Targeting Autophagy, Ferroptosis, and Neuroinflammation: Polyphenol-Mediated Modulation of Emerging Signaling Pathways in Neurodegeneration

Complex, intertwined processes, including impaired autophagy, ferroptosis, and chronic neuroinflammation, drive neurodegenerative disorders (NDD). Polyphenols, a class of plant-derived natural compounds, are emerging as promising modulators of these pathogenic mechanisms, acting via diverse signaling pathways. This review summarized the molecular underpinnings of autophagy dysfunction, ferroptotic cell death, and inflammatory signaling in the central nervous system (CNS). Focusing mainly on key regulators such as AMPK, mTOR, Beclin-1, GPX4, NRF2, p62/Keap1, and system Xc⁻. Additionally, the evidence for polyphenol-mediated modulation of these pathways was also examined and covered in this study, along with highlighting compounds such as kaempferol, curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), and many more. Polyphenols restore autophagic flux, suppress lipid peroxidation, restore redox balance, stabilizes mitochondrial function, and downregulate pro-inflammatory transcription factors (e.g., NF-κB, MAPKs). Furthermore, the interlink between autophagy and ferroptosis, such as ferritinophagy and lipophagy, as well as the dual roles of autophagy in either promoting or preventing ferroptosis depending on the cellular context, were also covered. The role of polyphenols in modulating these intersections to mitigate neuronal damage. Last, this review discussed the translational implications, including challenges in bioavailability, blood-brain barrier (BBB) penetration, and metabolic stability of polyphenols. Also, major potential therapeutic strategies include nanoformulations, targeted delivery, combinatorial therapies, and gaps such as timing, dosing, selectivity, and in vivo evidence in human disease. This review elucidates how polyphenols can harness emerging signaling nodes to yield novel therapeutic strategies for NDD by integrating insights across autophagy, ferroptosis, and neuroinflammation.