Ailanthone restrains hepatocellular carcinoma progression by inducing ferroptosis and disrupting mitochondrial homeostasis.

Ailanthone (AIL), a natural compound derived from the Ailanthus species, demonstrates substantial clinical efficacy in managing diverse diseases, notably cancer. Despite this, the precise mechanisms underlying AIL's regulation of hepatocellular carcinoma (HCC) progression remain unclear. Our investigation revealed that AIL effectively suppresses HCC cell proliferation in vitro and in vivo, and inhibits metastasis-related phenotypes in vitro. Mechanistically, we discovered that AIL directly interacted with HSP90, thereby enhancing the ubiquitination of GPX4 proteins. This interaction led to a reduction in GPX4 expression levels and subsequently induced ferroptosis in HCC cells. Furthermore, the combination of AIL with GPX4 inhibitors exhibited a strong synergistic anti-proliferative effect on HCC cells. Collectively, these findings underscore the critical role of the HSP90/GPX4/ferroptosis axis in AIL-mediated inhibition of HCC progression.