The Histone Lactylation of KREMEN2 Inhibits Ferroptosis Through the JAK2/STAT3/GPX4 Axis and Promotes the Progression of Mantle Cell Lymphoma

ABSTRACT

Mantle cell lymphoma (MCL) is an incurable B‐cell tumor, and new therapeutic targets are urgently needed. This study demonstrates that kringle‐containing transmembrane protein 2 (KREMEN2) is a key oncogenic factor in MCL. Mechanistically, lactate accumulated by abnormal tumor metabolism directly enhances the transcriptional expression of KREMEN2 by driving histone H3K18 lactylation (H3K18la). High expression of KREMEN2 further activates the Janus kinase 2/signal transducer and activator of transcription 3/Glutathione Peroxidase 4 (JAK2/STAT3/GPX4) signaling pathway to inhibit ferroptosis, and ultimately promotes malignant progression. Functionally, KREMEN2 knockdown induced ferroptosis and inhibited proliferation, and Erastin could not further induce ferroptosis in this state, demonstrating that KREMEN2 drove the progression of MCL by inhibiting the core ferroptotic phenotype. In addition, overexpression of downstream STAT3 can effectively reverse the phenotype caused by KREMEN2 knockdown. In vivo and in vitro experiments consistently demonstrated that inhibiting lactate production or knocking down KREMEN2 could inhibit tumor growth, and the combination of the two had a better effect. This study identifies a regulatory axis in MCL linking histone H3K18 lactylation to KREMEN2‐mediated JAK2/STAT3/GPX4 pathway activation, providing a potential basis for developing targeted therapies against this disease.