Phosphorus(V) Tris(ethoxycarbonyl)corrole As a Safe and Effective Photosensitizer for Hepatocellular Carcinoma Treatment in Zebrafish Xenograft Models

Corrole-based photosensitizers show great potential for tumor photodynamic therapy (PDT). While their photodynamic activity has been extensively studied at the cellular level, evaluation in mouse xenograft models remains challenging due to prolonged experimental timelines, complex drug administration, and high costs. To address these limitations, we developed a novel <i>in vivo</i> hepatocellular carcinoma model using wild-type AB zebrafish embryos as a xenograft platform. This model was employed to assess the antitumor efficacy, acute toxicity, and biodistribution of phosphorus-(V) tris-(ethoxycarbonyl)-corrole (<b>1</b>-<b>P</b>), an electron-deficient photosensitizer. Under red-light irradiation, <b>1</b>-<b>P</b> exhibited strong phototoxicity in zebrafish, inducing apoptosis in xenografted tumor cells. Biodistribution studies revealed <b>1</b>-<b>P</b> accumulation in the liver and digestive tract, demonstrating favorable tumor-targeting properties. Mechanistic investigations via qPCR indicated that <b>1</b>-<b>P-</b>mediated PDT activated the c-JUN N-terminal kinase pathway, upregulated SIRT1 expression, and suppressed tumor cell proliferation. This work not only supports the therapeutic potential of corroles in hepatocellular carcinoma PDT but also establishes zebrafish as an efficient model for photosensitizer screening and mechanistic analysis, offering significant translational and research value.