Aug 2026· Journal of Gastroenterology and Hepatology· 0 citations· 27 references
Medicine
TL;DR
It is revealed that AKR1B10 inhibits ferroptosis in HCC through the NQO1/GPX4 axis, promoting acquired resistance to lenvatinib.
Abstract
Background
Lenvatinib is utilized as a first-line therapy for hepatocellular carcinoma (HCC); however, the emergence of resistance significantly impairs its clinical efficacy. Ferroptosis, a newly recognized form of cell death, has been implicated in tumor progression and treatment resistance. This study investigates the interaction between ferroptosis and lenvatinib resistance in HCC and explores the underlying mechanisms.
Methods
A lenvatinib-resistant cell line was established, combined with multiplex transcriptome sequencing and external bioinformatics analysis to identify key resistance genes. The biological functions of lenvatinib resistance were validated through assays of cell viability, colony formation, apoptosis, and xenograft models. Ferroptosis effects were analyzed using assays such as transmission electron microscopy (TEM), C11-BODIPY staining, malondialdehyde (MDA) measurement, and Fe2+ detection. Furthermore, KEGG pathway enrichment analysis, Western blotting, immunofluorescence colocalization, and immunohistochemistry were conducted to explore the underlying mechanisms.
Results
Transcriptome sequencing combined with in vitro and in vivo experiments revealed that AKR1B10 was significantly downregulated following short-term lenvatinib treatment, but was upregulated with the induction of resistance. Knockdown of AKR1B10 markedly reversed acquired resistance to lenvatinib. Furthermore, we found that the upregulation of AKR1B10 substantially inhibited lenvatinib-induced ferroptosis. Mechanistically, the NQO1/GPX4 axis was identified as the downstream signaling pathway through which AKR1B10 regulates ferroptosis. Notably, overexpression of NQO1 effectively restored both ferroptosis and sensitization to lenvatinib induced by AKR1B10 knockdown.
Conclusions
This study reveals that AKR1B10 inhibits ferroptosis in HCC through the NQO1/GPX4 axis, promoting acquired resistance to lenvatinib. These findings suggest that AKR1B10 could be a novel therapeutic target for overcoming lenvatinib resistance.
Lenvatinib is approved as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), however, its clinical efficacy is frequently limited by the emergence of drug resistance. This study aimed to elucidate the underlying mechanisms by which HCC develops resistance to lenvatinib. Lenvatinib-resistant HCC cell lines were established and subjected to RNA sequencing (RNA-seq) to identify genes associated with drug resistance. HCC cell lines stably overexpressing the p53 R280S mutation were constructed via lentiviral transduction. The effects of p53 R280S on HCC cell proliferation, apoptotic, and lenvatinib sensitivity were evaluated using Cell Counting Kit-8 (CCK-8) assays, flow cytometry, colony formation assays, TUNEL staining, and a mouse subcutaneous xenograft model. The underlying molecular mechanisms were further investigated by Western blotting, immunohistochemical staining (IHC), and quantitative real-time PCR (qRT-PCR). RNA sequencing of lenvatinib-resistant HCC cell lines revealed p53 dysregulation, and sanger sequencing identified the p53 R280S missense mutation, which was shown to enhance lenvatinib resistance in vitro and in vivo. The p53 R280S mutant attenuated lenvatinib-induced apoptosis. Furthermore, mutant p53 upregulated Bcl-2 expression and downregulated BAX expression, thereby suppressing apoptotic signaling. The p53 R280S mutation promotes lenvatinib resistance in HCC by inhibiting apoptosis.
