Hepatocellular carcinoma (HCC), the primary liver malignancy, ranks as the seventh most frequently occurring cancer in the world and the second most common cause of cancer mortality, with its prognosis marred by late-stage diagnoses(Forner et al., 2018; McGlynn et al., 2021). Sorafenib, a multi-kinase targeted inhibitor curbing the Ras/Raf/MAPK pathway and angiogenic signals, emerged as the pioneering systemic therapy for advanced HCC (Iavarone et al., 2011, Terashima et al., 2016). Nonetheless, resistance to sorafenib treatment, whether inherent or acquired, presents a formidable barrier, culminating in treatment futility and dismal clinical outcomes. The pressing need lies in unraveling the mechanisms behind sorafenib resistance and pinpointing a novel biomarker capable of predicting its efficacy in HCC treatment.

Recent studies have pointed to the potential regulatory role of ferroptosis in tumor therapeutic responses (Wang et al., 2023). Characterized as an iron-dependent form of cell death, ferroptosis initiates extensive lipid peroxidation-induced damage to cellular membranes (Tang et al., 2021). Elevated iron levels and the accumulation of reactive oxygen species (ROS) have been identified as distinctive features of this process (Dixon et al., 2012). Crucial players in ferroptosis, such as glutathione (GSH) and its downstream protein glutathione peroxidase 4 (GPX4), are established as pivotal regulators governing iron metabolism, lipid peroxidation, and subsequent ferroptosis (Yang et al., 2014). Despite significant advancements in comprehending ferroptosis mechanisms, the intricate regulatory networks involved in therapy-associated ferroptosis largely remain elusive.

Several pharmacological and natural compounds have emerged, exhibiting regulatory roles in ferroptotic cell death and presenting promising avenues as potential tumor-suppressors within the scope of tumor therapeutics (Tang et al., 2021). Notably, sorafenib has recently garnered attention due to its potent ability to induce ferroptosis (Louandre et al., 2013, Sun et al., 2016). The anticancer mechanism of sorafenib primarily hinges on its capacity to induce ferroptosis by inhibiting system Xc−, which mediates cystine import, ultimately resulting in glutathione (GSH) depletion, and iron-dependent accumulation of lipid reactive oxygen species (ROS) in cells derived from liver, kidney, lung, or pancreatic cancer (Lachaier et al., 2014, Louandre et al., 2013). Understanding these mechanisms holds promise for developing strategies aimed at overcoming sorafenib resistance, though this remains a challenging endeavor (Wang et al., 2023). Furthermore, studies have revealed that sorafenib treatment significantly elevates the expression of dual-specificity phosphatase 4 (DUSP4), also known as MAPK phosphatase 2 (MKP2) (Chen et al., 2019). DUSP4 plays a crucial role in modulating cellular processes such as proliferation, differentiation, apoptosis, and cell cycle progression through interactions with the MAPK and p53 signaling pathways (Low and Zhang, 2016, Ratsada et al., 2020). However, the precise mechanism underlying sorafenib-mediated upregulation of DUSP4, particularly in the context of drug resistance across diverse cancers, remains to be fully elucidated (Balko et al., 2012, Cushman et al., 2015).

In this study, we delve into the intricate interplay between DUSP4 and sorafenib, with the aim of deciphering the mechanisms underpinning drug resistance in HCC. Our investigations reveal a significant correlation between elevated DUSP4 levels and sorafenib resistance in HCC. Furthermore, attenuation of DUSP4 expression heightens the susceptibility of HCC cells to ferroptosis inducers such as sorafenib and erastin, both in controlled in vitro settings and in vivo scenarios. The identification of DUSP4 as an inhibitor of ferroptosis unveils novel avenues for advancing HCC therapy through the synergistic interplay of ferroptosis and sorafenib.