LINC01607 promotes hepatocellular carcinoma progression and ferroptosis-associated therapy resistance with functional involvement of the p62–Keap1–Nrf2 pathway
Jul 2026· Cancer Drug Resistance· Vol 9· 0 citations· 31 references
Medicine
TL;DR
LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Abstract
Aim: Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear. Methods: LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways. Results: LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe2+ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62–Keap1–Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib. Conclusion: LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
PURPOSE
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with current therapies often limited by significant drug resistance. Owing to the Warburg effect, targeting cancer-specific metabolic vulnerabilities is a promising therapeutic strategy. This study aims to investigate the role of RNF114 in HCC progression and its regulatory mechanism, as well as its clinical translational potential as a therapeutic target.
METHODS
We evaluated the clinical significance of RNF114 using tissue microarrays and database analysis. RNF114 function in promoting HCC progression by regulating glucose uptake was investigated using knockdown experiments in cell lines and subcutaneous xenograft models. Furthermore, a therapeutic xenograft model was employed to assess the potential of RNF114 knockdown in overcoming Sorafenib resistance.
RESULTS
RNF114 was highly expressed in HCC and correlated with poor prognosis. Knockdown of RNF114 significantly suppressed HCC cell proliferation, migration, invasion, and glycolysis. Co-immunoprecipitation identified PACSIN3 as a key substrate of RNF114. RNF114 interacted with the SH3 domain of PACSIN3, promoting its ubiquitination and proteasomal degradation. Subcellular fractionation revealed that the F-BAR domain of PACSIN3 facilitated GLUT1 vesicular trafficking. Consequently, RNF114 impaired this process, leading to increased plasma membrane retention of GLUT1 and enhanced glycolytic flux. Consistently, in both HCC cells and subcutaneous xenograft models, RNF114 knockdown sensitized tumors to Sorafenib treatment.
CONCLUSIONS
Collectively, our findings reveal that the RNF114-PACSIN3-GLUT1 axis regulates glucose uptake and metabolic reprogramming in HCC, thereby promoting tumor progression and contributing to therapy resistance. Targeting this signaling axis provides a novel insight into metabolic therapy for HCC.
Yue Song, Yi-lu Lu, Qixiang Liu et al.· Cellular Oncology· 0 citations
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.
Jiahao Jiang, Bingkun Wang, Qingbin Wang et al.· Journal of Gastroenterology...· 0 citations
Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options, underscoring the urgent need for novel therapeutic targets. The copper transporter ATP7A has been implicated in cancer, but its precise role and regulatory mechanisms in HCC pathogenesis remain poorly understood. ATP7A expression was analyzed using public databases and validated in clinical HCC tissues and cell lines via qPCR and western blot. Functional assays were performed following ATP7A knockdown. Sensitivity to cuproptosis was assessed by measuring intracellular copper/ROS levels and IC50 of elesclomol‐Cu. The upstream regulatory axis was identified through bioinformatic prediction and verified by dual‐luciferase reporter and rescue experiments. The role of the LINC02038/miR‐506‐3p/ATP7A axis was further confirmed both in vitro and in a xenograft mouse model. ATP7A was significantly upregulated in HCC tissues and cell lines. ATP7A knockdown markedly inhibited HCC cell proliferation, migration, and invasion, while simultaneously sensitizing cells to cuproptosis. Mechanistically, LINC02038, which was highly expressed in HCC, functioned as a competing endogenous RNA (ceRNA) to sponge tumor‐suppressive miR‐506‐3p, thereby upregulating ATP7A expression. This LINC02038/miR‐506‐3p/ATP7A axis was demonstrated to coordinately regulate malignant phenotypes and the expression of key cuproptosis‐related proteins (DLAT, FDX1, LIPT1). In vivo, silencing LINC02038 effectively suppressed tumor growth and recapitulated the molecular alterations of this axis and cuproptosis regulators. Our findings reveal that the LINC02038/miR‐506‐3p/ATP7A axis played a crucial oncogenic role in HCC by driving tumor progression and modulating cuproptosis. This axis represents a promising prognostic biomarker and a potential therapeutic target for HCC intervention.
