Agrimol B induces apoptosis and ferroptosis in acute monocytic leukemia by targeting EGFR/ERK1/2 signaling and activating SIRT1.

Leukemia is an aggressive hematologic malignancy with high global morbidity and mortality. Despite advances in CAR-T cell therapy and targeted treatments, acute myeloid leukemia and high-risk relapsed cases continue to face formidable therapeutic challenges owing to heterogeneity and drug resistance. Agrimol B (AB), a bioactive natural compound isolated from the edible and medicinal plant Agrimonia pilosa Ledeb., has demonstrated notable anticancer potential. However, its role in leukemia has not yet been investigated. Here, we demonstrate that AB significantly reduces leukemia burden in an Acute Monocytic Leukemia (AMoL) mouse model and suppresses proliferation, invasion, and migration of THP-1 cells in vitro. Mechanistically, AB interacts with EGFR and inhibits ERK1/2 signaling, thereby activating FOXO1. In addition, AB upregulates SIRT1 expression and promotes FOXO1 deacetylation, leading to HMOX1 activation and subsequently triggers ferroptosis. These findings indicate that Agrimol B exerts potent anti-leukemic activity through multiple mechanisms, highlighting its potential as a therapeutic candidate for AMoL.