Rottlerin triggers dual degradation of SLC7A11 and GPX4 to drive ferroptosis and chemosensitization in hepatocellular carcinoma.

Natural products have emerged as promising therapeutic agents for targeting redox vulnerabilities in cancer. Rottlerin, a bioactive polyphenol derived from Mallotus philippinensis, exhibits broad anticancer properties through autophagy and apoptosis induction. However, its capacity to modulate ferroptosis, a druggable form of iron-dependent cell death, remains unexplored in hepatocellular carcinoma (HCC). Here, we demonstrate that rottlerin potently inhibits HCC proliferation by triggering ferroptosis execution, as evidenced by lipid peroxidation accumulation and ferroptosis inhibitor (ferrostatin-1)-rescued cell death. Strikingly, subtherapeutic doses of rottlerin enhanced the efficacy of clinical ferroptosis inducers (RSL3 and sorafenib), and this chemosensitization effect persisted in PKCδ-depleted models, indicating a target-agnostic mechanism. Mechanistically, rottlerin orchestrates ubiquitin-proteasomal degradation of two central ferroptosis defense nodes: the cystine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), thereby compromising cellular antioxidant capacity. This dual-degradation strategy distinguishes rottlerin from single-target phytochemicals and underlies its robust ferroptosis induction. Our work provides the first demonstration of rottlerin's ferroptotic activity in HCC, positioning it as a dual degrader capable of overcoming compensatory antioxidant adaptations. These findings advocate for rottlerin's clinical development either as monotherapy or in rational combinations to augment ferroptosis-targeted HCC treatment.