LINC01607 promotes hepatocellular carcinoma progression and ferroptosis-associated therapy resistance with functional involvement of the p62–Keap1–Nrf2 pathway

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.

Keywords

Hepatocellular carcinoma / LINC01607 / ferroptosis / sorafenib resistance

References

[1] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[2] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2018;68:394-424

[3] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet2018;391:1163-73

[4] Huarte M,Feldser D.A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.Cell2010;142:409-19 PMCID:PMC2956184

[5] Hung T,Lin MF.Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters.Nat Genet2011;43:621-9 PMCID:PMC3652667

[6] Xie C,Fang JH,Yang JE.Functional long non-coding RNAs in hepatocellular carcinoma.Cancer Lett2021;500:281-91

[7] Huo X,Wu G.Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells.Mol Cancer2017;16:165 PMCID:PMC5651571

[8] Zhang Y,Tao H.Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy.Cancer Lett2023;576:216405

[9] Chen X,Kroemer G.Broadening horizons: the role of ferroptosis in cancer.Nat Rev Clin Oncol2021;18:280-96

[10] Stockwell BR,Bayir H.Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease.Cell2017;171:273-85 PMCID:PMC5685180

[11] Gao M,Zhu J.Role of mitochondria in ferroptosis.Mol Cell2019;73:354-63.e3 PMCID:PMC6338496

[12] Dixon SJ,Lamprecht MR.Ferroptosis: an iron-dependent form of nonapoptotic cell death.Cell2012;149:1060-72 PMCID:PMC3367386

[13] Ajoolabady A,Kroemer G.Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy.Br J Cancer2023;128:190-205 PMCID:PMC9902568

[14] Chen J,Ge C,Wang F.The multifaceted role of ferroptosis in liver disease.Cell Death Differ2022;29:467-80 PMCID:PMC8901678

[15] Li L,Yu S.WNK1 interaction with KEAP1 promotes NRF2 stabilization to enhance the oxidative stress response in hepatocellular carcinoma.Cancer Res2024;84:2776-91

[16] Zhang D,Lu J.Mitochondrial TSPO promotes hepatocellular carcinoma progression through ferroptosis inhibition and immune evasion.Adv Sci2023;10:e2206669 PMCID:PMC10214260

[17] Tonelli C,Tuveson DA.Transcriptional regulation by Nrf2.Antioxid Redox Signal2018;29:1727-45 PMCID:PMC6208165

[18] Ma Q.Role of nrf2 in oxidative stress and toxicity.Annu Rev Pharmacol Toxicol2013;53:401-26 PMCID:PMC4680839

[19] Jaramillo MC.The emerging role of the Nrf2-Keap1 signaling pathway in cancer.Genes Dev2013;27:2179-91 PMCID:PMC3814639

[20] Jain A,Sjøttem E.p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription.J Biol Chem2010;285:22576-91 PMCID:PMC2903417

[21] Sun X,Chen R.Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.Hepatology2016;63:173-84 PMCID:PMC4688087

[22] Zhang DD.Mechanistic studies of the Nrf2-Keap1 signaling pathway.Drug Metab Rev2006;38:769-89

[23] Tian B,Guo XL.Regulation and role of nuclear factor-E2-related factor 2 (Nrf2) in multidrug resistance of hepatocellular carcinoma.Chem Biol Interact2018;280:70-6

[24] Yuan D,Li X.Long non-coding RNAs: potential biomarkers and targets for hepatocellular carcinoma therapy and diagnosis.Int J Biol Sci2021;17:220-35 PMCID:PMC7757045

[25] Shi M,Lyu H.Long non-coding RNAs: emerging regulators of invasion and metastasis in pancreatic cancer.J Adv Res2025;78:285-306 PMCID:PMC12684946

[26] Xiang S,Ren X,Zu X.Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer.Cell Mol Biol Lett2024;29:40 PMCID:PMC10964675

[27] Liu L,Zhang R.Sohlh2 promotes pulmonary fibrosis via repression of p62/Keap1/Nrf2 mediated anti-oxidative signaling pathway.Cell Death Dis2023;14:698 PMCID:PMC10598036

[28] Lee DH,Lee YS.PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway.Redox Biol2022;50:102235 PMCID:PMC8801383

[29] Yang R,Wang Z.Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis.Phytomedicine2024;122:155135

[30] Zhou Y,Shi Y.FAM117B promotes gastric cancer growth and drug resistance by targeting the KEAP1/NRF2 signaling pathway.J Clin Invest2023;133:e158705 PMCID:PMC9888386

[31] Wan ZH,Shi YY.RPB5-mediating protein promotes cholangiocarcinoma tumorigenesis and drug resistance by competing with NRF2 for KEAP1 binding.Hepatology2020;71:2005-22