“By uncovering how LUBAC and TRAF6 cooperate to regulate MALT1 protease activity, our study provides important clues for how this signaling pathway can be selectively targeted,” says Daniel Krappmann.

Understanding these regulatory mechanisms opens new avenues for therapeutic strategies aimed at modulating MALT1 protease activity – for example, to enhance anti-tumor immunity or to limit excessive inflammatory responses.

This work highlights a successful collaboration between the Molecular Targets and Therapeutics Center and the Computational Health Center at Helmholtz Munich, together with international and academic partners from the University of Melbourne (Australia), Friedrich Schiller University Jena, and Ludwig-Maximilians-University Munich. By combining molecular biology and computational modeling, the teams have advanced the understanding of signaling pathways that shape adaptive immunity.

Original publication

Graß et al., 2025: LUBAC modulates CBM complex functions downstream of TRAF6 in T cells. Nature Communications. DOI: 10.1038/s41467-025-65879-6

Prion diseases are caused by the accumulation of misfolded brain proteins known as prions, which trigger a cascade of abnormal folding in surrounding proteins. This chain reaction causes severe brain damage, memory loss, and rapidly progressing dementia. These conditions are currently incurable and uniformly fatal.

Ferroptosis: A Key Mechanism of Neuronal Damage

At the heart of the new finding is ferroptosis, a regulated form of cell death driven by iron overload, oxidative stress, and damage to cell membranes through lipid peroxidation. The study shows that endogenous and misfolded prion proteins create the cellular conditions that promote ferroptosis, particularly in neurons.

The discovery builds on earlier work by the team, which identified the Fatty Acid-Binding Protein 5 (FABP5) as a biomarker and contributor to ferroptosis in brain tissue. The team now demonstrates the prion protein’s role in creating a cellular environment conducive to ferroptosis by altering oxidative stress levels and lipid composition, revealing a previously unknown pathway of disease progression.

RAC3: A Missing Piece in the Puzzle

The study newly highlights the importance of RAC3, a protein that facilitates ferroptosis. Cells expressing RAC3 were substantially lost in brain regions affected by prion buildup, a decrease directly correlated with the severity of neuronal damage.

“RAC3 seems to play a facilitative role,” says corresponding author Joel Schick. “Its presence contributes to ferroptosis being triggered. This makes it a very compelling candidate for future therapeutic targeting.”

Towards New Treatment Strategies

Although this study focuses on CJD, its findings may extend to other prion-related disorders that share similar pathogenic mechanisms, such as mad cow disease. As ferroptosis gains recognition as a key player in various neurodegenerative diseases, deeper insights into its regulation in prion diseases could pave the way for novel therapeutic approaches.

“This study enhances our understanding of shared pathways in neurodegeneration,” explains Schick. “By targeting ferroptosis and key regulators like RAC3, we hope to open new avenues for treatment – not only for CJD but potentially for a broader spectrum of prion-related conditions.“

How Vitamin A and Antioxidants Combat Ferroptosis in Early Neurodevelopment

The research team led by Dr. Kamyar Hadian and Dr. Michelle Vincendeau has uncovered a new role for ferroptosis in neuronal development. In the study, now published in Nature Communications, the scientists explored neuronal differentiation under conditions with or without antioxidants. They found that mature neurons could only be generated in the presence of antioxidants. Surprisingly, they discovered that vitamin A could counteract ferroptotic stress and promote neurogenesis. This finding was further validated using physiologically relevant brain organoid models (“mini-brains-in-a-dish”), where inhibiting ferroptosis was essential for the proper organization. The study also revealed that all-trans-retinoic acid, an active metabolite of vitamin A, activates the retinoic acid receptor (RAR), which upregulates key regulators of ferroptosis suppression.

Together, these new findings uncover a key detrimental role of ferroptosis during neurodevelopment. With this insight, researchers can now more effectively regulate ferroptosis in neuronal production for stem-cell-based therapies. Moreover, the results show that managing vitamin A is essential when conducting studies involving ferroptosis-targeted treatments.

_{Funding information
M.V. was funded by the Deutsche Forschungsgemeinschaft (RTG2668 – project number 435874434, Sachbeihilfe – project number 496872373, Sachbeihilfe – project number 498956525, and Sachbeihilfe – project number 497803923)}

FABP5 - A Key Biomarker for Ferroptosis

In a long-running study, the team of researchers around Dr. Joel Schick, Group Leader in the Research Unit “Signaling and Translation” at Helmholtz Munich, successfully identified a specific biomarker for ferroptosis in vivo. The key protein identified during this process is the fatty acid binding protein five (FABP5), which exhibited upregulation during the progression of ferroptosis. This finding was observed not only in laboratory cells but also in a unique patient cohort – individuals who experienced cerebral hypoxia following cardiac arrest, prior to passing. In effect, dying twice.

Prior to this study, a definitive marker had not been identified to detect ferroptosis’ contribution to disease. This highly representative human pathology cohort provided a unique opportunity to detect ferroptosis in humans. Additionally, as most pathological investigations are conducted on paraffin-embedded tissue, the identification of FABP5 as a reliable marker enables the retrospective detection of ferroptosis in tissues.

