug-tolerant cancer cells

Acknowledgements

The authors recognize and appreciate the significant contributions of many researchers whose work has advanced this field but were not included here due to space limitations. Automated language-editing software (Grammarly) was solely used to improve readability. The authors take full responsibility for the integrity, originality, and accuracy of the work.

Authors contribution

Rizzollo F, Agostinis P: Conceptualization, methodology, writing-original draft, writing-review & editing.

Conflicts of interest

Patrizia Agostinis is an Editorial Board Member of Ferroptosis and Oxidative Stress. The other author declares no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by grants from the FWO (G0A3320N), the Stichting tegen Kanker (F/2022/2037), the KU Leuven C14/21/095 InterAction consortium, the EOS DECODE consortium N 30837538, the EOS MetaNiche consortium N 40007532, and the iBOF/21/053 ATLANTIS network and a Doctoral fellowship from the FWO (11L7622N).

Copyright

© The Author(s) 2026.

References

[1] Rizzollo F, More S, Vangheluwe P, Agostinis P. The lysosome as a master regulator of iron metabolism. Trends Biochem Sci. 2021; 46(12):960-975.

[2] Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024; 25(6):424-442.

[3] Kurz T, Eaton JW, Brunk UT. The role of lysosomes in iron metabolism and recycling. Int J Biochem Cell Biol. 2011; 43(12):1686-1697.

[4] Hider RC, Kong XL. Glutathione: A key component of the cytoplasmic labile iron pool. Biometals. 2011; 24(6):1179-1187.

[5] Philpott CC, Ryu MS, Frey A, Patel S. Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells. J Biol Chem. 2017; 292(31):12764-12771.

[6] Patel SJ, Frey AG, Palenchar DJ, Achar S, Bullough KZ, Vashisht A, et al. A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly. Nat Chem Biol. 2019; 15(9):872-881.

[7] Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014; 509(7498):105-109.

[8] Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014; 16(11):1069-1079.

[9] Goodwin JM, Dowdle WE, DeJesus R, Wang Z, Bergman P, Kobylarz M, et al. Autophagy-independent lysosomal targeting regulated by ULK1/2-FIP200 and ATG9. Cell Rep. 2017; 20(10):2341-2356.

[10] Ohshima T, Yamamoto H, Sakamaki Y, Saito C, Mizushima N. NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy. J Cell Biol. 2022; 221(10):e202203102.

[11] Kuno S, Fujita H, Tanaka YK, Ogra Y, Iwai K. Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO Rep. 2022; 23(5):e54278.

[12] Weber RA, Yen FS, Nicholson SPV, Alwaseem H, Bayraktar EC, Alam M, et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol Cell. 2020; 77(3):645-655.e7.

[13] Yambire KF, Rostosky C, Watanabe T, Pacheu-Grau D, Torres-Odio S, Sanchez-Guerrero A, et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. Elife. 2019; 8:e51031.

[14] Hughes CE, Coody TK, Jeong MY, Berg JA, Winge DR, Hughes AL. Cysteine toxicity drives age-related mitochondrial decline by altering iron homeostasis. Cell. 2020; 180(2):296-310.e18.

[15] Kurz T, Terman A, Gustafsson B, Brunk UT. Lysosomes in iron metabolism, ageing and apoptosis. Histochem Cell Biol. 2008; 129(4):389-406.

[16] Barra J, Crosbourne I, Roberge CL, Bossardi-Ramos R, Warren JSA, Matteson K, et al. DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth. Oncogene. 2024; 43(9):650-667.

[17] Cañeque T, Baron L, Müller S, Carmona A, Colombeau L, Versini A, et al. Activation of lysosomal iron triggers ferroptosis in cancer. Nature. 2025; 642(8067):492-500.

[18] 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(5):1060-1072.

[19] Müller S, Sindikubwabo F, Cañeque T, Lafon A, Versini A, Lombard B, et al. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat Chem. 2020; 12(10):929-938.

[20] Rodriguez R, Schreiber SL, Conrad M. Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol Cell. 2022; 82(4):728-740.

