Work

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

Year: 2026

Type: article

Abstract: 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.

Source: iScience

DOI: 10.1016/j.isci.2026.117259