Our lab had long been interested in PRMT5, an epigenetic regulator frequently overexpressed in lymphoma and known to support tumor growth and survival. Previous studies—including work from our group—had shown that PRMT5 regulates key oncogenic pathways such as PI3K–AKT signaling and MYC activity. My initial goal was to better understand how PRMT5 contributes to lymphoma biology, particularly from a metabolic perspective.
During these studies, we began to notice something intriguing. Across multiple experiments, PRMT5 expression seemed to correlate with the antioxidant capacity of lymphoma cells. When PRMT5 levels were high, cells maintained a stronger redox balance. When PRMT5 was inhibited, we repeatedly observed reduced glutathione levels and increased oxidative stress. At the time, we viewed this mainly as a metabolic phenotype—just another way PRMT5 might support tumor cell fitness.
But we did not immediately connect it to ferroptosis.
That connection came later.
As ferroptosis began to gain attention as a distinct form of regulated cell death—driven by lipid peroxidation and tightly linked to cellular redox homeostasis—it caught my attention. The central role of glutathione in suppressing ferroptosis made me think back to our earlier observations. If PRMT5 was indeed regulating antioxidant capacity, could it also be controlling ferroptosis?
This question marked the beginning of a new direction for the project.
We started with a simple idea: are B-cell lymphoma cells sensitive to ferroptosis? Based on findings from other cancer types, we expected ferroptosis to represent a potential vulnerability. However, the results were not what we anticipated.
Across multiple lymphoma cell lines, we initially observed that inhibiting PRMT5 alone did not lead to any obvious changes in lipid peroxidation. Basal levels remained low, and there was no clear evidence of ferroptosis induction.
At first, this was puzzling. If PRMT5 was linked to antioxidant regulation, why didn’t its inhibition trigger ferroptotic stress on its own? It seemed that, at least under these conditions, ferroptosis might not play a major role in these cells.
In hindsight, this absence of change was not a dead end—but a hint that something was actively holding ferroptosis in check.
This shift in perspective changed everything.
Given our earlier observations on PRMT5 and redox regulation, we hypothesized that PRMT5 might be part of this suppression mechanism. When we inhibited PRMT5 alone, we did not see dramatic lipid peroxidation. But when we combined PRMT5 inhibition with ferroptosis-inducing agents, the effect was striking. Cells that were previously resistant suddenly became highly sensitive.
I still remember the moment we first saw the sharp increase in lipid peroxidation by flow cytometry after combining PRMT5 inhibition with dimethyl fumarate (DMF). It was a clear signal that something fundamental had shifted.
It became clear that ferroptosis was not absent—it was being actively restrained.
From there, we worked to uncover the underlying mechanism. We found that PRMT5 regulates the expression of SLC7A11, a key transporter that imports cystine for glutathione synthesis. By maintaining SLC7A11 expression, PRMT5 sustains intracellular glutathione levels and protects cells from lipid peroxidation.
We then traced this regulation upstream and identified an unexpected transcriptional pathway. PRMT5 signals through the AKT–MYC axis to upregulate ATF5, a transcription factor that had not been well explored in the context of ferroptosis. ATF5, in turn, drives SLC7A11 expression and also reinforces the pathway by promoting ATF4 expression.
Together, this PRMT5–AKT–MYC–ATF5–SLC7A11 axis establishes a stable transcriptional program that actively suppresses ferroptosis in lymphoma cells.
What I found particularly exciting about this mechanism is how it brings together several core features of lymphoma biology—epigenetic regulation, oncogenic signaling, and metabolic control—into a single functional framework. Rather than acting through one pathway, PRMT5 appears to coordinate a broader cellular state that shields tumor cells from ferroptotic stress.
Once we understood this, the therapeutic implications became clear. If PRMT5 is maintaining a ferroptosis-resistant state, then inhibiting PRMT5 might expose a hidden vulnerability.
To test this idea, we combined PRMT5 inhibitors with dimethyl fumarate (DMF), an FDA-approved drug known to induce ferroptosis. While each treatment alone had only modest effects, the combination showed strong synergy, both in cell lines and in patient-derived xenograft models. Seeing this synergy emerge from the biology we had uncovered was one of the most rewarding moments of the project.
Looking back, what stands out most to me is how this study evolved from an observation that initially seemed peripheral. The link between PRMT5 and antioxidant capacity was not something we set out to pursue in depth. But paying attention to that pattern—and being willing to connect it to a new concept—opened up an entirely new direction.
It also reinforced an important lesson: some of the most interesting discoveries come not from confirming what we expect, but from following what does not immediately make sense.
Ferroptosis is still an emerging field, particularly in hematologic malignancies. Our work suggests that in B-cell lymphoma, ferroptosis is not simply inactive—it is actively suppressed by oncogenic programs. Understanding how tumor cells build this protective barrier may be key to overcoming therapeutic resistance.
For me, this project was not just about defining a new mechanism, but about learning to recognize connections across different areas of biology—and trusting unexpected observations.
And sometimes, the most important discoveries begin with a question you never intended to ask.