Ferroptosis is emerging as a key intersection in tumor metabolism research. The real question, however, is not whether ferroptosis is “good” or “bad,” but whether it can be regulated according to purpose: inducing ferroptosis in tumors to kill cancer cells, inhibiting it in normal cells to provide protection, and achieving cross-species regulation through intervention in iron homeostasis. This special issue is organized around the theme of “on-demand regulation of ferroptosis” and presents five articles along three directions—induction, inhibition, and intervention—to outline the research landscape of ferroptosis regulation.
I. Inducing Ferroptosis to Kill Tumors
Two studies approach this from the angles of molecular chaperone targets and microbial extracts, demonstrating that ferroptosis can be effectively induced in prostate cancer and triple-negative breast cancer, clearly pointing toward “killing tumors.”
1. Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer
Full Article: https://link.springer.com/article/10.1007/s13659-025-00586-9
This study reveals that the marine natural product nidurufin triggers ferroptosis in prostate cancer cells by targeting HSP70 and disrupting the HSP70–AR–MBOAT2 signaling axis, and significantly inhibits tumor growth and metastasis in a zebrafish xenograft model. This finding links molecular chaperone stress to ferroptosis sensitivity, provides a new target for prostate cancer therapy, and establishes a potential strategy of “targeting HSP70 to induce ferroptosis.”
2. The ethyl acetate extract from Trichoderma viride fermentation acts by downregulating the leukocyte transendothelial migration signaling pathway to induce ferroptosis in triple-negative breast cancer cells
Full Article: https://link.springer.com/article/10.1007/s13659-025-00569-w
This study found that the ethyl acetate extract from Trichoderma viride fermentation (TVEAE) effectively induces ferroptosis in triple-negative breast cancer cells by downregulating the leukocyte transendothelial migration signaling pathway. As triple-negative breast cancer lacks well-defined targeted therapeutic sites, this study expands the application prospects of ferroptosis inducers from microbial sources for refractory breast cancer and identifies multiple structurally novel anti-TNBC metabolites.
II. Inhibiting Ferroptosis to Protect Cells
Two studies identified potent anti-ferroptotic lead compounds from carbazole alkaloids and neo-clerodane diterpenoids, expanding the scaffold types for anti-ferroptosis and collectively pointing toward the direction of “protecting cells.”
3. Euchrestifolines A–O, fifteen novel carbazole alkaloids with potent anti-ferroptotic activity from Murraya euchrestifolia
Full Article: https://link.springer.com/article/10.1007/s13659-024-00483-7
This study isolated fifteen novel carbazole alkaloids, Euchrestifolines A–O, from Murraya euchrestifolia. It is the first report that carbazole alkaloids possess anti-ferroptotic activity, with some compounds showing EC50 values as low as 0.04–1 μM, significantly superior to the positive control ferrostatin-1. This study provides potent natural lead structures for inhibiting lipid peroxidation and opens a new direction for the discovery of ferroptosis-related lead compounds.
4. Novel neo-clerodane diterpenoids from Teucrium quadrifarium and their anti-ferroptosis effect
Full Article: https://link.springer.com/article/10.1007/s13659-024-00489-1
This study isolated four novel neo-clerodane diterpenoids, Teucrifarides A–D, from Teucrium quadrifarium. Among them, compounds 1 and 12 showed significant inhibitory effects on RSL3-induced ferroptosis in HT-22 cells, with EC50 values of 11.8 ± 1.0 μM and 4.52 ± 1.24 μM, respectively. This study further expands the scaffold types of anti-ferroptotic compounds and provides new natural product lead structures for the strategy of “killing tumors while protecting normal cells.”
III. Intervening in Iron Homeostasis and Cross-Species Regulation
This study accomplished the facile synthesis of glomuferrin and rhizoferrin and demonstrated that they can act as ferroptosis inhibitors in rice blast disease, indicating that siderophores can inhibit ferroptosis by intervening in iron homeostasis, and that the mechanism also exists in plant diseases, making them important tools for cross-species regulation.
5. Facile synthesis and biological evaluation of glomuferrin and rhizoferrin as ferroptosis inhibitors in rice blast disease
Full Article: https://link.springer.com/article/10.1007/s13659-026-00619-x
This study accomplished the facile synthesis of glomuferrin and rhizoferrin and demonstrated that they can act as ferroptosis inhibitors to block appressorium development in the rice blast fungus. In Pyricularia oryzae, intracellular Fe3+and ROS accumulation promote lipid peroxidation, triggering conidial ferroptosis and thereby driving infection. This study inhibits ferroptosis by intervening in iron homeostasis via siderophores. Although it is not a tumor model, iron homeostasis regulation is a core node in tumor iron metabolism and ferroptosis, providing tools and mechanistic inspiration for cross-species ferroptosis intervention.
The five articles, from the three perspectives of tumor therapy, cell protection, and cross-species intervention, showcase different directions in ferroptosis research—inducing it in tumors and inhibiting it in normal cells or plants. Hsp70, Trichoderma viride, carbazole alkaloids, neo-clerodane diterpenoids, and siderophores provide targets, inducers, inhibitors, and tools for iron homeostasis intervention, respectively. Together, these works suggest that the value of ferroptosis is not fixed but varies with the direction of regulation and the application context. For this reason, how to choose the appropriate regulatory strategy according to the specific context has become key to translating ferroptosis research into applications.