Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related death worldwide. With over 800,000 new cases diagnosed annually, it poses a severe global health challenge, disproportionately affecting Asian populations, which account for approximately 70 % of the global burden [1,2]. The primary etiological factors include chronic hepatitis B (HBV) and hepatitis C (HCV) viral infections, with a rising incidence linked to metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease [3]. Despite improvements in early detection, the prognosis for advanced HCC remains poor, with a 5-year survival rate of only 18–20 %, largely due to the limited efficacy of available therapies and the development of therapeutic resistance [4]. Current treatment strategies for HCC include surgical resection, liver transplantation, locoregional therapies, and systemic agents. First-line systemic options, such as the multi-kinase inhibitor sorafenib and immune checkpoint inhibitors (e.g., atezolizumab plus bevacizumab), have improved outcomes but are hindered by variable response rates, acquired resistance, and significant side effects [5]. Therefore, identifying new therapeutic agents with distinct mechanisms of action remains an urgent clinical need.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target in HCC [6]. Malignant cells often exhibit elevated iron and reactive oxygen species (ROS) levels, rendering them particularly vulnerable to ferroptosis induction. Artesunate (Art), a well-tolerated derivative of artemisinin used clinically against malaria, has garnered attention for its broad anticancer properties. Its bioactive endoperoxide bridge reacts with intracellular Fe2+ to generate cytotoxic carbon-centered radicals, leading to lipid peroxidation and ferroptosis [7]. Previous studies have demonstrated that Art can induce ferroptosis and show synergistic effects with sorafenib in HCC models [8].

However, while Art's role as a ferroptosis inducer is established [9,10], the upstream regulatory mechanisms that govern this process, particularly at the level of post-transcriptional RNA modification, remain completely unknown. Specifically, it is unclear whether and how epitranscriptomic regulation, such as N6-methyladenosine (m6A) RNA methylation, influences Art-induced ferroptosis in HCC. Given that m6A modification is a key regulator of mRNA fate and has been implicated in autophagy and cell death pathways [11,12], we hypothesized that Art might exert its anti-HCC effects through an m6A-dependent mechanism.

In this study, we systematically investigate the pharmacodynamic mechanism of Art in HCC, focusing on its ability to promote autophagy-dependent ferroptosis via the m6A methylation pathway. We identify a novel regulatory axis centered on the methyltransferase WTAP, the reader protein YTHDC2, and the autophagy gene ATG5. Our findings not only elucidate a previously unrecognized layer of Art's anticancer action but also reveal new potential targets for therapeutic intervention in HCC.