Redox destabilization by ibrutinib promotes ferroptosis in diffuse large B-cell lymphoma (DLBCL)

Area of Science:

• Oncology
• Cell Death Pathways
• Hematologic Malignancies

Background:

• Diffuse Large B-cell Lymphoma (DLBCL) presents significant clinical heterogeneity and treatment resistance, especially in high-risk subtypes.
• Current DLBCL therapies primarily focus on apoptosis, leaving non-apoptotic cell death mechanisms underexplored.
• Understanding alternative cell death pathways is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate ferroptosis as a potential therapeutic target in DLBCL.
• To evaluate the additive effects of ferroptosis induction and ibrutinib in DLBCL treatment.
• To elucidate the mechanisms by which ibrutinib enhances ferroptosis sensitivity.

Main Methods:

• Transcriptomic and lipidomic analyses of DLBCL cells.
• Inhibition of GPX4 to induce ferroptosis.
• Combination therapy studies with GPX4 inhibition and ibrutinib.
• Investigation of ibrutinib's molecular activities on ferroptosis pathways.

Main Results:

• DLBCL cells express elevated levels of core ferroptosis protective machinery.
• GPX4 inhibition triggers rapid lipid ROS accumulation and cell death in DLBCL models.
• Ibrutinib demonstrates additive effects with GPX4 inhibition, enhancing ferroptosis sensitivity.
• Ibrutinib acts as a glutathione scavenger and inhibits GPX4 protein expression.

Conclusions:

• Ferroptosis serves as a viable basis for additive therapy in DLBCL, particularly in combination with ibrutinib.
• Ibrutinib possesses unrecognized activity in modulating anti-oxidant defense, thereby enhancing ferroptosis.
• These findings offer a novel therapeutic avenue for overcoming treatment resistance in DLBCL.