Targeting Autophagy with Puerarin: From a Natural Isoflavone to Therapeutic Applications

Autophagy is an evolutionarily conserved lysosomal degradation process that eliminates damaged organelles and misfolded proteins to maintain cellular homeostasis. Its dysfunction drives cancer, neurodegeneration, and cardiovascular, hepatic, renal and skeletal muscle disorders, making autophagy a promising therapeutic target. Puerarin, a characteristic isoflavone from the leguminous medicinal plant Pueraria lobata, exerts broad pharmacological functions via autophagy modulation, yet no systematic review summarizes its tissue-specific regulatory patterns. This narrative review collects and categorizes recent cellular and animal studies on puerarin–autophagy crosstalk from mainstream databases. It organizes puerarin’s bidirectional autophagy effects across multiple organs and summarizes core signaling pathways, including AMPK/mTOR and PI3K/Akt/mTOR. Puerarin exhibits context-dependent dual regulation of autophagy: it induces protective autophagy to relieve metabolic and degenerative organ injuries, while inhibiting excessive autophagy to alleviate fibrosis and tumor progression. Its regulatory roles depend on Nrf2, JNK/Beclin1 and mitophagy-related axes in cardiac, hepatic, pulmonary, renal, bone, muscle and nervous tissues, as well as various tumor models. These mechanistic insights may support the development of natural isoflavone-based therapeutic strategies targeting autophagy and broaden the value-added utilization of Pueraria lobata as a medicinal and agricultural resource.