Niangmei Cheng, Kexin Liu, Xin Qi et al.· Molecular and Cellular Bioch...· 0 citations
Nasopharyngeal carcinoma (NPC) is a highly aggressive malignancy. The natural compound ruscogenin (Rus) shows anti-cancer potential. This study elucidates the specific mechanism of action in nasopharyngeal carcinoma (NPC) by investigating its effects on NPC cells and the underlying molecular pathway. The human nasopharyngeal carcinoma (NPC) cell line, C666-1, was treated with various concentrations of Rus. A series of in vitro assays was performed to evaluate cell viability, proliferation, migration, invasion, apoptosis, and ferroptosis. The role of lysine-specific demethylase 1A (KDM1A) was investigated using Western blot and molecular docking, and its mediating role was validated through overexpression rescue experiments. Ruscogenin dose-dependently diminished the proliferative, clonogenic, migratory, and invasive capacities of C666-1 cells. Mechanistically, Rus treatment induced both apoptosis, evidenced by the activation of executioner caspase-3 and a shift towards pro-apoptotic signaling via the Bax/Bcl-2 balance, and ferroptosis, marked by elevated lipid peroxidation and intracellular iron. These anti-tumor effects were strongly correlated with the downregulation of KDM1A. Crucially, the forced overexpression of KDM1A significantly attenuated Rus-induced apoptosis and ferroptosis, and reversed the suppression of malignant phenotypes, confirming KDM1A's critical mediating role. Ruscogenin inhibits the malignant progression of nasopharyngeal carcinoma by downregulating KDM1A, thereby promoting apoptosis and ferroptosis. These findings identify the Rus-KDM1A axis as a promising therapeutic target for NPC treatment.
Bo Zhang· Journal of Visualized Experi...· 0 citations
Background Bufothionine, a major bioactive component of dried toad skin, has shown anti-tumor potential. However, its efficacy and underlying mechanisms in colorectal cancer (CRC) remain unclear. Objective This study aimed to investigate the therapeutic potential of bufothionine and its underlying mechanisms against CRC. Methods Anti-tumor efficacy was assessed using in vitro (CCK-8, migration assays) and in vivo (HT-29 xenograft) models. Network pharmacology, molecular docking and molecular dynamics simulations were employed to predict targets. Mechanisms were validated by biochemical assays, Western blot, IHC, and qPCR, with ferrostatin-1 applied to confirm ferroptosis specificity. Results Bufothionine significantly inhibited HT-29 cell proliferation and migration. Integrated network pharmacology and computational modeling identified p53 and STAT3 as core targets, with potential interactions predicted between bufothionine and key ferroptosis regulators (including SLC7A11). In vitro, bufothionine induced ferroptosis, characterized by increased Fe2+, ROS, and MDA levels, and a decreased GSH/GSSG ratio; these effects were partially reversed by ferrostatin-1. In vivo, bufothionine reduced tumor weight indices, improved liver function by attenuating AST and ALP elevations without hepatosplenic toxicity, and regulated inflammatory cytokines. Mechanistically, bufothionine suppressed inflammatory activation (NLRP3, IL-1β), inhibited STAT3 phosphorylation, and modulated p53 activity, leading to the subsequent inhibition of the SLC7A11/GPX4 axis in both cells and tumor tissues. Conclusion Bufothionine suppresses CRC by the STAT3/p53/SLC7A11 signaling axis in a manner associated with ferroptosis, suggesting its potential as a therapeutic agent for colorectal cancer.
Rui-Fang Xie, Nan Xiang, Guidan Zhou et al.· Frontiers in Pharmacology· 0 citations
Lenvatinib has been approved by the FDA as a front-line treatment for advanced hepatocellular carcinoma (HCC), but its survival benefits are limited by acquired drug resistance. In this study, we investigate the mechanisms underlying lenvatinib resistance in HCC by establishing lenvatinib-resistant (LenR) patient-derived tumor xenograft (PDTX) and analyzing their genetic profiles via single-cell RNA sequencing (scRNA-seq). Through single-cell regulatory network inference and clustering (SCENIC) analysis, we find that Annexin A1 (
ANXA1
) is significantly enriched in LenR HCC clusters. Using knockdown and overexpression strategies, we demonstrate the critical role of ANXA1 in regulating cancer stemness-driven lenvatinib resistance. ANXA1 mediates resistance by regulating S100A6 expression, while its expression is regulated by SOX2 via promoter activation, forming a positive feedback loop with STAT3. Notably, we reveal that ANXA1 secreted from LenR HCC cells reshapes the tumor microenvironment (TME) by inducing M2 macrophage polarization via FPR2 binding and activation of ERK and NF-κB signaling, leading to decreased T cell infiltration. Targeting ANXA1 via an adeno-associated virus serotype 8 (AAV8) approach improves lenvatinib efficacy in our LenR
Tp53
KO
/
Myc
OE
HCC mouse model, accompanied by the suppression of an immunosuppressive TME. In conclusion, HCC-derived ANXA1 regulates lenvatinib resistance both intrinsically and extrinsically. Targeting the SOX2/ANXA1/STAT3/S100A6 positive loop may provide a novel therapeutic strategy for HCC treatment.