[21] Rizzollo F, Escamilla-Ayala A, Fattorelli N, Lysiak NB, More S, Hernández Varas P, et al. BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states. Nat Metab. 2025; 7(9):1851-1870.

[22] Saimoto Y, Kusakabe D, Morimoto K, Matsuoka Y, Kozakura E, Kato N, et al. Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization. Nat Commun. 2025; 16(1):3554.

[23] Loo TM, Zhou X, Tanaka Y, Sugawara S, Yamauchi S, Kawasaki H, et al. Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis. Nat Commun. 2025; 16(1):6617.

[24] Liu X, Zhao Z, Bian Z, Benthani FA, Hu Y, Liang D, et al. Endocytosis is essential for cysteine-deprivation-induced ferroptosis. Mol Cell. 2025; 85(17):3333-3342.e4.

[25] Scorrano L, de Matteis MA, Emr S, Giordano F, Hajnóczky G, Kornmann B, et al. Coming together to define membrane contact sites. Nat Commun. 2019; 10(1):1287.

[26] Voeltz GK, Sawyer EM, Hajnóczky G, Prinz WA. Making the connection: How membrane contact sites have changed our view of organelle biology. Cell. 2024; 187(2):257-270.

[27] Prinz WA, Toulmay A, Balla T. The functional universe of membrane contact sites. Nat Rev Mol Cell Biol. 2020; 21(1):7-24.

[28] von Krusenstiern AN, Robson RN, Qian N, Qiu B, Hu F, Reznik E, et al. Identification of essential sites of lipid peroxidation in ferroptosis. Nat Chem Biol. 2023; 19(6):719-730.

[29] Sassano ML, Tyurina YY, Diokmetzidou A, Vervoort E, Tyurin VA, More S, et al. Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis. Nat Cell Biol. 2025; 27(6):902-917.

[30] Zhang Z, Zhou H, Gu W, Wei Y, Mou S, Wang Y, et al. CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes. Nat Chem Biol. 2024; 20(6):699-709.

[31] Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature. 2018; 554(7692):382-386.

[32] Boutry M, Kim PK. ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division. Nat Commun. 2021; 12(1):5354.

[33] Sheftel AD, Zhang AS, Brown C, Shirihai OS, Ponka P. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood. 2007; 110(1):125-132.

[34] Hamdi A, Roshan TM, Kahawita TM, Mason AB, Sheftel AD, Ponka P. Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism. Biochim Biophys Acta BBA Mol Cell Res. 2016; 1863(12):2859-2867.

[35] Das A, Nag S, Mason AB, Barroso MM. Endosome-mitochondria interactions are modulated by iron release from transferrin. J Cell Biol. 2016; 214(7):831-845.

[36] Devireddy LR, Hart DO, Goetz DH, Green MR. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 2010; 141(6):1006-1017.

[37] Tian Z, Chen R, Fang G, Qiu K, Wu W, Shao X, et al. Mitochondria acidify lysosomes through membrane contacts. Cell Rep. 2026; 45(3):117112.

[38] Russo M, Chen M, Mariella E, Peng H, Rehman SK, Sancho E, et al. Cancer drug-tolerant persister cells: From biological questions to clinical opportunities. Nat Rev Cancer. 2024; 24(10):694-717.

[39] Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010; 141(1):69-80.

[40] Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017; 551(7679):247-250.

[41] 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(7664):453-457.

[42] Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019; 575(7784):693-698.

[43] Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019; 575(7784):688-692.

[44] Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem. 2017; 9(10):1025-1033.

[45] Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu H, Zhu LJ, et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell. 2019; 51(5):575-586.e4.

[46] Zhang HL, Hu BX, Ye ZP, Li ZL, Liu S, Zhong WQ, et al. TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer. Sci Transl Med. 2024; 16(753):eadk0330.

[47] Palma M, Chaufan M, Breuer CB, Müller S, Sabatier M, Fraser CS, et al. Lymph node environment drives FSP1 targetability in metastasizing melanoma. Nature. 2026; 649(8096):477-486.

[48] Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019; 73(2):354-363.e3.