SIRT1 Modulates the Photodynamic Anticancer Activity of 5,10,15-Triethoxycarbonyl P(V) Corrole in Hepatocellular Carcinoma

<b>Background</b>: Hepatocellular carcinoma (HCC) remains a global health challenge with limited therapeutic efficacy. Photodynamic therapy (PDT) using 5,10,15-triethoxycarbonyl P(V) corrole (<b>1-P</b>) shows promise, but its molecular mechanisms and regulatory factors, particularly the role of SIRT1, are poorly understood. <b>Methods</b>: The effects of <b>1-P</b> combined with red light irradiation (625 nm) on HCC cells (HepG2, PLC/PRF5, MHCC97H) were evaluated via MTT, clonogenic assays, flow cytometry (apoptosis, mitochondrial membrane potential, ROS), and Western blotting (p53, Bax, Bcl-2, cleaved caspase-3, SIRT1). SIRT1-overexpressing cells and xenograft mouse models were used to validate its regulatory role. <b>Results</b>: <b>1-P</b> with irradiation dose-dependently inhibited cell viability (IC50: 0.965-1.478 μM), suppressed clonogenicity, induced apoptosis (up to 68.8%), reduced mitochondrial membrane potential, and elevated ROS. Mechanistically, <b>1-P</b> upregulated Bax/p53/cleaved caspase-3 and downregulated Bcl-2/SIRT1. SIRT1 overexpression rescued <b>1-P</b>-induced apoptosis (30-50% reduction), restored mitochondrial function, and attenuated ROS accumulation. In vivo, <b>1-P</b> significantly inhibited tumor growth in mice, but SIRT1 overexpression diminished this effect (<i>p</i> < 0.05). <b>Conclusions</b>: <b>1-P</b> exerts potent photodynamic anticancer effects via mitochondrial dysfunction, oxidative stress, and apoptosis induction. SIRT1 is a critical modulator of <b>1-P</b> activity, highlighting its potential as a therapeutic target to enhance PDT efficacy in HCC.