Unveiling polyphyllin's role in neuroprotection: A pharmacological perspective

Introduction: Polyphyllins are bioactive steroidal saponins predominantly derived from Paris polyphylla (Chinese: Chonglou, 重楼), an herb long employed in Traditional Chinese Medicine (TCM) for detoxification, inflammation control, and pain relief, commonly administered as decoctions or powdered Rhizoma Paridis. Beyond these traditional uses, growing evidence supports their neuroprotective efficacy, especially in the context of neurodegenerative diseases (NDs), where inflammation, oxidative stress, and dysregulated cell death are central to disease progression. Methods: A comprehensive literature search was conducted up to March 2025. Out of 423 initially retrieved articles, 143 were included based on relevance to neuroprotective mechanisms, pharmacokinetics, and translational potential. Reviews, non-English articles, and studies not focused on brain-related mechanisms were excluded. Results: Polyphyllins demonstrate potent neuroprotective activities through anti-inflammatory, antioxidant, and autophagy-modulating mechanisms. PP-II interrupts the KEAP1-NRF2 interaction, activating antioxidant gene expression, while PP-I induces mitophagy via the PINK1-Parkin pathway. PP-VII modulates neuroinflammation through activation of the cGAS-STING axis. These actions collectively protect neurons, preserve mitochondrial function, and reduce pathological cascades associated with NDs. However, poor solubility and limited blood-brain barrier permeability remain key translational barriers. Discussion: The promising therapeutic effects of polyphyllins in ND models align with their historical use in TCM. Advances in nanomedicine, including lipid nanoparticles and carbon dots; have improved polyphyllin delivery to the central nervous system. Nevertheless, the absence of clinical trials and the need for safety profiling require resolution before clinical adoption. Future investigations should prioritize optimized drug formulations and validation in human models to bridge preclinical evidence with therapeutic applications.