Disease Understanding and Therapeutic Implications

These findings mark a significant milestone in the study of ferroptosis and its implications for human diseases. The retrospective detection of this enigmatic form of cell death opens doors for further research and potential therapeutic interventions.

“Our discovery of a specific biomarker for ferroptosis in human pathological conditions represents a significant breakthrough in our understanding of this complex form of cell death,” states Hao Peng, the first author of the study.

“With this study we identified an important new tool to characterize the role of ferroptosis. This finding brings us closer to unraveling the mysteries of ferroptosis and its implications for human diseases”, adds Dr. Schick.

An oncogene is a gene that has the potential to cause cancer. In the EBV the primary oncogene is the latent membrane protein 1 (LMP1): It drives oncogenic cell transformation and tumor development. The authors show in the study that the viral LMP1 protein forms a direct complex with TRAF6, a protein derived from the host cell that is involved in biochemical signal transmission processes such as the activation of the NF-kappaB pathway (a cellular pathway, regulating genes involved in immunity, inflammation and cell survival). Furthermore, the researchers provide detailed insights into the molecular functions and structure of the LMP1-TRAF6 complex and demonstrate that the direct interaction of the two proteins is critical for LMP1 to activate the NF-kappaB pathway and to promote cell survival in lymphoma cells.

In summary, the LMP1-TRAF6 complex is identified as an important novel virus-host interface that is critical for the survival of EBV-positive lymphoma cells. By disrupting the direct complex of LMP1 and TRAF6 with inhibitory peptides it is possible to efficiently interfere with the survival of EBV-transformed human B cells. With this study the authors identify and validate the complex of LMP1 and TRAF6 as a promising novel therapeutic target structure in EBV-associated cancer, a breakthrough in the EBV and cancer field.“This publication and our studies on the interaction between the LMP1 protein of EBV and the cellular TRAF6 protein will allow the development of innovative inhibitory molecules as future drugs directed against EBV-driven cancer”, says Arnd Kieser, the last author of the paper.

^{Funding information:
Major funding (to Arnd Kieser): DFG grants Ki 825/1-3,TTU 07.802, TTU 07.809, and TTU 07.825 from the German Research Center for Infection Research (DZIF) - Additional funding of cooperation partners: Grant RTG 2467 (project number 391498659) by German Research Foundation (DFG) to Stephan Feller, grant TTU 07.710 from the German Research Center for Infection Research (DZIF) to Andreas Moosmann}

Farnesoid X Receptor Activation by Bile Acids Prevents Ferroptotic Cell Death

A team of researchers led by Dr. Kamyar Hadian from the Research Unit Signaling and Translation at Helmholtz Munich performed a chemical genetics screen to identify novel regulators of ferroptosis. This means, that the scientists exposed cells to thousands of diverse compounds with known mode of action and subsequently assessed cell viability. This approach was employed to elucidate the pathways and regulators associated with ferroptosis. They discovered that the nuclear receptor Farnesoid X Receptor (FXR) is a potent inhibitor of lipid peroxidation and ferroptosis. The FXR is mainly expressed in the liver, kidney, and small intestine, and is activated by bile acids. This study, published in Nature Communications, demonstrates that the FXR is a master regulator of ferroptosis by upregulating the transcription of essential ferroptosis gatekeepers, thereby inhibiting lipid peroxidation and ferroptosis. Hence, the activation of FXR by bile acids or specific small molecules effectively rescued cells from ferroptotic cell death.

These findings suggest that organs and tissues that are generally at higher exposure to toxins or drug metabolites have upregulated FXR as a protective measure against ferroptotic cell death. Specific compounds that activate FXR will be evaluated in future studies as novel molecules in the treatment of degenerative diseases such as acute kidney or liver injury to prevent cell death by ferroptosis. Moreover, this study provides an unexpected novel function for bile acids as suppressors of lipid peroxidation and ferroptosis.

About the scientists

Juliane Tschuck, doctoral researcher at the Research Unit Signaling and Translation at Helmholtz Munich

Dr. Kamyar Hadian, Deputy Director of the Research Unit Signaling and Translation at Helmholtz Munich

Ulrike Protzer developed TherVacB, a promising therapeutic hepatitis B vaccine capable of reactivating antiviral immune responses and a promising solution to the global health challenge of chronic hepatitis B. Preclinical models have demonstrated its effectiveness, and initial clinical trials are set to begin soon. The m4 Award will play a vital role in facilitating the essential development stages required for the ultimate formulation of TherVacB, and preparations for the establishment of a spin-off company to drive further clinical development.

Kamyar Hadian's pioneering efforts are focused on the treatment of RA. His project has yielded first-in-class inhibitors that show promise in improving the outcome of RA treatment in preclinical models. With the support of the m4 Award, the project will optimize compounds and advance these toward clinical testing, potentially revolutionizing the treatment of rheumatoid arthritis.

The groundbreaking work of Ulrike Protzer and Kamyar Hadian holds immense promise in advancing the treatment of hepatitis B and RA, offering new solutions to patients in need of innovative therapies.

More information

Read the full press release BioM here.

