MALT1 inhibitor MI-2 induces ferroptosis by direct targeting of GPX4

Mishima E, O'Neill TJ, Hoefig KP, Chen D, Behrens G, Henkelmann B, Ito J, Nakagawa K, Heissmeyer V, Conrad M, Krappmann D. (2025) MALT1 inhibitor MI-2 induces ferroptosis by direct targeting of GPX4. Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2507997122. doi: 10.1073/pnas.2507997122. Epub 2025 May 9

Ferroptosis, a form of cell death driven by excessive lipid peroxidation, is induced by inhibiting GPX4, a key regulator of ferroptosis. Wang et al. reported that MALT1 protease activity regulates GPX4 protein stability, thereby modulating sensitivity of cancer cells to ferroptosis (1). Their study suggests that MALT1 protects GPX4 from ubiquitin-dependent degradation by cleavage of the E3 ubiquitin ligase Roquin-1 (RC3H1). However, ferroptosis induction by MALT1 inhibition was investigated using MI-2, a low-potency, irreversible MALT1 inhibitor (IC50 2.1 µM; Fig. 1A) (2). Here, we reexamine the role of the MALT1–Roquin-1 axis and unravel the actual ferroptosis-inducing mechanism of MI-2. more