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Effects of three flavonoids on the metabolism of lenvatinib

Yang Jinzhao,Chen Jie,Li Qingqing,Xu Ren-ai,Chen Xiaohai

Lenvatinib is a first-line therapy for the treatment of hepatocellular carcinoma (HCC), an active multi-target tyrosine kinase inhibitor (TKI). The interaction between Traditional Chinese Medicine (TCM) and chemicals has increasingly become a research hotspot. The objective of this study was to pinpoint the effects of three flavonoids on the metabolism of lenvatinib. Enzyme reaction system was established and optimized in vitro, and in vivo experiments were conducted in Sprague-Dawley (SD) rats, where the analytes were detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We found that among three flavonoids, luteolin and myricetin had strong inhibitory effects on lenvatinib metabolism, with half-maximal inhibitory concentration (IC50) values of 11.36 ± 0.46 µM and 11.21 ± 0.81 µM in rat liver microsomes (RLM), respectively, and 6.89 ± 0.43 µM and 12.32 ± 1.21 µM in human liver microsomes (HLM), respectively. In Sprague-Dawley rats, the combined administration of lenvatinib and luteolin obviously expanded the exposure to lenvatinib; however, co-administered with myricetin did not have any changes, which may be due to the poor bioavailability of myricetin in vivo. Furthermore, the inhibitory type of luteolin on lenvatinib showed an un-competitive in RLM and a mixed in HLM. Collectively, flavonoids with liver protection, especially luteolin, may inhibit lenvatinib metabolism in vitro and in vivo.

Polymorphs and Pseudopolymorphs of Lenvatinib Mesylate: Crystal Structure, Equilibrium Solubility, and Stability Study

Shuqi Lu,Kaxi Yu,Shuping Wang,Jiyong Liu,Shuna Liu,Xiurong Hu,Guping Tang

Lenvatinib is a cancer treatment drug approved by the U.S. Food and Drug Administration, which is a multitarget tyrosinase inhibitor. The commercially available form is its mesylate. In this work, five lenvatinib mesylate (LEM) solid-state forms, including two polymorphs (LEM-A, LEM-C) and three pseudopolymorphs (a hydrate (LEM-H) and two iso-structural solvates (LEM-H-EA and LEM-H-THF)), were prepared and characterized using various methods. Powder diffractions of LEM-A and LEM-C have been reported, but their crystal structures were reported for the first time by us. Hydrate and two iso-structural solvates were also first prepared and characterized by thermal analysis, X-ray diffraction, and so forth. The mutual transformation of different forms was studied. Two solvates easily lost their solvent and turned into LEM-B, which provided the possibility for the preparation of LEM-B. In addition, thermal stability and solubility of LEM-A, LEM-C, and LEM-H were determined, along with the respective molecular conformation, their inter- and intramolecular interactions, and packing arrangements.

Investigation on the binding behavior between BSA and lenvatinib with the help of various spectroscopic and in silico methods

Bao-Li Wang,Song-Bo Kou,Zhen-Yi Lin,Jie-Hua Shi

Lenvatinib was a multi-tyrosine kinase inhibitor (TKI) used for treating advanced renal cell carcinoma and differentiated thyroid cancer. Multiple fluorescence spectroscopy including SSF, SF, 3DF, UV, FTIR, and molecular modeling were utilized for better understanding the binding interaction between lenvatinib and bovine serum albumin (BSA). SSF spectroscopy results showed lenvatinib quenched the intrinsic fluorescence of BSA in the form of the mixed mechanism. The binding constants (K b ) of lenvatinib on BSA were about 10 4  M −1 , indicating the affinity on BSA was moderate. Based on the analysis of the thermodynamic parameters, it can be inferred that lenvatinib spontaneously binds onto BSA and the hydrogen bonding and hydrophobic interactions are responsible for both bindings. The outcomes of UV, SF spectroscopy and FTIR showed the conformational change of BSA was caused due to binding lenvatinib. The outcomes of the molecular docking revealed that lenvatinib inserted into the hydrophobic groove between sub-domain IIA, IIB and IIIA, which further demonstrated the competition experiments result of ibuprofen and phenylbutazone markers. Furthermore, molecular docking and molecular dynamics (MD) simulations were performed to investigate the binding behavior of lenvatinib with BSA. The effect of some ions such as K + , Cu 2+ , Ca 2+ , Mg 2+ , Ni 2+ , Zn 2+ and Fe 3+ on the binding affinity was also discussed.

