Icaritin Represses Autophagy to Promote Colorectal Cancer Cell Apoptosis and Sensitized Low‐Temperature Photothermal Therapy via Targeting HSP90‐TXNDC9 Interactions

Abstract Colorectal cancer (CRC) ranks among the leading causes of cancer‐related dea ths worldwide, and the rising incidence and mortality of CRC underscores the urgent need for better understanding and management strategies. Icaritin (ICA) is the metabolites of icariin, a natural flavonoid glycoside compound derived from the stems and leaves of Epimedium . It has broad spectrum antitumor activity and inhibits the proliferation, migration, and invasion of CRC cells, and causes S phase cell cycle arrest. It exerts its antitumor effects against CRC through repressing autophagy to promote CRC cell apoptosis via interfering the HSP90‐TXNDC9 interactions. The safety and efficacy of ICA are also affirmed in a mouse xenograft model. Additionally, to test whether ICA exerts synergistic effects with low‐temperature photothermal therapy (LTPTT), a novel nanodrug delivery system, employing SiO 2 nanocarriers, is designed aiming to load ICA with photothermal materials polydopamine (PDA), and folic acid (FA). This SiO 2 /Ica‐PDA‐FA multifunctional nanocomposite actively targets tumor tissues through the high affinity of FA for cancer cells. Once internalized, the acidic intracellular environment triggers the controlled release of ICA, inhibiting HSP90‐TXNDC9 interactions. By LTPTT and ICA drug therapy under near‐infrared illumination, a dual synergistic antitumor effect is achieved, holding promise for enhancing therapeutic outcomes in CRC treatment.