Lymphoma remains a major hematological malignancy associated with treatment resistance and systemic toxicity, highlighting the need for novel anticancer agents derived from natural products. In this study, dicentrine (5), an aporphine alkaloid isolated from Stephania venosa, was investigated for its anti-lymphoma activity in Raji and Ramos cells. Among the isolated compounds, dicentrine (5) exhibited the strongest cytotoxic activity, with IC₅₀ values of 9.03 ± 0.53 and 5.16 ± 0.44 µg/mL in Raji and Ramos cells, respectively, while demonstrating favorable selectivity toward lymphoma cells relative to peripheral blood mononuclear cells (PBMCs). Dicentrine (5) significantly suppressed c-Myc and phosphorylated c-Myc expression, reduced lymphoma cell proliferation, and decreased total viable cell numbers in a dose-dependent manner. Cell cycle analysis revealed G0/G1 arrest in Raji cells and G2/M arrest in Ramos cells. Furthermore, dicentrine (5) induced apoptosis, as evidenced by increased Annexin V-positive populations and elevated cleaved caspase-3 expression. Molecular docking analysis demonstrated strong binding affinities of dicentrine (5) toward Akt, PI3K, caspase-3, and caspase-9, while network pharmacology identified AKT1 and the PI3K/Akt signaling pathway as potential targets associated with lymphoma suppression. Western blot analysis further demonstrated that dicentrine (5) significantly reduces total Akt protein expression. Overall, the present findings indicate that dicentrine (5) suppresses lymphoma progression by inhibiting cell proliferation and promoting apoptotic cell death, highlighting its potential as a promising natural therapeutic candidate for lymphoma.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy with poor prognosis, frequent relapse, and treatment-related toxicity. The discovery of novel anti-leukemic agents with improved selectivity remains an urgent clinical need. In this study, rhizomes of Angiopteris evecta, a medicinal plant used in Thai traditional medicine, were collected from twelve locations in Thailand and extracted using solvents of increasing polarity. Among thirty-six crude fractional extracts, the ethyl acetate crude fractional extract from source No. 003 (AE EtOAc No. 003) exhibited the strongest cytotoxic activity against KG-1a and EoL-1 leukemic cell lines, with low toxicity toward normal peripheral blood mononuclear cells. Bioactivity-guided fractionation yielded the ternary mixture, a furanone-rich mixture dominated by 5-(1-hydroxyethyl)-dihydro-2-furanone. The ternary mixture inhibited leukemic cell proliferation by inducing apoptosis, causing cell cycle arrest, and downregulating WT1 expression in EoL-1 cells. Network pharmacology and molecular docking analyses implicated AKT1, MAPK signaling, apoptosis-related pathways, and WT1 as key molecular targets. In addition, AE EtOAc No. 003 and the ternary mixture suppressed TNF-α and IL-6 production in LPS-stimulated macrophages. Collectively, A. evecta-derived furanone compounds represent promising lead candidates for anti-leukemic drug development.

The tumor microenvironment plays a critical role in therapeutic resistance in diffuse large B-cell lymphoma (DLBCL), yet actionable targets within the immune cells remain largely undefined. Through integrative multiomics profiling, we identified tumor necrosis factor receptor superfamily member 1A ( TNFRSF1A ) as a key prognostic determinant associated with predicted R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance, specifically localizing its expression to tumor-associated macrophages (TAMs). Mechanistic investigation via ligand–receptor network analysis and in silico perturbation revealed that TNFRSF1A ⁺ TAMs sustain a pro-oncogenic and immunosuppressive niche, by driving nuclear factor-κB (NF-κB)-dependent B-cell activating factor (BAFF) secretion and immune checkpoint ligand (programmed death-ligand 1/programmed death-ligand 2) expression. Pharmacogenomic screening coupled with molecular dynamics simulations identified curcumin as a potential modulator of TNFRSF1A-associated signaling. Subsequent experimental validation using small interfering RNA-mediated knockdown and coculture assays confirmed that disrupting the macrophage-intrinsic TNFRSF1A/NF-κB/BAFF axis eliminated the protective support provided by TAMs to lymphoma cells. Additionally, a novel risk model derived from the TNFRSF1A ⁺ TAM transcriptional signature demonstrated robust predictive accuracy for patient outcomes across independent cohorts. Our findings elucidate the role of TNFRSF1A ⁺ TAMs in driving DLBCL progression, highlight the TNFRSF1A/NF-κB/BAFF axis as a vulnerability in the DLBCL microenvironment, and propose curcumin as a viable therapeutic strategy to disrupt this supportive microenvironment.