Hepatocellular carcinoma (HCC), which accounts for 90% of all primary liver cancers, is the fourth most common cause of cancer-related mortality and ranks sixth in terms of incidence [1]. In China, patients with HCC comprise approximately 50% of all newly diagnosed cases worldwide [2]. HCC has a 5-year survival rate of only 18% and is the second most deadly cancer [3]. As one of the least mutated solid tumors in somatic cells, the current well-known major mutation drivers of HCC include telomerase reverse transcriptase (TERT), tumor protein 53 (TP53), and catenin beta 1 (CTNNB1), which are undruggable [4,5]. Most HCC occurs in patients with underlying liver disease, mainly caused by hepatitis B or C virus (HBV or HCV) infection or alcohol abuse [6]. The first systemic drug approved by the Federal Drug Agency (FDA) for the first-line treatment of HCC, sorafenib, is a multi-kinase inhibitor that extends the survival of patients with HCC by no more than 3 months [1,6]. Therefore, there is an urgent need to identify positional therapeutic targets and predictive biomarkers for HCC treatment.

Recently, it was reported that sorafenib treatment could induce ferroptosis in several types of cancer [[7], [8], [9]]. Ferroptosis is a form of non-apoptotic cell death caused by the iron-dependent accumulation of lipid hydroperoxides [10,11]. During ferroptosis, the toxic lipid reactive oxygen species (ROS), produced by the Fenton reaction of iron, generate lipid peroxides by attacking the carbon-carbon double bonds of phospholipids (PLs) containing polyunsaturated fatty acids (PUFAs) [12,13]. Interestingly, supplementation with monounsaturated or saturated fatty acids resulted in resistance to lipid peroxidation and subsequent inhibition of ferroptosis by competitively reducing PUFA-PL levels [14,15]. Meanwhile, multiple proteins, such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), cystine-glutamate antiporter (xCT), GTP cyclohydrolase-1 (GCH1), and dihydroorotate dehydrogenase (DHODH), have been found to be involved in ferroptosis regulation via limiting lipid peroxidation [[10], [11], [12],[16], [17], [18]]. To date, most ferroptosis modulators and ferroptosis-inducing compounds have only been tested in cellular models and have not yet been translated into clinical benefit. Thus, it is important to explore effective ways to sensitize drug-resistant cancers, such as HCC, which is prone to sorafenib resistance, to ferroptosis [19].

The liver, the central organ of fatty acid metabolism, is enriched with a diverse range of lipids [20,21]. Meanwhile, aberrant lipid metabolism contributes to the initiation, progression, and therapeutic failure of HCC, which inhabits a lipid-rich environment [[22], [23], [24]]. Interestingly, lipid metabolism is closely related to the occurrence and development of ferroptosis [25]. Therefore, investigating the potential mechanism underlying the ferroptosis-mediated defense of liver cancer cells in the lipid-rich tumor microenvironment might provide prospective therapeutic approaches to HCC treatment.

In the present study, we identified solute carrier family 27 member 4 (SLC27A4), a fatty acid transporter protein, as a novel ferroptosis inhibitory protein. We observed that SLC27A4 was significantly upregulated in relapsed HCC tissues compared with non-relapsed HCC tissues and that patients with HCC expressing higher levels of SLC27A4 had shorter overall survival (OS) (P < 0.001, HR = 1.84) and relapse-free survival (RFS) (P < 0.001, HR = 1.63). Overexpression of SLC27A4 in HCC cells promoted cellular uptake of exogenous monounsaturated fatty acids (MUFAs), which led to an increase in PLs containing MUFAs, resulting in inhibition of lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4-mediated ferroptosis defense promoted HCC sensitivity to sorafenib. Taken together, these findings revealed a new mechanism underlying ferroptosis defense and suggested that SLC27A4 might be a potential target for HCC treatment.