According to the latest global cancer statistics 2022, lung cancer is the leading cause of global cancer mortality, with a five-year survival rate of only ∼20 % (Bray et al., 2024). Non-small cell lung cancer (NSCLC) represents approximately 85 % of all lung cancer incidence (Duma et al., 2019). The main therapeutic approaches for patients with NSCLC include surgical resection, radiation, systemic therapies (chemotherapy, targeted agents, and immunotherapy), and combined-modality regimens (Wang et al., 2017b). Chemotherapy is one of most common and effective therapeutic strategy for NSCLC (Boolell et al., 2015). Currently, combination of cisplatin and gemcitabine (GEM) is a standard chemotherapy regimen as first-line treatment for advanced NSCLC (Scagliotti et al., 2008). Additionally, GEM is employed to treat patients with platinum-resistant or insensitive NSCLC and has demonstrated improvements in patient prognosis (Duma et al., 2019). However, GEM monotherapy has a low effectiveness rate (<20 %), and the development of inevitable drug resistance significantly limits its clinical application (Crino and Cappuzzo, 2002). Despite significant advancements in NSCLC therapy, overall patient prognoses remain poor (Farías et al., 2014). To improve therapeutic outcomes for NSCLC, novel strategies that specifically target molecular pathways involving NSCLC progression need to be urgently developed.

The RNA-binding protein Quaking (QKI) comprises three main isoforms with diverse C-terminals, including QKI-5, QKI-6, and QKI-7 (Neumann et al., 2022). QKI has been shown to act as a tumor suppressor in the various malignant carcinomas by regulating RNA stability, alternative splicing, and translation (Darbelli and Richard, 2016). Overexpression of QKI-5 inhibited lung cancer cell growth by activating the TGF-β/SMAD signaling and upregulating netrin-4 expression (Wang et al., 2021, Wu et al., 2023). A few studies have reported that non-coding RNAs act as upstream regulator of QKI-5. miR-224 promotes NSCLC cell proliferation by activating miR-196b-5p/NFKBIA signaling pathway through direct targeting of QKI-5 (Zhu et al., 2023b). Lnc10 binds to QKI-5 and reduces its stability, preventing germ cell apoptosis by inhibiting p38 MAPK pathway (Li et al., 2019). However, the functional role of long non-coding RNAs (lncRNAs) regulated by QKI-5 in NSCLC remains uninvestigated.

LncRNA, more than 200 nucleotides in length, fall under the category of non-coding RNAs. LncRNA acts as a “master regulator” in chromosome modification, transcriptional and post-transcriptional regulation, cell apoptosis and proliferation, and RNA splicing processes (Yan and Bu, 2021). Increasing evidences have shown that dysregulated lncRNAs, acting as pro-oncogenes or tumor suppressors, are closely associated with cancer initiation and progression (Tan et al., 2021). LncRNA PCAT1 activates SOX2 to accelerate tumorigenesis and immunosuppression in NSCLC by downregulating the cGAS/STING signaling pathway (Gao et al., 2022). LncRNA HMS interacts with RNA-binding protein HuR to stabilize the oncogene HOXC10 mRNA in lung adenocarcinoma (Priyanka et al., 2021). Additionally, lncRNA ABHD11-AS1 binds with RNA-binding protein SART3 and promotes lung cancer progression by regulating alternative splicing of CD44 pre-mRNA (Wang et al., 2024a). These results suggest that lncRNAs play a crucial role in tumor progression, highlighting a potential novel approach for cancer therapy.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death defined by the lethal accumulation of reactive oxygen species (ROS) and lipid peroxides (Dixon et al., 2012). The main pathway of ferroptosis involves the inactivation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), both of which protect cells from oxidative damage and maintain redox homeostasis. SLC7A11 is an essential component of the system Xc-, which responsible for importing extracellular cystine and exporting intracellular glutamate (Liang et al., 2022). Recent studies have demonstrated that SLC7A11 is closely associated with the progression and prognosis of NSCLC (Wang et al., 2024b). LncRNAs have been reported to closely involve with ferroptosis. LncRNA HMG promotes p53 degradation, and upregulates SLC7A11 to inhibit ferroptosis in colorectal cancer (Xin et al., 2024). LncRNA HEPFAL enhances ferroptosis in hepatocellular carcinoma by promoting SLC7A11 ubiquitination (Zhang et al., 2022a). Additionally, lncRNA ROR1-AS1 suppresses ferroptosis in lung cancer cells by interacting with IGF2BP1 to upregulate SLC7A11 expression (Yao et al., 2024). These facts indicate that lncRNAs exert critical roles in the regulation of ferroptosis, and targeting lncRNA-mediated ferroptosis could offer a promising novel therapeutic strategy for certain types of cancers.

WWP1, a WW Domain-containing E3 Ubiquitin Protein Ligase 1, functions as a context-dependent regulator in cancer, acting as either an oncogene or tumor suppressor through the ubiquitination of diverse substrates (Behera and Reddy, 2023). In esophageal squamous cell carcinoma (ESCC), GPRC5A promotes lung macro-metastasis by WWP1-mediated polyubiquitination of LATS1 and subsequent activation of the YAP1 oncogenic pathway (Zhou et al., 2024).

In this study, we found that QKI-5 negatively regulates long non-coding RNA, linc01833, which is upregulated in NSCLC. Linc01833 upregulated SLC7A11 expression by inhibiting the E3 ubiquitin ligase WWP1-mediated ubiquitination of SLC7A11, thereby promoting NSCLC progression. Additionally, targeting linc01833 sensitized NSCLC cells to gemcitabine treatment.