Atractylenolide I stabilizes HMOX1 to induce ferroptosis and enhance lenvatinib efficacy in hepatocellular carcinoma

Lenvatinib resistance limits the therapeutic efficacy of hepatocellular carcinoma (HCC), highlighting the need for effective strategies to enhance treatment response. Atractylenolide I (AT-1), a bioactive compound derived from Atractylodes macrocephala , exhibits antitumor activity, yet its mechanism in HCC remains unclear. Here, we demonstrate that AT-1 suppresses HCC growth by inducing ferroptosis and enhances Lenvatinib efficacy. AT-1 increases intracellular Fe 2+ accumulation, lipid peroxidation, and reactive oxygen species, consistent with ferroptotic cell death. Mechanistically, AT-1 directly binds to heme oxygenase-1 (HMOX1) and stabilizes its protein expression by inhibiting ubiquitination at lysine residues K177 and K179, thereby preventing proteasomal degradation. Genetic or pharmacological inhibition of HMOX1 abrogates AT-1-induced ferroptosis and antitumor effects in vitro and in vivo . Notably, AT-1 synergistically enhances Lenvatinib-mediated tumor suppression in HCC models. These findings identify HMOX1 stabilization as a core ferroptosis-regulating mechanism and support AT-1 as a promising adjuvant strategy for HCC therapy.