Hammerhead ribozymes are a class of small RNA molecules with catalytic activity. Their compact size, high catalytic efficiency, structural simplicity, and modular design flexibility make them ideal tools for RNA manipulation and gene regulation. In recent years, these ribozymes have demonstrated tremendous application potential across diverse fields, including gene regulation, disease therapy, and biosensing, significantly advancing related research. This article provides a comprehensive review of recent progress in hammerhead ribozyme research within synthetic biology, thoroughly examines the current challenges, and outlines future development directions, aiming to offer valuable perspectives and insights for their biomedical applications.

Background: Hepatocellular carcinoma (HCC) remains a global health challenge with limited therapeutic efficacy. Photodynamic therapy (PDT) using 5,10,15-triethoxycarbonyl P(V) corrole (1-P) shows promise, but its molecular mechanisms and regulatory factors, particularly the role of SIRT1, are poorly understood. Methods: The effects of 1-P 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. Results: 1-P 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, 1-P upregulated Bax/p53/cleaved caspase-3 and downregulated Bcl-2/SIRT1. SIRT1 overexpression rescued 1-P-induced apoptosis (30–50% reduction), restored mitochondrial function, and attenuated ROS accumulation. In vivo, 1-P significantly inhibited tumor growth in mice, but SIRT1 overexpression diminished this effect (p < 0.05). Conclusions: 1-P exerts potent photodynamic anticancer effects via mitochondrial dysfunction, oxidative stress, and apoptosis induction. SIRT1 is a critical modulator of 1-P activity, highlighting its potential as a therapeutic target to enhance PDT efficacy in HCC.