Catherine Yu Jia Gu, C. Leung, R. Leung et al.· Cell Death & Disease· 0 citations
BACKGROUND
Tumor-associated macrophages (TAMs), as core components of the triple-negative breast cancer (TNBC) tumor microenvironment (TME), can promote tumor progression. Ferroptosis has been shown to be involved in TNBC progression, but its regulatory mechanisms in TNBC TAMs remain incompletely understood.
METHODS
Clinical samples of TNBC were collected, and in vitro co-culture systems and BC xenograft models were established. By combining the results of the TCGA-BRCA and METABRIC transcriptomic cohort analyses, the expression characteristics and immune associations of ACOD1 were examined. Functional exploration was conducted through CCK-8, EdU, and colony formation assays and the detection of ferroptosis-related indicators. Molecular mechanisms were investigated using co-immunoprecipitation (Co-IP), CETSA, DARTS, SPR, and molecular docking.
RESULTS
ACOD1 expression was upregulated in immune-infiltrated subtypes, such as Basal-like/TNBC and HER2-enriched subtypes and significantly positively correlated with the infiltration of myeloid immune cells, including macrophages. Further results revealed that ACOD1 is highly expressed in TNBC TAMs and is driven by TME signals, independent of the classical M2 polarization pathway. The knockdown of ACOD1 in TAMs inhibited MDA-MB-231 cell proliferation and in vivo tumor growth and reduced ferroptosis resistance in TAMs. Mechanistically, ACOD1 knockdown did not affect KEAP1 expression but did reduce the expression of NRF2 and its downstream target genes HO-1 and NQO1, decreased NRF2 nuclear translocation, and increased KEAP1-NRF2 binding. Knockdown of KEAP1 or overexpression of NRF2 enhanced ferroptosis resistance. Additionally, ACOD1 knockdown decreased itaconate (ITA) levels in TAMs. The ITA derivative 4-OI was directly bound to KEAP1, weakened the KEAP1-NRF2 interaction, inhibited NRF2 ubiquitination, and stabilized NRF2 expression.
CONCLUSION
ACOD1, through its enzymatic product ITA, promotes ITA binding to KEAP1, which inhibits the KEAP1-NRF2 interaction and thus activates NRF2-mediated antioxidant and ferroptosis resistance responses in TAMs, promoting TNBC progression.
Jie Yang, Xiyin Li, Xin Qu et al.· Pathology, Research and Prac...· 0 citations
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant tumors of the central nervous system, demanding innovative therapeutic strategies. Ferroptosis, an iron-driven lipid peroxidation-dependent cell death, has emerged as a potential means to overcome resistance, with glutathione peroxidase 4 (GPX4) as its key suppressor. MLN4924 (pevonedistat), a first-in-class inhibitor of neddylation currently in clinical trials, has shown strong antitumor activity across multiple malignancies. However, its role in ferroptosis regulation and the underlying molecular mechanisms remain poorly defined. Here, we show that MLN4924 induces ferroptosis, with GPX4 emerging as a central regulatory node. GPX4 expression is elevated in gliomas compared to normal brains, and its higher levels correlate with increased grades and worse patient prognosis. MLN4924 downregulates GPX4 mRNA by suppressing STAT3 signaling, whereas RSL3 directly inhibits GPX4 enzymatic activity. The combination of MLN4924 and RSL3 synergistically potentiates ferroptosis and, in vivo, suppresses subcutaneous tumor growth with a considerable biosafety. Collectively, these findings identify GPX4 as the principal mediator of MLN4924-induced ferroptosis and establish that dual targeting of GPX4 transcription and activity represents a promising therapeutic strategy for GBM.
Zhou Jing, Fangyuan Wang, Hao Li et al.· Carcinogenesis· 0 citations
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