Mitophagy and Mitochondrial Function Regulation by Traditional Chinese Medicine Small Molecules in Cancer Therapy: Mechanisms, Challenges, and Translational Opportunities

In recent years, small molecules derived from traditional Chinese medicine (TCM) have garnered increasing attention in anticancer research due to their well-defined structures, multi-target regulatory capabilities, and low toxicity. Mitophagy, a critical process for selectively clearing damaged mitochondria and maintaining cellular homeostasis, plays a significant role in tumor development. This review explores the types and molecular mechanisms of mitophagy, its dual role in tumor progression, and its functions across various cancers. We also summarize 21 representative TCM-derived small molecules, such as ginsenosides, oridonin, and sanguinarine, which directly or indirectly regulate key mitophagy-related signaling pathways, including PINK1/Parkin and BNIP3/NIX. These TCM small molecules modulate mitophagy and mitochondrial function, induce tumor cell apoptosis, overcome drug resistance, and improve the tumor microenvironment. This review systematically integrates the molecular mechanisms of mitophagy and its dynamic regulation in cancer, highlighting how TCM small molecules maintain mitochondrial homeostasis, remodel the tumor microenvironment, and reverse therapeutic resistance. It aims to provide a theoretical foundation for future research on anticancer TCM and to inspire the clinical development of effective, low-toxicity, mitochondria-targeted therapies.