Histone lactylation, a recently identified post-translational modification, is closely linked to the pathogenesis and progression of malignant tumors, making it a promising therapeutic target for acute myeloid leukemia (AML). Increasing clinical and experimental evidence indicates that elevated serum lactate dehydrogenase (LDH) levels serve as both a diagnostic biomarker and an indicator of poor prognosis in AML, reflecting enhanced glycolytic activity and chemotherapy resistance. Patrinia scabiosaefolia Fisch (PS), a traditional medicinal herb, exhibits broad pharmacological activities, including heat-clearing, detoxifying, antibacterial, antiviral, and antitumor effects. However, the molecular mechanisms underlying its antileukemic activity, particularly in AML, remain insufficiently defined. To elucidate how DEPS exerts therapeutic effects in AML through the HIF-1α-histone lactylation axis, we systematically established the association between DEPS-mediated inhibition of histone lactylation and cellular hypoxia. Lactylation pan-antibody incubation confirmed preliminarily that DEPS significantly inhibits histone lactylation modification. Lactate restoration experiments further demonstrated that DEPS markedly suppresses lactate-induced activation of HIF-1α signaling, reducing downstream metabolic proteins and VEGFA expression. Under hypoxic conditions, AML cells displayed increased proliferation and histone lactylation, both of which were attenuated by DEPS treatment. Sodium L-lactate enhanced the expression of HIF-1α and its downstream effectors (HK2, PDK1, PKM2, GLUT1, LDHA, and VEGFA), whereas subsequent DEPS exposure significantly reversed these changes. Ultimately, DEPS inhibits H3/H4 lysine lactylation, induces G2/M cell-cycle arrest, and promotes apoptosis in THP-1 and HL-60 cells, including doxorubicin-resistant HL-60 cells. Collectively, our findings reveal previously uncharacterized antileukemic mechanisms of DEPS involving suppression of the HIF-1α signaling pathway and histone lactylation. These results highlight the importance of epigenetic regulation in AML and support the therapeutic potential of DEPS in AML treatment and reversal of chemoresistance.
Zhang et al. (2026) studied this question.