Systematic review of medicinal plants and their active compounds that target autophagy in Parkinson's disease, summarizing preclinical evidence for multi-target neuroprotective effects while noting limited mechanistic validation and a lack of rigorous clinical trials.

Emphasizes autophagy modulation and related anti-inflammatory/antioxidant mechanisms as promising translational avenues and flags specific gaps—target specificity, toxicity, standardization, and need for mechanistic and clinical validation—that are critical for prioritizing plant-derived leads for…

ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) significantly affects patients' quality of life. Natural plant therapies, characterized by holistic, multi-target regulatory effects, have demonstrated unique value in managing complex diseases, particularly through regulating autophagy, inhibiting neuroinflammation, and reducing oxidative stress. Combined with their favourable safety profile-especially lower hepatotoxicity and nephrotoxicity-they represent an important direction in anti-PD drug development. AIM OF THE REVIEW: This review systematically examines the ethnopharmacological applications of natural plants that regulate autophagy in PD treatment, summarizing current progress and challenges to inform traditional Chinese medicine (TCM) modernization and anti-PD drug development. METHODS: This study investigates natural herbal therapies for PD, focusing on their regulatory mechanisms of autophagy. Primary sources included traditional medical classics and ethnomedicinal literature, supplemented by data from online databases such as PubMed, China National Knowledge Infrastructure (CNKI), Web of Science, and Wanfang. A systematic search was conducted using keywords including "PD," "autophagy," "regulatory mechanisms," "medicinal plants," "TCM compound preparations," "single herbal extracts," and "active compounds" to identify relevant studies published in recent years. Original research articles (in vitro, in vivo, or clinical) and high-quality reviews with mechanistic data involving autophagy in PD were included. Topical-independent literature, thesis, conference abstracts, books, case reports, and commentaries were excluded. Only articles published in English or Chinese were considered. RESULTS: Incorporating medicinal plants into PD management offers significant advantages in multi-target regulation and safety. However, a critical examination reveals several complexities. While modulating multiple autophagy-related pathways provides a theoretical advantage over single-target drugs, this broad-spectrum activity raises concerns about target specificity and off-target effects, which remain poorly characterized. Current evidence largely relies on correlational observations rather than direct mechanistic validation, leaving uncertainty about whether these compounds genuinely engage key autophagy targets under physiological conditions. Regarding safety, although centuries of traditional use of TCM compound preparations imply tolerability, assuming medicinal plants are inherently safer than Western drugs is problematic, as many constituents exhibit dose-dependent toxicity, and the lack of rigorous long-term trials limits generalizability. Furthermore, the prevailing reductionist approach-isolating active components for mechanistic studies-may overlook synergistic interactions inherent in herbal formulations, thus failing to capture their full therapeutic potential. Bridging traditional knowledge and modern evidence-based medicine requires not only advanced target identification techniques but also a holistic framework that respects herbal therapy's foundations while subjecting it to the same scientific scrutiny as conventional treatments. CONCLUSIONS: Although medicinal plants have garnered considerable attention for the treatment of PD, claims of their "significant clinical efficacy" should be approached with caution. Current evidence is primarily derived from basic research or observational studies and lacks validation through rigorous randomized controlled trials. Moreover, while autophagy regulation remains a prominent area of research, the multi-component and multi-target nature of compound formulations means their mechanisms cannot be explained by a single pathway. The transition from traditional use to evidence-based treatment continues to face challenges, including standardization, quality control, and dosage optimization. Therefore, although medicinal plants show potential, their therapeutic value must be confirmed through more rigorous methodologies and large-scale clinical trials.