Zhe Liu, Weixi Shan, Wen-Yu Zhou et al.· Journal of biochemical and m...· 0 citations
Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with persistent challenges such as drug resistance and tumor progression despite significant therapeutic advancements. The roles of ferroptosis and long non-coding RNAs (lncRNAs) in BC are not yet fully elucidated, underscoring the need for novel therapeutic targets. In this study, we investigated the function of LINC01929 in BC through a combination of in vitro and in vivo experiments, bioinformatics analysis, RNA pull-down mass spectrometry, and clinical tissue validation. We found that LINC01929 is significantly overexpressed in BC tissues and is associated with poor patient prognosis. Mechanistically, LINC01929 promoted malignant phenotypes in BC cells and was associated with reduced ferroptosis-related stress, with these effects being at least partly dependent on transferrin receptor (TFRC). Conversely, silencing LINC01929 led to reduced TFRC expression and induced ferroptosis in BC cells. Clinical data further confirmed that elevated TFRC levels correlate with aggressive tumor features and unfavorable outcomes. These findings suggest that targeting LINC01929 to regulate TFRC-mediated ferroptosis could represent a promising therapeutic strategy for BC, positioning both LINC01929 and TFRC as potential biomarkers and therapeutic targets.
Gang Li, Zhijun Yu, Hongmei Xu et al.· Cell Death Discovery· 0 citations
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths, with limited therapeutic options. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising approach for HCC intervention due to its close association with multiple aspects of liver cancer, such as proliferation, metastasis, and drug resistance. In this study, we identified the oncogene mitochondrial ribosomal protein S30 (MRPS30) associated with HCC prognosis through multi-omics analysis. Using HCC cell lines with MRPS30 knockdown/overexpression and xenograft tumor models, we confirmed that MRPS30 inhibits ferroptosis by upregulating Glutathione Peroxidase 4(GPX4), thereby promoting the malignant progression of HCC and resistance to lenvatinib. Mechanistically, MRPS30 specifically interacts with GPX4 and inhibits the lysine 48 (K48)-linked ubiquitination of GPX4 to maintain its protein stability. By stabilizing GPX4, MRPS30 reduces malondialdehyde (MDA) accumulation and maintains glutathione (GSH) homeostasis, thereby inhibiting ferroptosis and ultimately enhancing the malignant behaviors and drug resistance of HCC. In conclusion, we identified MRPS30 as a prognosis-related gene in HCC and revealed its role in regulating HCC proliferation, metastasis, and drug resistance through ferroptosis. Our findings uncover a key driver of ferroptosis resistance mediated by the MRPS30/GPX4 axis and further confirm that ferroptosis is a promising therapeutic strategy for HCC treatment.
Weihui Guo, Yu Weng, Fang Wu et al.· International Journal of Bio...· 0 citations
Simple Summary Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. This study aimed to investigate the expression and role of LINC01446 in ESCC, particularly its involvement in tumor progression and ferroptosis defense. Based on bioinformatics analysis of the TCGA and GEO datasets, LINC01446 was significantly upregulated in ESCC and correlated with poorer overall survival (OS). Functional assays revealed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion. In addition, its knockdown induced ferroptosis in ESCC cells, as evidenced by elevated oxidized C11-BODIPY staining, increased malondialdehyde (MDA) levels, and decreased glutathione (GSH) levels. Mechanistically, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) was identified as a downstream target of LINC01446 using RNA sequencing and Western blotting, the expression of which was positively correlated in ESCC tissues. Further experiments suggested that cytoplasmic LINC01446 might act as a competing endogenous RNA (ceRNA) that sponges miR-338-3p, thereby alleviating its repressive effect on APEX1 expression. Dual-luciferase and AGO2-RIP assays supported a regulatory relationship among LINC01446, miR-338-3p, and APEX1, consistent with a ceRNA-mediated mechanism. Moreover, LINC01446 knockdown suppressed tumor growth and reduced APEX1 expression in vivo, accompanied by increased MDA levels, suggesting enhanced lipid peroxidation and a possible increase in ferroptosis. These findings suggest that the LINC01446/miR-338-3p/APEX1 axis may contribute to ESCC progression and ferroptosis defense, warranting further investigation into its potential therapeutic and prognostic value.
Yunlong Jia, J. Si, Zhendong Zhang et al.· Cancers· 0 citations
