Liver cancer ranks as the sixth most common type of cancer and the fourth leading cause of cancer-related mortality, with hepatocellular carcinoma (HCC) comprising approximately 85–90 % of cases (Hsu et al., 2024, Siegel et al., 2022). Sorafenib, initially identified as an inhibitor of multiple oncogenic kinases, is currently employed as a first-line therapy for advanced HCC (Gao et al., 2023, Huang et al., 2020, Tang et al., 2020). Unfortunately, sorafenib resistance poses a significant clinical challenge, leading to a poor prognosis for patients with HCC. Recent studies have indicated that sorafenib may induce ferroptosis by modulating iron metabolism (Chen et al., 2021). Ferroptosis, an emerging form of programmed cell death, is characterized by iron-dependent phospholipid peroxidation (Hadian and Stockwell, 2020, Stockwell et al., 2017, Xie et al., 2016). Targeting ferroptosis has emerged as a promising therapeutic strategy for addressing therapy-resistant tumors, including HCC (Conrad et al., 2021, Nie et al., 2018, Wang et al., 2023b). Extensive preclinical and clinical research efforts are currently focused on elucidating the mechanisms underlying ferroptosis in tumorigenesis and therapy resistance, with the aim of identifying more effective molecular markers and therapeutic targets to improve treatment outcomes.

Considering the pivotal role of the iron ion concentration in ferroptosis, modulating iron ion transport proteins is an innovative strategy for inducing iron-dependent cell death in cancer cells, including HCC cells (Zhang et al., 2022a, Zhu and Du, 2024). Among these proteins, lipocalin 2 (LCN2) is a member of the lipocalin family and is recognized as a secreted glycoprotein that plays a key role in regulating iron homeostasis (Wang et al., 2023a). LCN2 is capable of binding to iron-chelating molecules called siderophores, thereby diminishing cellular iron content, impairing the Fenton reaction and subsequent ROS accumulation required for ferroptosis (Xiao et al., 2017, Yao et al., 2021).

RNA-binding proteins (RBPs) represent a diverse class of biomolecules characterized by their selective and high-affinity interactions with RNA molecules, and significantly influence cellular physiology by orchestrating the posttranscriptional regulation of target RNA transcripts (Lunde et al., 2007). Through the modulation of RNA metabolism processes, including pre-mRNA splicing, polyadenylation, RNA export, and RNA stability, a diverse array of RBPs exert essential functions in the oncogenic mechanisms underlying various malignancies (Li et al., 2021). Certain RBPs, including methyltransferase-like 3 (METTL3), human antigen R (HuR), and eukaryotic initiation factor 4E (eIF4E), have been shown to be critical in cancer by regulating processes including cell proliferation, apoptosis, invasion, and metastasis (Li et al., 2022). Furthermore, RBPs can also impact cancer cell metabolic reprogramming, tumor microenvironment modulation, and immune evasion (Hashimoto and Kishimoto, 2022). Nevertheless, the regulatory mechanisms by which RBPs modulate ferroptosis in cancer remains poorly understood. Consequently, there is significant interest in identifying novel RBPs involved in regulating ferroptosis and investigating their potential clinical significance in HCC.

Major vault protein (MVP), alternatively referred to lung resistance-related protein (LRP), serves as the main constituent of cellular ribonucleoprotein complexes known as vaults (Tanaka and Tsukihara, 2012). MVP is recognized for its regulatory involvement in various cellular processes, including cellular differentiation, nucleocytoplasmic transport, cell survival (encompassing autophagy and apoptosis), intracellular signal transduction and immune defense (Ben et al., 2013, Berger et al., 2009, Dortet et al., 2011, Kolli et al., 2004, Kowalski et al., 2007, Liu et al., 2012, Ryu and Park, 2009, Steiner et al., 2006, Teng et al., 2017, Yuan et al., 2021). However, there have been no reports on the role of MVP as an RBP in different diseases, including cancer.

In this study, by RBPs screening and integrating analyses, we first discovered that MVP functions as an RBP, playing a key role in ferroptosis evasion, contributing HCC tumorigenesis and sorafenib resistance. Mechanistically, MVP binds to the LCN2 mRNA and maintains its stability. Increased LCN2 subsequently depletes iron and increases the insensitivity of HCC to ferroptosis inducers. Furthermore, we find that PGAM5 could directly bind and dephosphorylate MVP at S873, a newly identified phosphorylation site, thereby facilitating the binding of MVP to LCN2 mRNA. Importantly, we identify that the FDA-approved drug tenapanor significantly disrupts the interaction between MVP and LCN2 mRNA, which highlights the synergistic efficacy of sorafenib in HCC treatment. Overall, this study reveals a critical mechanism by which cancer cells evade ferroptosis, emphasizing the potential of MVP as both a prognostic indicator and a therapeutic target to improve outcomes in HCC treatment.