Ferroptosis, a form of iron-dependent cell death, is attracting growing interest in cancer research. A better understanding of the mechanisms that make tumour cells susceptible to, or conversely resistant, that make tumour cells susceptible, or conversely resistant, to this process could pave the way for new therapeutic approaches, particularly in lung cancer.

In a study published in the journal Molecular Cell (CRL2FEM1B uses heme to recruit BACH1 for degradation and regulate ferroptosis in lung cancer.), the team led by Luca Lignitto, head of the Haem, Ubiquitin and Lung Cancer team at the CRCM, has shed light on a previously unknown molecular mechanism linking haem metabolism to the regulation of ferroptosis. This discovery reveals how a small molecule naturally present in cells can act as a veritable ‘molecular glue’ to control the fate of cancer cells.

We met with Luca to discuss the key findings of this research, its implications for lung cancer research, and the prospects it opens up for the development of future treatment strategies.

Can you summarize this study in a few sentences for a non-specialist audience?

Luca Lignitto : “Cells use sophisticated sensing mechanisms to monitor their internal environment and respond to changes in metabolic and stress conditions. In this study, we discovered how a molecule called heme functions as a signal that controls a cancer cell’s sensitivity to a form of iron-dependent cell death called ferroptosis. We found that heme enables the E3 ubiquitin ligase FEM1B to recognize and degrade a transcription factor named BACH1, which normally protects cancer cells from ferroptosis. This mechanism helps determine whether lung cancer cells resist or succumb to oxidative damage-induced cell death.”

What is the main discovery of this work, and why is it important for lung cancer research?

LL : “Our main discovery is that heme directly controls BACH1 stability through the E3 ubiquitin ligase FEM1B. Mechanistically, heme promotes the interaction between FEM1B and BACH1 through a mechanism reminiscent of molecular glue degraders, leading to BACH1 ubiquitination and degradation. This uncovers a direct link between heme sensing, targeted protein degradation, and ferroptosis sensitivity. From a translational perspective, this finding is particularly relevant because, while BACH1 promotes lung cancer progression and metastasis, our data show that it also renders lung cancer cells vulnerable to ferroptosis, revealing a potential therapeutic opportunity. More broadly, our work identifies a new mechanism through which metabolic signals can regulate tumor cell fate.”

Ferroptosis has attracted considerable interest as a potential anti-cancer strategy. How does your work advance efforts to exploit ferroptosis therapeutically?

LL : “Ferroptosis-based therapies will likely require not only agents that trigger ferroptosis, but also strategies that identify or create ferroptosis-sensitive tumor states. Our work contributes to this effort by uncovering a mechanism that controls ferroptosis sensitivity through regulated BACH1 degradation. By modulating the FEM1B–heme–BACH1 axis, it may be possible to influence how effectively tumor cells respond to ferroptosis-inducing therapies. More broadly, these findings provide a mechanistic framework for exploiting ferroptosis vulnerabilities in lung cancer and potentially other tumor types.”

How important were structural, biochemical, or genomic approaches in deciphering this pathway?

LL : “These approaches were indispensable! We started with a biological question, but answering it required understanding the pathway at several different scales. Structural biology allowed us to visualize how heme promotes the interaction between FEM1B and BACH1. Biochemical and cellular approaches established the functional consequences of this interaction, while genomic analyses revealed how BACH1 degradation rewires transcriptional programs linked to ferroptosis and tumor biology. The story only came together because we were able to integrate these different perspectives into a coherent mechanism!”

What were the biggest technical or conceptual challenges encountered during the project?

LL : “The biggest challenge was figuring out how heme was actually controlling BACH1 degradation. We knew that heme played an important role, but for a long time we did not understand the underlying mechanism. The idea that a small metabolite could directly promote the interaction between an E3 ubiquitin ligase and its substrate was not something we initially expected. Demonstrating this required years of work and the integration of structural, biochemical, and cellular data. Looking back, much of the project revolved around solving this single question, and many of the key discoveries emerged only after we finally understood how heme coordinates the assembly of the FEM1B–BACH1 complex.”

What additional studies are needed before these findings could potentially translate into clinical applications?

LL : “While our study uncovers a new mechanism controlling ferroptosis sensitivity, translating these findings into therapeutic applications will require several additional steps. First, we need to establish how broadly the FEM1B– heme–BACH1 pathway contributes to tumor biology across different cancer contexts and in patient-derived models. Second, it will be important to determine whether components of this pathway can serve as biomarkers of ferroptosis sensitivity and treatment response. Finally, the molecular mechanism we uncovered raises the intriguing possibility of pharmacologically modulating BACH1 stability through targeted protein degradation strategies. Exploring these opportunities will be an important focus of future preclinical studies.”

Could this mechanism be relevant beyond lung cancer, in other cancer types that depend heavily on iron metabolism?

LL : “Absolutely. We suspect that the relevance of this mechanism extends well beyond lung cancer. BACH1 has emerged as an important regulator of tumor progression in several cancer types, while alterations in iron and heme metabolism are hallmarks of many aggressive tumors. Cancers such as pancreatic, breast, and liver cancer are particularly compelling candidates because they often display metabolic features that could make them sensitive to regulation by the FEM1B– heme–BACH1 axis. While this remains to be formally tested, the broad conservation of this pathway suggests that it may represent a more general mechanism linking metabolic state to ferroptosis sensitivity across multiple cancers.”

Is there a simple analogy that can help explain how heme acts as a molecular switch controlling the cell’s sensitivity to ferroptosis?

LL : “A useful analogy comes from the field of targeted protein degradation. Heme behaves somewhat like a natural molecular glue: it helps FEM1B and BACH1 stick together, allowing FEM1B to mark BACH1 for destruction. By controlling BACH1 levels, heme ultimately influences how sensitive cancer cells are to ferroptosis. What makes this particularly interesting is that heme has traditionally been viewed as a metabolic cofactor, whereas our work reveals an unexpected role as a direct regulator of protein degradation.”

Looking ahead, what are the next research questions your team wants to address?

LL : “One of our next goals is to obtain a high-resolution structural view of the heme–FEM1B–BACH1 complex. Although our study established the mechanism functionally, we still lack a complete picture of how heme coordinates the interaction between FEM1B and BACH1 at the structural level. We would therefore like to pursue cryo-EM studies of the complex. Such work could provide fundamental insights into this unusual mode of substrate recognition and help guide future efforts to therapeutically manipulate the pathway.”

And finally, is there a memorable or funny story from the project that you can share?

LL : “One memorable, funny moment from the project involved Bashir, PhD student in our team and lead author of the study. He was trying to load protein samples into an acrylamide gel, but every time he pipetted them into the wells, they would simply float away… After several attempts, increasingly puzzled by this apparently impossible phenomenon, and after coming up with incredible hypotheses — perhaps a molecular glue-dependent effect! — he eventually discovered the problem, he was loading the samples in 10× running buffer…”