An aptamer-conjugated mesoporous polydopamine formulation for synergistic targeted and photothermal therapy of hepatocellular carcinoma

Yue Yang,Chonggao Wang,Shiwei Liu,Yewei Zhang

This study aimed to create multifunctional nanoparticles (NPs), specifically [email protected] (AMLC), for the purpose of developing effective strategies for treating hepatocellular carcinoma (HCC) through targeted therapy and photothermal therapy (PTT). The study involved synthesizing mesoporous polydopamine (MPDA)-NPs, loading lenvatinib (Len) and Cy5.5 via incubation, and modifying AS1411 aptamer onto MPDA via a covalent chemical reaction. The NPs were characterized using techniques such as ultra-micro spectrophotometry, Fourier transform infrared spectroscopy, and transmission electron microscopy. Target-specific uptake and cell-killing assays were utilized to evaluate AMLC-mediated synergistic therapy while using Western blotting and immunofluorescence to confirm the underlying mechanism. Consequently, the nanoparticles (NPs) were successfully synthesized, demonstrating excellent solvent solubility and stability, with controlled drug release achieved in acidic environments (maximum release efficiency≈80 %). In vitro and in vivo studies revealed that these NPs could more effectively target hepatocellular carcinoma (HCC) cells, enhancing the targeting capability of lenvatinib. Under near-infrared (NIR) laser irradiation, the targeted photothermal therapy (PTT) exhibited significantly improved anticancer efficacy, with AMCL+PTT treatment resulting in up to 76 % tumor volume reduction‌ ( P  < 0.01). The study demonstrates that AMLC, a multifunctional nano-delivery system, significantly enhances Lenvatinib's tumor-targeting capacity while exhibiting excellent biocompatibility. Combined with photothermal therapy (PTT), it demonstrates potent antitumor efficacy, showing promising clinical translation potential for hepatocellular carcinoma (HCC) therapy.

Lactylation-Driven HECTD2 Limits the Response of Hepatocellular Carcinoma to Lenvatinib

Runyu Dong,Yao Fei,Yiren He,Peng Gao,Bo Zhang,Menglin Zhu,Zhixiong Wang,Longfei Wu,Shuai Wu,Xiaoming Wang,Juan Cai,Zhiqiang Chen,Xueliang Zuo

Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify the potential regulators of lenvatinib resistance in HCC. Patient-derived organoids, patient-derived xenograft mouse models, and DEN/CCl 4 induced HCC models are constructed to evaluate the effects of HECTD2 both in vitro and in vivo. HECTD2 is found to be highly expressed in lenvatinib-resistant HCC cell lines, patient tissues, and patient-derived organoids and xenografts. In vitro and in vivo experiments demonstrated that overexpression of HECTD2 limits the response of HCC to lenvatinib treatment. Mechanistically, HECTD2 functions as an E3 ubiquitin ligase of KEAP1, which contributes to the degradation of KEAP1 protein. Subsequently, the KEAP1/NRF2 signaling pathway initiates the antioxidative response of HCC cells. Lactylation of histone 3 on lysine residue 18 facilitates the transcription of HECTD2. Notably, a PLGA-PEG nanoparticle-based drug delivery system is synthesized, effectively targeting HECTD2 in vivo. The NPs achieved tumor-targeting, controlled-release, and biocompatibility, making them a promising therapeutic strategy for mitigating lenvatinib resistance. This study identifies HECTD2 as a nanotherapeutic target for overcoming lenvatinib resistance, providing a theoretical basis and translational application for HCC treatment.

Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma

Pu Jun,Ma Jingjing,Liu Yan,Cui Rongrong,Yao Yao,Zhang Guanjun,Hou Peng,Liu Xi,Yang Qi,Ji Meiju

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC.

Bioinformatics and experimental validation of mechanisms underlying lenvatinib therapy for hepatocellular carcinoma

Cheng Zeng,Xiaoyi Yang,Lantian Wang,Huiling He,Zhe Tang

The RBMS1–SLC7A11 axis regulates ferroptosis susceptibility and lenvatinib sensitivity in hepatocellular carcinoma

Qin Yong,Xu Shengqian,Ye Hailin,Wang Chaojun,Pan Wenjuan

Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Although lenvatinib is widely deployed as a frontline systemic therapy for advanced disease, its clinical utility is frequently subverted by primary or adaptive non-responsiveness. Evasion of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key survival mechanism for tumor cells under therapeutic stress. While the RNA-binding protein RBMS1 is known to participate in oncogenic progression and ferroptotic regulation across several malignancies, whether it modulates lenvatinib sensitivity in hepatocellular carcinoma by intersecting with the SLC7A11-dependent antioxidant pathway has not been established. Expression profiles of RBMS1 and SLC7A11 were interrogated in paired clinical tissue samples and public transcriptomic datasets. Stable lentiviral overexpression or short hairpin RNA-mediated knockdown was executed in HepG2 and Huh7 cells to modulate candidate gene abundance. Cellular phenotypes, comprising viability, clonogenicity, migration, invasion, and drug sensitivity, were mapped via cell counting kit-eight, colony formation, wound healing, and transwell migration assays. Ferroptotic kinetics and oxidative shifts were tracked by measuring intracellular reactive oxygen species and lipid peroxidation using fluorescent probes. Finally, a subcutaneous xenograft model was established to validate the synergistic potential of RBMS1 depletion with lenvatinib therapy in vivo. In clinical specimens, SLC7A11 was markedly upregulated and tied to shortened overall survival, while RBMS1 expression exhibited a strong upward trend that correlated robustly with SLC7A11 abundance in broader transcriptomic cohorts. Functionally, overexpressing RBMS1 accelerated malignant behaviors, expanded SLC7A11 protein levels, neutralized reactive oxygen species, and shielded cells from lipid peroxidation, ultimately lowering lenvatinib sensitivity. Conversely, silencing RBMS1 yielded opposite phenotypes, aggravating ferroptotic oxidative damage and amplifying lenvatinib responsiveness. Epistatic rescue experiments demonstrated that SLC7A11 knockdown completely abrogated the anti-ferroptotic defense and drug tolerance conferred by RBMS1 hyperactivation. In vivo animal models corroborated these dynamics, showing that RBMS1 knockdown significantly potentiated the antitumor efficacy of lenvatinib. These findings position RBMS1 as a novel upstream post-transcriptional regulator of SLC7A11-dependent ferroptosis susceptibility and lenvatinib responsiveness in hepatocellular carcinoma. By reinforcing the SLC7A11 antioxidant network, RBMS1 shields malignant cells from drug-induced oxidative catastrophe. Targeting this newly uncovered post-transcriptional axis represents a viable therapeutic strategy to overcome lenvatinib tolerance in advanced disease.

Gold-Polyphenol Nanoplatform for Lenvatinib Delivery and Photothermal Therapy in Hepatocellular Carcinoma Treatment

