Pharmacological evolution of natural product-based and chemically engineered autophagy-modulating strategies in...

Pharmacological modulation of autophagy has become an important neuropharmacological strategy for neurodegenerative diseases. However, the comparative development of natural product-based and chemically engineered autophagy-modulating strategies has not been systematically mapped. This study aimed to characterize the global research landscape, pharmacological strategy distribution, mechanistic hotspots, and translational development of autophagy modulation in neurodegenerative diseases from 2006 to 2025. Publications were retrieved from the Web of Science Core Collection and analyzed using VOSviewer, CiteSpace, bibliometrix, and SCImago Graphica. A total of 4344 records were classified at the publication level into four mutually exclusive categories according to a predefined classification dictionary, with assignments independently reviewed by two investigators and discrepancies resolved by consensus. Chemically designed, semisynthetic, or target-oriented approaches are collectively referred to as chemically engineered strategies in this study. Research output increased markedly after 2014. China contributed the largest number of publications (n = 1678, 38.6%), followed by the United States (n = 627, 14.4%). Chemically engineered strategies constituted the largest analytical category (n = 2255, 51.91%), followed by natural product-based strategies (n = 1058, 24.36%), mechanism-focused or unresolved studies (n = 920, 21.18%), and overlapping strategies (n = 111, 2.56%). Natural product-based strategies showed an overall increase in relative contribution after 2014. Recent hotspots were organized around selective autophagy, particularly mitophagy; autophagic maturation and lysosomal quality control; and crosstalk with stress and cell death pathways such as ferroptosis. The field is shifting from generalized autophagy induction toward mechanism-defined, increasingly selective, and pharmacologically testable interventions. Future studies should integrate target engagement, concentration-response relationships, flux-resolved assays, brain exposure, cargo selectivity, and long-term safety assessment to improve translational credibility.