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Ginkgolic Acids Degradation by the <em>Ginkgo biloba</em> Endophytic Fungus <em>Fusarium</em> sp. DLT-118
Foods. 2026 Apr 6;15(7):1247. doi: 10.3390/foods15071247.
ABSTRACT
Ginkgolic acids (GAs), the principal toxic constituents in Ginkgo biloba, pose health risks including cytotoxicity, allergenicity, and pro-inflammatory effects, limiting the application of Ginkgo resources in the food and health product industries. Developing efficient and environmentally friendly removal methods is essential. The endophytic fungus Fusarium sp. DLT-118, isolated from Ginkgo biloba, degraded 96.47% of GAs in Ginkgo biloba leaf extract (GE) at an initial concentration of 1 mg/mL within 7 days at 28 Β°C, while concurrently enhancing the antioxidant activity of GE, as indicated by a reduction in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging IC50 from 755.7 ΞΌg/mL to 544.6 ΞΌg/mL. Morphological and oxidative stress analyses showed critical cellular adaptations and stress responses under degradation conditions. Integrated multi-omics analysis indicated that GE stress induced the remodeling of fungal amino acid, lipid, and energy metabolism, as well as the adjustment of membrane and transport functions, to facilitate GAs detoxification. Cytotoxicity assays indicated no significant cytotoxicity of the degradation products towards human normal lung epithelial cells (Beas-2B) and gastric mucosal epithelial cells (GES-1). These findings highlight Fusarium sp. DLT-118 as a promising agent for the efficient removal of GAs, offering a potential strategy for the production of GA-reduced Ginkgo-based food and health products.
PMID:41976541 | PMC:PMC13073844 | DOI:10.3390/foods15071247
UBTF-HSP90A-MIF stress circuit drives lenvatinib resistance and immune exclusion in hepatocellular carcinoma
J Adv Res. 2026 Apr 5:S2090-1232(26)00280-8. doi: 10.1016/j.jare.2026.04.002. Online ahead of print.
ABSTRACT
INTRODUCTION: The clinical benefit of combining lenvatinib with PD-1 blockade in HCC is frequently constrained by adaptive resistance and the development of an immune-cold tumor microenvironment.
OBJECTIVES: This study aimed to elucidate the molecular mechanisms underlying adaptive resistance and immune exclusion during lenvatinib-PD-1 therapy in HCC, with a particular focus on a UBTF/HSP90A/MIF regulatory circuit. We examined whether genetic or pharmacologic targeting of macrophage migration inhibitory factor (MIF) could restore lenvatinib sensitivity, remodel the tumor immune microenvironment, and serve as a predictive biomarker in clinical cohorts.
METHODS: Paired lenvatinib-sensitive and -resistant HCC models were interrogated using integrated multi-omic and functional approaches, including RNA sequencing, promoter pull-down assays, ChIP, luciferase reporter assays, PLA, and flow cytometry. Key findings were validated in patient-derived organoids and xenografts, as well as in an immunocompetent hydrodynamic HCC mouse model. Clinical relevance was evaluated in independent cohorts treated with lenvatinib plus anti-PD-1 therapy.
RESULTS: UBTF directly bound to and transcriptionally activated the HSP90A promoter, resulting in increased HSP90A expression and stabilization of MIF. MIF signaling through CD74 co-activated the PI3K-AKT and MAPK pathways, sustaining tumor cell proliferation under lenvatinib pressure. Single-cell RNA sequencing and multiplex immunohistochemistry revealed macrophage enrichment and CD8+ T-cell exclusion in resistant tumors. Genetic ablation of Mif (Alb-Cre; Mifflox/flox) or pharmacologic inhibition with 4-IPP (4-Iodo-6-phenylpyrimidine) restored lenvatinib sensitivity, reprogrammed the tumor immune microenvironment, and, when combined with PD-1 blockade, achieved superior tumor control and prolonged survival. In clinical datasets, low pretreatment MIF expression was associated with improved responses to lenvatinib plus PD-1 therapy.
CONCLUSIONS: These findings define a UBTF/HSP90A/MIF axis linking proteostasis and cytokine signaling to immune-metabolic dysfunction and lenvatinib resistance in HCC. MIF emerges as both a mechanistic driver and a predictive biomarker, supporting prospective evaluation of therapeutic strategies combining lenvatinib-PD-1 with MIF- or HSP90A-targeted interventions to personalize TKI-ICI therapy.
PMID:41946392 | DOI:10.1016/j.jare.2026.04.002