Xu Chen,Hongwei Tang,Mingxun Chen,Yujiang Ji,Wen-Zhi Guo

Lenvatinib serves as a crucial therapeutic agent for hepatocellular carcinoma; however, its clinical application is severely restricted by poor aqueous solubility, suboptimal bioavailability, and systemic adverse effects. To overcome these limitations, we developed a novel gold-polyphenol-based self-assembled nanoplatform (ALE) via a green, one-pot synthesis strategy integrating epigallocatechin gallate (EGCG), lenvatinib, and gold ions. The resulting ALE nanoparticles exhibited uniform morphology, excellent physiological stability, and an exceptional photothermal conversion efficiency (PCE) of 51.2% under 808 nm laser irradiation. In vitro studies demonstrated that ALE-mediated photothermal therapy (PTT) significantly inhibited tumor cell proliferation by inducing apoptosis through the upregulation of heat shock proteins (HSP70/90) and caspase-3 activation. Notably, the treatment also triggered a potent pro-inflammatory response, evidenced by the increased secretion of TNF-α, IL-6, and TGF-β. In vivo, ALE served as an effective contrast agent for photoacoustic (PA) imaging, enabling precise tumor delineation. Furthermore, ALE-mediated PTT effectively alleviated tumor hypoxia and achieved complete tumor suppression in an H22 liver cancer xenograft model without causing systemic toxicity or organ damage.This study presents a robust, safe, and multifunctional nanoplatform that enhances the therapeutic efficacy of lenvatinib through synergistic photothermal ablation and tumor microenvironment modulation.

Dabrafenib Alleviates Hepatotoxicity Caused by Lenvatinib via Inhibiting the Death Receptor Signaling Pathway

Xinyu Tao,Mengting Cheng,Xiangliang Huang,Jiajia Chen,Yunfang Zhou,Ting Liu,Xiaochun Zheng,Nonger Shen,Yiwen Zhang,Peihua Luo,Qiaojun He,Hao Yan,Ping Huang

Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.

Ultrasound-triggered nano delivery of lenvatinib for selective immunotherapy treatment against hepatocellular carcinoma

Sun Lu,Qi Jun,Ding Lei,Wang Zixuan,Ji Guofeng,Zhang Ping

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.

Effect and Mechanism of the Lenvatinib@H-MnO2-FA Drug Delivery System in Targeting Intrahepatic Cholangiocarcinoma

Ning Zhouyu,Yang Lina,Yan Xia,Wang Dan,Hua Yongqiang,Shi Weidong,Lin Junhua,Meng Zhiqiang

Background: To investigate the effects of the Lenvatinib@H-MnO2-FA administration system on the proliferation and apoptosis of Intrahepatic cholangiocarcinoma (ICC) and the underlying molecular mechanism. Materials and Methods: In this research, hollow MnO2 (H-MnO2) was synthesized via the modified Stöber method, and H-MnO2 was modified with polyethylene glycol-bis (Amine) (NH2-PEG-NH2) and folic acid (FA) to obtain H-MnO2-PEG-FA (H-MnO2-FA). Lenvatinib was coated in the hollow cavity of H-MnO2-PEG-FA to further form a nanometre drug-carrying system (Lenvatinib@H-MnO2-PEG-FA). Lenvatinib@H-MnO2-FA was characterized through transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to verify that Lenvatinib was loaded on nanoparticles. Functionally, confocal laser scanning microscopy (CLSM), 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed to determine the effect of Lenvatinib@H-MnO2-FA on the proliferation and apoptosis of ICC cells (9810 cells). Finally, the protein levels of Raf-1MEK1/2-ERK1/2 signalling pathway components were detected through Western blotting analysis. Results: We successfully synthesised a Lenvatinib@H-MnO2-PEG-FA administration system. The resulting nanomaterials had excellent biological stability and improved targeting effects. Functionally, Lenvatinib@ H-MnO2-FA inhibited the proliferation of 9810 cells. The Bcl-2 protein level was significantly downregulated, and the caspase-3 protein level was significantly upregulated, indicating that Lenvatinib@H-MnO2- PEG- FA promoted the apoptosis of 9810 cells. Mechanistically, Lenvatinib@H-MnO2-FA increased the phosphorylation levels of Raf, MEK1/2, and ERK1/2. Conclusion: H-MnO2-FA can more effectively deliver Lenvatinib to inhibit proliferation and promote apoptosis in ICC, which could be the promising drug delivery nano-vehicles for delivery drugs.