Check out more about Prof. Ulrike Protzer at the Institute of Virology and about the Hadian Group at the Research Unit Signaling and Translation.

Lymphoma is a type of cancer that is very heterogeneous in nature and originates in the lymphatic system. Many fast-growing aggressive lymphomas are resistant to current therapies. MALT1 protease is important for the survival of many aggressive lymphomas and thus a promising target to treat such cancers. Several academic and industrial drug discovery programs, one headed by Prof. Daniel Krappmann at Helmholtz Munich’s Molecular Targets and Therapeutic Center, have promoted clinical trials that evaluate MALT1 inhibitors for the treatment of cancer. However, the exact mechanisms of how MALT1 drives lymphoma cell survival have largely remained elusive. The present study led by the biomedical scientist Daniel Krappmann in cooperation with computational scientist Michael Menden demonstrates that MALT1 protease activity drives lymphoma cell survival by controlling mRNA metabolism. The work highlights that oncogenic mutations inside the cancer cells are directly affecting the stability of distinct mRNAs, opening an avenue for new therapeutic targets and molecular biomarkers to classify patients and predict patient responses to therapy.

Development of New Precision Therapies for Lymphomas

Based on these findings, the researchers aim to develop new biomarkers for the prediction of lymphoma patients that will most likely profit from MALT1-directed therapy, which in turn will help to improve the design of the clinical trials. Further, the data will facilitate monitoring of the patients' clinical responses, when they are treated with MALT1 inhibitors. Finally, regulation of mRNA metabolism may open avenues for new therapeutic approaches to improve anti-lymphoma therapies.

Original publication

Wimberger et. al. (2023): Oncogene-induced MALT1 protease activity drives post-transcriptional gene expression in malignant lymphomas. Blood. doi/10.1182/blood.2023021299

About the scientists

Prof. Dr. Daniel Krappmann, Director of Signaling and Translation at the Molecular Targets and Therapeutic Center at Helmholtz Munich

Prof. Dr. Michael P. Menden, Principal Investigator at the Institute of Computational Biology at the Computational Health Center at Helmholtz Munich and Associate Professor at the University of Melbourne, Department of Biochemistry and Pharmacology

_{Funding information}

_{This work was supported by the Deutsche Krebshilfe award grant 70112622 and the Deutsche Forschungsgemeinschaft (DFG) – Project ID 210592381 – SFB 1054 A04 and ID 360372040 – SFB 1335 P07 to D.K. and the European Union's Horizon 2020 Research and Innovation Programme (Grant agreement No. 950293 - COMBAT-RES) to M.P.M and by the Federal Ministry of Education and Research (BMBF)-funded German Network for Bioinformatics Infrastructure (de.NBI).}

Precise Attack on Tumor Remnants

The promising antibody* is the result of many years of basic research. “We could not have developed this antibody to this point without a great deal of perseverance,” Zeidler says. “The reason it is so well suited for cancer therapy is that it can distinguish tumor cells from healthy cells much more precisely than chemotherapy, for example. Treatment therefore promises significantly fewer side effects.” Combined with a radionuclide from the radiopharmaceutical biotech company ITM, which destroys the targeted cancer cells with its radiation, the new drug candidate is entering a clinical trial conducted by Münster University Hospital and led by Prof. Walter Stummer. “Our goal is to eliminate completely any remaining cancer cells that could not be removed or destroyed with classical treatment,” Zeidler explains. In this way, the drug should prevent the tumor from re-growing or at least delay this process.

Launch of Trials in German Hospitals

In addition to Münster University Hospital, the university hospitals in Essen, Cologne and Wurzburg are offering treatments as part of this clinical trial. Patient recruitment for the study is currently ongoing. Further details can be found in the press release of ITM Isotope Technologies Munich: https://www.itm-radiopharma.com/news/press-releases/press-releases-detail/ITM,_Helmholtz_Munich_and_University_Hospital_M%C3%BCnster_Announce_Start_of_Phase_I_Clinical_Trial_with_Radiotherapeutic_ITM-31_for_Glioblastoma-605/

*Learn more about the antibody developed by Helmholtz Munich:

The antibody binds specifically to the enzyme carbonic anhydrase XII, which is found exclusively on cancer cells in the brain - presumably, because it is of great importance for their rapid growth. Coupled to lutetium-177, a radioactive emitter, the antibody has a dual effect: first, it inhibits the enzyme, and second, it directs lutetium-177 specifically to tumor cells that could not be eliminated by standard therapies and that form the origin of a new tumor. The radiation released during the radioactive decay of lutetium-177 destroys the tumor cells in the immediate environment.

The research focus of SAT is to investigate molecular mechanisms of cellular signaling in response to environmental stimuli and immune stimulators. The goal is to understand the physiological significance of signaling pathways and to uncover dysfunctions in these processes in the development of disease. With these findings, SAT is developing new therapeutic methods to enable targeted and improved therapies for human diseases. Key areas for clinical translation are the development of new concepts for the treatment of cancer and immune diseases. The work of SAT is supported by four research groups (see graphic). To support drug discovery research at Helmholtz Munich, SAT operates the 'Compound Screening Platform' led by Dr. Kamyar Hadian.