Fundamentals and emerging frontiers in p53-targeted drug development

As a key tumor suppressor protein, p53 plays a central role in biological processes such as cell cycle regulation, DNA repair, apoptosis, and metabolism. However, p53 gene mutations or functional inactivation are prevalent in over 50% of human cancers, leading to tumorigenesis, development, and drug resistance, making it an important target for anticancer drug development. Currently, p53-targeted therapy faces challenges such as diverse mutation types, insufficient drug specificity, and drug resistance. This article systematically reviews the fundamental theories and cutting-edge advances in the development of p53-targeted drugs. It elaborates on the structure and function of p53 and its mutation-induced carcinogenic mechanisms, then focuses on analyzing the research history and clinical translation status of small-molecule drugs (e.g., APR-246), discusses the application prospects of gene therapy and immunotherapy strategies, and introduces emerging therapies based on CRISPR and PROTAC technologies. By integrating the latest research findings, this article aims to provide theoretical basis and directional guidance for the precise development and clinical translation of p53-targeted drugs.