Targeting ferroptosis as a new paradigm for overcoming sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most prevalent primary liver malignancy, is characterized by a rising global incidence, dismal prognosis, and high mortality rates attributed to its complex etiology and therapeutic resistance. Sorafenib is the first approved systemic therapy for advanced HCC. However, its clinical benefit is frequently limited by primary or acquired resistance, with most patients experiencing disease progression within approximately 6 months of treatment. This challenge highlights the urgent need to elucidate underlying mechanisms driving treatment failure. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been recognized as a critical player in cancer biology. Accumulating evidence indicates that sorafenib resistance is closely associated with ferroptosis-evasion programs, including persistent activation of nuclear factor erythroid 2-related factor 2 (NRF2) signaling, lipid metabolic reprogramming, reinforcement of the cystine/glutamate antiporter System Xc- and glutathione peroxidase 4 (GPX4) antioxidant axis, and iron metabolic dysregulation. Importantly, these observations expand the resistance framework beyond apoptosis-centered mechanisms and identify ferroptosis as an additional actionable vulnerability. In this review, we integrate current knowledge on the interplay between sorafenib and ferroptosis, highlighting how ferroptotic dysregulation contributes to therapeutic resistance. By elucidating these mechanisms, we further propose rational strategies to overcome sorafenib resistance by targeting ferroptosis pathways, such as modulating NRF2 activity, rewiring lipid metabolism, or enhancing iron-dependent oxidative stress. Overall, incorporating ferroptosis into the HCC resistance framework offers a promising avenue to improve sorafenib efficacy and patient outcomes.